HK1189521B - Drug cores for sustained release of therapeutic agents - Google Patents

Description

Drug core for sustained release of therapeutic agents

The present application is a divisional application entitled "drug core for sustained release of therapeutic drug" filed on 2008/9/5, application No. 200880114948.2.

Cross Reference to Related Applications

According to 35u.s.c. § 119(e), this non-provisional application claims US60/970,699 filed 9, 7, 2007; US60/970,709 filed on 7.9.2007; the priority rights of US60/970,820 filed on 7.9.2007 and US61/049,317 filed on 30.4.2008.

The subject matter of this application is related to the subject matter of U.S. patent application 11/695,537 (attorney docket number SLW2755.001US1), filed on day 4, 2, 2007, which U.S. patent application 11/695,537 claims the benefit of U.S. provisional application 60/871,864, filed on month 12, 2006.

The subject matter of the present application is related to U.S. patent application 61/057,246 (attorney docket No. SLW2755.036PRV), filed on 30/5/2008, U.S. patent application 61/132,927 (attorney docket No. SLW2755.036PV2), filed on 24/6/2008, and U.S. patent application _________ (subject matter of attorney docket No. SLW2755.044US1), entitled "larmamillips and deposited.

Background

In the field of drug delivery (e.g., ocular drug delivery), patients and physicians face a variety of challenges. In particular, the repeatability of treatment (multiple injections, multiple eye drop instillation per day regimen), associated costs, and lack of patient compliance can significantly impact the effectiveness of available treatments, leading to decreased vision and often blindness.

Patient compliance with drug application (e.g., instillation of eye drops) may be unstable and in some cases the patient may not follow the prescribed treatment regimen. The lack of compliance includes the inability to instill drops, inadequate technique (instillation less than needed), overuse of drops (resulting in systemic side effects), and use of non-prescribed drops or failure to follow a treatment regimen that requires multiple instillations of drops. Many drugs may require up to four instillations per day by the patient.

In addition to compliance, the cost of at least some eye drop medications is increasing, resulting in some patients with limited revenue being faced with the option of purchasing a base medication rather than purchasing a prescribed medication. Insurance often cannot cover the full cost of the prescribed eye drop medication, or in some cases the eye drop contains multiple different medications.

In addition, in many cases, topically applied drugs have the highest ocular effect within about two hours, after which additional drug administration should be performed to maintain therapeutic benefit. In addition, inconsistencies in self-administration or ingestion regimens may result in less than optimal treatment. PCT publication WO06/014434(Lazar) may be related to these and/or other problems associated with eye drops.

One promising approach to ocular drug delivery is the placement of implants that release drugs in the tissues proximal to the eye. Although this approach may provide some improvements over eye drops, some potential problems with this approach may include: implantation of the implant at the desired tissue location, retention of the implant at the desired tissue location, and sustained release of the drug at the desired therapeutic level over an extended period of time. In the case of glaucoma treatment, for example, where visits to the treating physician may be at intervals of months, premature reduction and/or premature release of drug from the implant may result in insufficient drug being delivered for a portion of the treatment time. This can lead to potentially impaired vision or blindness in the patient.

In light of the above, it would be desirable to provide an improved method of manufacturing a drug delivery implant that overcomes at least some of the above-mentioned disadvantages.

Disclosure of Invention

The present invention relates to various embodiments of drug inserts and drug cores containing therapeutic drugs for use in implant bodies adapted for placement in tissues, fluids, cavities, or conduits of the body. The implant body may be adapted to be disposed in or adjacent to an eye of a patient. The implant releases a drug to the body over a period of time, for example into the eye or surrounding tissue, or both, for treating a condition (malcondition) medically indicative of a patient using the therapeutic drug. The invention also relates to various embodiments of methods of producing the drug insert and drug core, and to various embodiments of methods of treating a patient using an implant or drug insert comprising the drug insert.

In various embodiments, the present invention provides a drug insert adapted for placement within an implant, an implant adapted for placement within or adjacent to an eye of a patient, a drug insert comprising a drug core (which drug insert may comprise a sheath body partially covering the drug core), the drug core comprising a therapeutic drug and a matrix (wherein the matrix comprises a polymer), the sheath body being disposed over a portion of the drug core for controlling release of the drug from the portion upon insertion of the implant into the patient and thereby defining at least one exposed surface of the drug core adapted for release of the drug or any combination thereof, wherein an amount of the therapeutic drug in a volumetric portion of the drug core is similar to an amount of the therapeutic drug in any other equal volumetric portion of the drug core. For example, the therapeutic agent may be uniformly and homogeneously dispersed throughout the matrix, or the therapeutic agent may at least partially form solid or liquid inclusions within the matrix. For example, the amount of the therapeutic agent within the volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 30%. For example, the amount of the therapeutic agent within the volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 20%. For example, the amount of the therapeutic agent within the volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 10%. For example, the amount of the therapeutic agent within the volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 5%. For example, the amount of therapeutic agent in one volumetric portion of the drug core is equal to the amount of therapeutic agent in any other equal volumetric portion of the drug core. In various embodiments, the drug insert may be adapted to release and/or for providing sustained release of a therapeutic agent to the eye, surrounding tissue, system, or any combination thereof.

In various embodiments, the present invention provides a plurality of drug inserts as described above, wherein each of the plurality of inserts includes a similar amount of drug dispersed therein, respectively. For example, similar amounts of the drugs dispersed therein, respectively, may vary by no more than about 30% therebetween. For example, similar amounts of the drugs dispersed therein, respectively, may vary by no more than about 20% therebetween. For example, similar amounts of the drugs dispersed therein, respectively, may vary by no more than about 10% therebetween. For example, similar amounts of the drugs dispersed therein, respectively, may vary by no more than about 5% therebetween.

In various embodiments, the present invention provides a drug core comprising a therapeutic drug and a matrix for placement into a drug insert or implant, wherein the matrix comprises a polymer, the drug insert or implant being adapted for placement within or adjacent to an eye of a patient, wherein the therapeutic drug is uniformly and homogeneously dispersed throughout the matrix, or the therapeutic drug at least partially forms a solid or liquid inclusion within the matrix; wherein the amount of the therapeutic agent in the volumetric portion of the drug core is similar to the amount of the therapeutic agent in any other equal volumetric portion of the drug core. For example, the amount of the therapeutic agent within one volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 30%. For example, the amount of the therapeutic agent within one volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 20%. For example, the amount of the therapeutic agent within one volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 10%. For example, the amount of the therapeutic agent within one volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 5%. For example, the amount of therapeutic agent in one volumetric portion of the drug core is the same as the amount of therapeutic agent in any other equal volumetric portion of the drug core. In various embodiments, the drug insert may be adapted to release and/or for providing sustained release of a therapeutic agent to the eye, surrounding tissue, system, or any combination thereof.

In various embodiments, the present invention provides an implant for the sustained delivery of a therapeutic agent to a patient, wherein the entire implant comprises a drug core comprising the therapeutic agent and a matrix, wherein the matrix comprises a polymer. Optionally, porous or absorbent materials can be used to make the entire implant or plug (plug) that can be saturated with the active agent.

In various embodiments, the present invention provides a filled precursor sheath adapted to produce a plurality of drug inserts by dividing the filled precursor sheath, each drug insert adapted to be disposed within a respective implant adapted to be disposed within or adjacent to an eye of a patient, the filled precursor sheath comprising a precursor sheath body and a prodrug core contained therein, the prodrug core comprising a therapeutic drug and a matrix, wherein the matrix comprises a polymer, wherein the therapeutic drug is uniformly and homogeneously dispersed throughout the matrix, or the therapeutic drug at least partially forms a solid or liquid enclosure within the matrix, wherein the amount of therapeutic drug in a volumetric portion of the prodrug core is similar to the amount of therapeutic drug in any other equal volumetric portion of the prodrug core, the precursor sheath body is substantially impermeable to the drug, each of the plurality of inserts segmented therefrom being adapted to release the drug upon placement of the insert in the implant and insertion of the implant into the patient, the respective sheath body of each of the plurality of inserts segmented from the filled precursor sheath being disposed over a portion of the respective drug core of each of the plurality of inserts to inhibit release of the drug from the portion and thereby define at least one exposed surface of the drug core adapted to release the drug. For example, the amount of therapeutic agent in one volumetric portion of the prodrug core may differ from the amount of therapeutic agent in any other equal volumetric portion of the prodrug core by no greater than about 30%. For example, the amount of therapeutic agent in one volumetric portion of the prodrug core may differ from the amount of therapeutic agent in any other equal volumetric portion of the prodrug core by no greater than about 20%. For example, the amount of therapeutic agent in one volumetric portion of the prodrug core may differ from the amount of therapeutic agent in any other equal volumetric portion of the prodrug core by no greater than about 10%. For example, the amount of therapeutic agent in one volumetric portion of the prodrug core may differ from the amount of therapeutic agent in any other equal volumetric portion of the prodrug core by no more than about 5%. For example, the amount of therapeutic agent in one volumetric portion of the drug core is the same as the amount of therapeutic agent in any other equal volumetric portion of the drug core. In various embodiments, the drug insert may be adapted to release and/or for providing sustained release of a therapeutic agent to the eye, surrounding tissue, system, or any combination thereof.

In various embodiments, the present invention provides an implant body for placement in or adjacent to an eye of a patient, the implant body including a channel adapted to receive a drug insert therein such that an exposed surface of the drug insert is exposed to tear fluid when the drug insert is disposed within the implant and the implant is disposed in or adjacent to the eye, the drug insert including a substantially drug impermeable sheath body including a drug core including a therapeutic drug and a matrix, the matrix including a polymer, wherein the therapeutic drug is uniformly and homogeneously dispersed throughout the matrix or the therapeutic drug forms a solid or liquid inclusion at least partially within the matrix, wherein an amount of the therapeutic drug in a volumetric portion of the drug core is similar to an amount of the therapeutic drug in any other equal volumetric portion of the drug core, the body comprises a biocompatible material and is adapted to be held in or adjacent to the eye for a period of time. For example, the amount of the therapeutic agent within one volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 30%. For example, the amount of the therapeutic agent within one volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 20%. For example, the amount of the therapeutic agent within one volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 10%. For example, the amount of the therapeutic agent within one volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 5%. For example, the amount of therapeutic agent in one volumetric portion of the drug core is the same as the amount of therapeutic agent in any other equal volumetric portion of the drug core. In various embodiments, the drug insert may be adapted to release and/or for providing sustained release of a therapeutic agent to the eye, surrounding tissue, system, or any combination thereof.

In various embodiments, the present invention provides an implant body for disposition in or adjacent an eye of a patient, the implant body comprising a channel adapted to receive a drug core therein such that an exposed surface of the drug core is exposed to tear fluid when the drug core is disposed within the implant and the implant is disposed in or adjacent the eye, the drug core comprising a therapeutic agent and a matrix, the matrix comprising a polymer, wherein an amount of the therapeutic agent in one volumetric portion of the drug core is similar to an amount of the therapeutic agent in any other equal volumetric portion of the drug core, wherein the therapeutic agent is sufficiently soluble in the matrix such that a therapeutic amount of the agent is released from the exposed surface of the drug core to tear fluid in contact with the exposed surface when the implant body is disposed in or adjacent the eye, the body comprises a biocompatible material and is adapted to be held within or adjacent to the eye for a period of time. For example, the amount of the therapeutic agent within a volumetric portion of the drug core may differ from the amount of the therapeutic agent in any equal volumetric portion of the drug core by no greater than about 30%. For example, the amount of the therapeutic agent within a volumetric portion of the drug core may differ by no greater than about 20% from the amount of the therapeutic agent in any equal volumetric portion of the drug core. For example, the amount of the therapeutic agent within a volumetric portion of the drug core may differ from the amount of the therapeutic agent in any equal volumetric portion of the drug core by no greater than about 10%. For example, the amount of the therapeutic agent within a volumetric portion of the drug core may differ from the amount of the therapeutic agent in any equal volumetric portion of the drug core by no greater than about 5%. In various embodiments, the drug core may be adapted to release the drug to the eye, surrounding tissue, system, or any combination thereof, and/or to provide sustained release of the therapeutic drug to the eye, surrounding tissue, system, or any combination thereof.

In various embodiments, the present invention provides a method of producing a drug insert for an implant body adapted for placement within or adjacent to an eye of a patient, the insert comprising a drug core, the drug core comprising a therapeutic drug and a matrix, wherein the matrix comprises a polymer, wherein the therapeutic agent is uniformly and homogeneously dispersed throughout the matrix, or wherein the therapeutic agent at least partially forms solid or liquid inclusions within the matrix, wherein the amount of therapeutic agent in one volumetric portion of the drug core is similar to the amount of therapeutic agent in any other equal volumetric portion of the drug core, the sheath body being disposed over a portion of the drug core, at least one exposed surface for inhibiting release of the drug from the portion and thereby defining a drug core adapted to release the drug upon insertion of the implant into a patient; the method includes injecting a mixture including a matrix precursor and a drug into the sheath body at a sub-ambient temperature of less than about 20 ℃ such that the sheath body is substantially filled; the mixture including the matrix precursor is then cured within the sheath body to form the drug insert such that a drug core having an exposed surface is formed therein. In various embodiments, the drug insert may be adapted to release and/or for providing sustained release of a therapeutic agent to the eye, surrounding tissue, system, or any combination thereof.

In various embodiments, the present invention provides a method of producing a drug insert for an implant body adapted for placement within or adjacent to an eye of a patient, the method comprising injecting a mixture comprising a therapeutic drug and a matrix precursor into a precursor sheath body at a sub-ambient temperature of less than about 20 ℃, wherein the therapeutic drug is uniformly and homogeneously dispersed throughout the matrix, or the therapeutic drug forms at least partially a solid or liquid inclusion within the matrix, wherein the amount of the therapeutic drug in one volumetric portion of the drug core is similar to the amount of the therapeutic drug in any other equal volumetric portion of the drug core, the precursor sheath body being substantially impermeable to the drug such that the precursor sheath is substantially filled to provide a filled precursor sheath; then allowing the mixture to solidify such that a prodrug core is formed within the precursor sheath body, and then dividing the filled precursor sheath to form a plurality of drug inserts therefrom, wherein each drug insert comprises a drug core and a sheath body disposed over a portion of the drug core for inhibiting release of the drug from said portion and thereby defining at least one exposed surface of the drug core when the insert is disposed in the implant and the implant is inserted into the patient; each insert adapted to fit within a corresponding implant body and to release a therapeutic amount of a drug to tear fluid through an exposed surface of the insert; wherein each of the plurality of drug inserts has a substantially same length, wherein the amount of drug in each of the plurality of drug inserts segmented from the filled precursor sheath is similar.

For example, the amount of the therapeutic agent within one volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 30%. For example, the amount of the therapeutic agent within one volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 20%. For example, the amount of the therapeutic agent within one volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 10%. For example, the amount of the therapeutic agent within one volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 5%. For example, the amount of drug in each of the plurality of drug inserts may vary by no more than about 30% therebetween. For example, the amount of drug in each of the plurality of drug inserts may vary by no more than about 20% therebetween. For example, the amount of drug in each of the plurality of drug inserts may vary by no more than about 10% therebetween. For example, the amount of drug in each of the plurality of drug inserts may vary by no more than about 5% therebetween.

In further embodiments, the method of producing a drug insert further comprises, after the curing step as described herein, extruding the drug core from the sheath body either before or after dividing the filled sheath body into a plurality of drug inserts, thereby forming a drug core without the sheath body material.

In various embodiments, the above-described method is used to produce an implant for sustained delivery of a therapeutic agent to a patient, wherein the entire implant comprises a drug core comprising the therapeutic agent and a matrix, wherein the matrix comprises a polymer. Optionally, porous or absorbent materials may be used to make the entire implant or plug that may be saturated with the active agent. In other embodiments, the therapeutic agent and matrix described herein are added to a mold to form a drug core; the drug core is then cured and then used as an implant for the sustained delivery of the therapeutic drug to the patient.

In various embodiments, the present invention provides a drug insert manufactured by the method of the present invention.

In various embodiments, the present invention provides methods of treating a condition in a patient in need thereof, comprising disposing an implant of the present invention comprising a drug insert, or a drug core of the present invention obtained by dividing a filled precursor sheath, or a drug implant of the present invention, or a drug insert prepared by the methods of the present invention in or adjacent to an eye of a patient such that the drug is released into body tissue or fluid, wherein the therapeutic drug is suitable for treating the condition.

In various embodiments, the present invention provides the use of a drug insert of the present invention, or a drug core obtained by dividing a filled precursor sheath of the present invention, or a drug implant of the present invention, or a drug insert prepared by a method of the present invention, for the manufacture of an implant suitable for treating a condition in a patient in need thereof.

In various embodiments, the present invention provides a drug insert adapted for placement within a punctal plug (punctal plug) for sustained release of latanoprost to the eye for the treatment of glaucoma, the insert comprising a core comprising latanoprost and a matrix, wherein the matrix comprises a silicone polymer, and a sheath body partially covering the core, the latanoprost being contained as droplets within the silicone, wherein an amount of latanoprost in a volumetric portion of the drug core is similar to an amount of latanoprost in any other equal volumetric portion of the drug core, the sheath body being disposed over a portion of the core for inhibiting release of latanoprost from the portion, an exposed surface of the core not covered by the sheath body being adapted for release of latanoprost to the eye.

In various embodiments, the present invention provides a drug insert adapted for disposition within a punctal plug (punctal plug) for the sustained release of cyclosporine to the eye for the treatment of dry eye or inflammation, the insert comprising a core and a sheath body partially covering the core, the core comprising a cyclosporin and a matrix, wherein the matrix comprises a polyurethane polymer, the cyclosporin being contained within the polyurethane, wherein the amount of cyclosporin in a volumetric portion of the drug core is similar to the amount of cyclosporin in any other equal volumetric portion of the drug core, the sheath body disposed over a portion of the core for inhibiting the release of cyclosporin from said portion, and an exposed surface of the core not covered by the sheath body being adapted for release of cyclosporin to the eye.

In various embodiments, the present invention provides a drug insert for placement within an implant, the implant adapted for placement within or adjacent to a cavity, tissue, conduit, or fluid of a body for sustained release of a therapeutic drug to the cavity, tissue, conduit, or fluid or surrounding tissue or any combination thereof, the insert comprising a drug core and a sheath body partially covering the drug core, the drug core comprising a therapeutic drug and a matrix, wherein the matrix comprises a polymer, wherein the therapeutic drug is uniformly and homogeneously dispersed throughout the matrix, or the therapeutic drug at least partially forms a solid or liquid inclusion within the matrix, wherein an amount of the therapeutic drug in a volumetric portion of the drug core is similar to an amount of the therapeutic drug in any other equal volumetric portion of the drug core, the sheath body is disposed over a portion of the drug core for inhibiting release of the drug from the portion upon insertion of the implant into a patient and thereby defines at least one exposed surface adapted to release the drug to the cavity, tissue, conduit, or fluid or surrounding tissue or any combination thereof.

In various embodiments, the present invention provides a drug insert for placement within an implant adapted for placement within or adjacent to an eye of a patient for providing systemic sustained release of a therapeutic drug, the insert comprising a drug core and a sheath body partially covering the drug core, the drug core comprising a therapeutic drug and a matrix, wherein the matrix comprises a polymer, wherein the therapeutic drug is uniformly and homogeneously dispersed throughout the matrix, or the therapeutic drug at least partially forms a solid or liquid inclusion within the matrix, wherein an amount of the therapeutic drug in a volumetric portion of the drug core is similar to an amount of the therapeutic drug in any other equal volumetric portion of the drug core, the sheath body being disposed on a portion of the drug core for inhibiting release of the drug from said portion upon insertion of the implant into the patient and thereby defining a drug core adapted for systemic release of the drug At least one exposed surface.

In various embodiments, the present invention provides a drug core comprising a therapeutic drug and a matrix (wherein the matrix comprises a polymer) for placement as or into a drug insert or implant, said drug insert or implant being adapted for placement in or adjacent to a cavity, tissue, duct, or fluid of the body for providing sustained release of the therapeutic drug to said cavity, tissue, duct, or surrounding tissue, or any combination thereof, wherein the therapeutic drug is uniformly and homogeneously dispersed throughout the matrix, or the therapeutic drug at least partially forms solid or liquid inclusions within the matrix; wherein the amount of the therapeutic agent in one volumetric portion of the drug core is similar to the amount of the therapeutic agent in any other equal volumetric portion of the drug core.

In various embodiments, the present invention provides a drug core comprising a therapeutic drug and a matrix (wherein the matrix comprises a polymer) for being or being disposed as or in a drug insert or implant, the drug insert or implant being adapted to be disposed within or adjacent to an eye of a patient for providing systemic sustained release of the therapeutic drug, wherein the therapeutic drug is uniformly and homogeneously dispersed throughout the matrix, or the therapeutic drug at least partially forms solid or liquid inclusions within the matrix; wherein the amount of the therapeutic agent in one volumetric portion of the drug core is similar to the amount of the therapeutic agent in any other equal volumetric portion of the drug core. The drug core may be formed into an implant or drug insert by molding a matrix containing the therapeutic drug into an appropriate shape. This form of implant has no sheath or external implant body or shell.

While not intended as a limitation on the present invention, it should be understood that the therapeutic agent is transferred to the surface through the matrix such that the agent is dispersed, dissolved, or otherwise entrained by the bodily fluid for delivery to the target tissue. The transfer may be the result of and/or be affected by diffusion, intermolecular interactions, domain formation and transfer, infusion of bodily fluids into the matrix, or other mechanisms. For delivery to the eye, a therapeutic amount of the drug is transferred to the exposed surface of the matrix, such that the tear fluid washes away the drug for delivery to one or more target tissues.

To better illustrate the invention described herein, a non-limiting list of exemplary aspects and embodiments of the invention is provided below.

Aspect a1 relates to a drug insert for placement within an implant, the implant being adapted for placement within or adjacent to a cavity, tissue, conduit, or fluid of a body, the insert comprising a drug core and a sheath body partially covering the drug core, the drug core comprising a therapeutic drug and a matrix, the matrix comprising a polymer, the sheath body being disposed over a portion of the drug core for inhibiting release of the drug from the portion upon insertion of the implant into the patient and thereby defining at least one exposed surface of the drug core adapted to release the drug to the cavity, tissue, conduit, or fluid, or any combination thereof, and wherein an amount of the therapeutic drug in a volumetric portion of the drug core is similar to an amount of the therapeutic drug in any other equal volumetric portion of the drug core.

Embodiment a2 is directed to the drug insert of aspect a1, wherein the amount of the therapeutic agent within the volumetric portion of the drug core differs from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 30%.

Embodiment A3 is directed to the drug insert of aspect a1, wherein the amount of the therapeutic agent within the volumetric portion of the drug core differs from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 20%.

Embodiment a4 is directed to the drug insert of aspect a1, wherein the amount of the therapeutic agent within the volumetric portion of the drug core differs from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 10%.

Embodiment a5 is directed to the drug insert of aspect a1, wherein the amount of the therapeutic agent within the volumetric portion of the drug core differs from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 5%.

Embodiment a6 relates to the drug insert of aspect a1, wherein the implant is a punctal plug.

Embodiment a7 relates to the plurality of drug inserts of aspect a1, wherein each of the plurality of inserts comprises a similar concentration of drug relative to the other of the plurality of inserts.

Embodiment A8 relates to the plurality of drug inserts of embodiment 7 wherein similar concentrations of the drugs differ by no more than about 30%.

Embodiment a9 relates to the plurality of drug inserts of embodiment 7 wherein similar concentrations of the drugs differ by no more than about 20%.

Embodiment a10 relates to the plurality of drug inserts of embodiment 7 wherein similar concentrations of the drugs differ by no more than about 10%.

Embodiment a11 relates to the plurality of drug inserts of embodiment 7 wherein similar concentrations of the drugs differ by no more than about 5%.

Embodiment a12 relates to the drug insert of aspect a1, wherein the exposed surface is adapted to release a therapeutic amount of the drug into tear fluid over a period of at least several days upon insertion of the implant into a patient.

Embodiment a13 is directed to the plurality of drug inserts of embodiment 7 wherein the exposed surface of each of the plurality of drug inserts is adapted to release a therapeutic amount of a drug into tear fluid over a period of at least several days upon insertion of the implant into a patient, wherein the therapeutic amount of drug released by each of the plurality of drug inserts is similar.

Embodiment a14 is directed to a plurality of embodiment a13, wherein the therapeutic amount of drug released by each of the plurality of inserts varies by no more than about 30% therebetween.

Embodiment a15 is directed to a plurality of embodiment a13, wherein the therapeutic amount of drug released by each of the plurality of inserts varies by no more than about 20% therebetween.

Embodiment a16 is directed to a plurality of embodiment a13, wherein the therapeutic amount of drug released by each of the plurality of inserts varies by no more than about 10% therebetween.

Embodiment a17 is directed to a plurality of embodiment a13, wherein the therapeutic amount of drug released by each of the plurality of inserts varies by no more than about 5% therebetween.

Embodiment a18 is directed to the drug insert of aspect a1, wherein the drug core comprises about 0.1% to about 50% by weight of the drug.

Embodiment a19 relates to the drug insert of aspect a1, wherein the matrix comprises a non-biodegradable silicone or polyurethane, or a combination thereof.

Embodiment a20 is directed to the drug insert of aspect a1, wherein the sheath body comprises a polymer comprising at least one of polyimide, PMMA, or PET or a metal, wherein the polymer is extruded or cast, the metal comprising stainless steel or titanium.

Embodiment a21 relates to the drug insert of aspect a1, wherein the drug comprises a glaucoma drug, a muscarinic drug, a β blocker, an α agonist, a carbonic anhydrase inhibitor, a prostaglandin, or a prostaglandin analog; anti-inflammatory agents; an anti-infective agent; a dry eye drug; or any combination thereof.

Embodiment a22 is directed to the drug insert of embodiment a21 wherein the anti-inflammatory agent comprises a steroid, a soft steroid, or an NSAID as well as other compounds having analgesic properties.

Embodiment a23 is directed to the drug insert of embodiment a21 wherein the anti-infective comprises an antibiotic, an antiviral, or an antifungal agent.

Embodiment a24 is directed to the drug insert of embodiment a21 wherein the dry eye drug comprises cyclosporine, an antihistamine, a mast cell stabilizer such as olopatadine, a demulcent, or sodium hyaluronate.

Embodiment a25 relates to the drug insert of aspect a1, wherein the drug comprises latanoprost and the amount of drug in the drug insert is about 10-50 μ g.

Embodiment a26 is directed to the drug insert of aspect a1 wherein the drug insert comprises a release rate modifying material comprising an inert filler material, a salt, a surfactant, a dispersant, a second polymer, an oligomer, or a combination thereof.

Embodiment a27 is directed to the drug insert of aspect a1, wherein the drug core is substantially cylindrical having an axis, wherein the exposed surface of the drug core is disposed on one end of the cylinder and the surface of the drug core covered by the sheath body comprises the remainder of the cylindrical surface.

Embodiment a28 relates to the drug insert of aspect a1 wherein the drug is dissolved in a matrix within the drug core.

Embodiment a29 is directed to the drug insert of embodiment a28 wherein the drug comprises cyclosporine and the matrix comprises polyurethane.

Embodiment a30 relates to the drug insert of aspect a1, wherein the drug is at least partially present throughout the matrix as a plurality of solid or liquid inclusions, the inclusions comprising droplets of the drug having a diameter of no greater than about 100 μ ι η at a temperature below about 25 ℃ (when the drug is liquid below about 25 ℃), or the inclusions comprising particles of the drug having a diameter of no greater than about 100 μ ι η (when the drug is solid below about 25 ℃).

Embodiment a31 is directed to the drug insert of embodiment a30 wherein the average inclusion diameter and the size distribution of the plurality of inclusion diameters within the population of inclusions have an effect on the rate of release of the drug from the drug core to the patient.

Embodiment a32 is directed to the drug insert of embodiment a30 wherein the average diameter of the inclusions is less than about 20 μm.

Embodiment a33 is directed to the drug insert of embodiment a32 wherein the standard deviation of the diameters of the inclusions is less than about 8 μm.

Embodiment a34 is directed to the drug insert of embodiment a30 wherein the average diameter of the inclusions is less than about 15 μm.

Embodiment a35 is directed to the drug insert of embodiment a34 wherein the standard deviation of the diameters of the inclusions is less than about 6 μm.

Embodiment a36 is directed to the drug insert of embodiment a30 wherein the average diameter of the inclusions is less than about 10 μm.

Embodiment a37 is directed to the drug insert of embodiment a36 wherein the standard deviation of the diameters of the inclusions is less than about 4 μm.

Embodiment a38 is directed to the drug insert of embodiment a30 wherein the diameter distribution of the inclusions is a monodisperse distribution.

Embodiment a39 is directed to the drug insert of embodiment a30 wherein the inclusions comprise predominantly a cross-sectional size of about 0.1 μm to about 50 μm.

Embodiment a40 is directed to the drug insert of embodiment a30 wherein the drug forms inclusions in the matrix that are in a liquid physical state at less than about 25 ℃.

Embodiment a41 is directed to the drug insert of embodiment a40 wherein substantially all of the inclusions are drug liquids having a diameter of less than about 30 μm within the matrix.

Embodiment a42 is directed to the drug insert of embodiment a40 wherein the droplets have an average diameter of less than about 10 μm.

Embodiment a43 is directed to the drug insert of embodiment a42 wherein the standard deviation of the diameters of the inclusions is less than about 4 μm.

Embodiment a44 relates to the drug insert of embodiment a40 wherein the drug is latanoprost.

Embodiment a45 is directed to the drug insert of embodiment a30 wherein the drug forms inclusions in the matrix that are in a solid physical state below about 25 ℃.

Embodiment a46 is directed to the drug insert of embodiment a45 wherein substantially all of the inclusions are drug particles having a diameter of less than about 30 μm within the matrix.

Embodiment a47 is directed to the drug insert of embodiment a45 wherein the average particle diameter within the matrix is about 5-50 μm.

Embodiment a48 is directed to the drug insert of embodiment a45 wherein the drug is bimatoprost, olopatadine, or cyclosporine.

Embodiment a49 relates to the drug insert of aspect a1, wherein the core comprises two or more therapeutic agents.

Embodiment a50 is directed to the drug insert of aspect a1, wherein the drug core comprises a first drug core and a second drug core.

Embodiment a51 is directed to the drug insert of embodiment a50, wherein the drug insert comprises two drug cores disposed within a sheath body, the first drug core comprising a first drug and a first matrix, the second drug core comprising a second drug and a second matrix, wherein the first drug and the second drug are different, and wherein the first matrix and the second matrix are the same or different from each other; the implant body includes an aperture adapted to receive the first and second cores disposed within the sheath body, and the drug core within the sheath is adapted to be disposed within the aperture of the implant body.

Embodiment a52 is directed to the drug insert of embodiment a50 wherein the first matrix and the second matrix differ from each other in at least one of composition, area of exposed surface, surfactant, cross-linking agent, additive, matrix material, formulation, release rate modifying agent, or stability.

Embodiment a53 is directed to the drug insert of embodiment a50 wherein the first drug core and the second drug core are disposed within the sheath body such that the first drug core has a surface that is directly exposed to tear fluid and the second drug core does not have a surface that is directly exposed to tear fluid when the drug insert is disposed within the implant body and the implant body is disposed in or adjacent to the eye of the patient.

Embodiment a54 is directed to the drug insert of embodiment a50 wherein the first drug core and the second drug core are disposed side-by-side within the sheath body.

Embodiment a55 is directed to the drug insert of embodiment a50 wherein the first drug core and the second drug core are each cylindrical and disposed with the sheath body, the first drug core being located proximal to the proximal end of the orifice of the implant body and the second drug core being located proximal to the distal end of the orifice when the drug insert is disposed within the implant body.

Embodiment a56 is directed to the drug insert of embodiment a50 wherein the first drug core and the second drug core are each cylindrical, with the proviso that the first drug core has a first central opening, the drug core is concentrically positioned within a sheath body located within an implant body aperture adapted to receive the drug insert, and the second drug core is configured to fit within the first central opening of the first drug core.

Embodiment a57 is directed to the drug insert of embodiment a56 wherein the first and second drug cores are concentrically positioned within an orifice of the implant body, the first drug core having a first central opening exposing a first interior surface, the second drug core having a second central opening exposing a second interior surface, the second drug core configured to fit within the first central opening of the first drug core, and wherein the orifice extends from a proximal end to a distal end of the implant body and is adapted to allow tear fluid to pass through the orifice and contact the first and second interior surfaces of the first and second central openings and release the first and second therapeutic agents into the lacrimal duct of the patient upon insertion of the implant body into the patient.

Embodiment a58 is directed to the drug insert of embodiment a50 wherein the first therapeutic agent has a release profile wherein the first agent is released at therapeutic levels throughout the first time period and the second therapeutic agent has a second release profile wherein the second agent is released at therapeutic levels throughout the second time period.

Embodiment a59 relates to the drug insert of embodiment a58 wherein the first time period and the second time period are one week to five years.

Embodiment a60 is directed to the drug insert of embodiment a58 wherein the first release profile and the second release profile are substantially the same.

Embodiment a61 is directed to the drug insert of embodiment a58 wherein the first release profile and the second release profile are different.

Embodiment a62 is directed to the drug insert of embodiment a50 wherein any inclusions in the first drug core and the second drug core, respectively, have an average diameter of less than about 20 μm.

Embodiment a63 is directed to the drug insert of embodiment a50 wherein any inclusions in the first drug core and the second drug core, respectively, have a standard deviation in diameter of less than about 8 μm.

Embodiment a64 is directed to the drug insert of embodiment a50 wherein the implant body includes a central bore extending from the proximal end to the distal end of the implant body so as to be adapted to allow tear fluid to pass through the implant body and release the first and second therapeutic agents into the tear fluid and into the lacrimal duct of the patient when the implant body is disposed in or adjacent the eye.

Embodiment a65 is directed to the drug insert of embodiment a50 wherein the first drug provides a first effect and a side effect to the patient and the second drug provides a second effect that reduces or counteracts the side effect of the first drug.

Embodiment a66 is directed to the drug insert of embodiment a50, further comprising disposing a drug-impregnated porous material within the first matrix, the second matrix, or both, wherein the drug-impregnated porous material is adapted to allow tear fluid to release the first drug, the second drug, or both, from the drug-impregnated porous material at therapeutic levels for a sustained period of time when the implant comprising the drug core is disposed within a punctum (punctum), and wherein the drug-impregnated porous material is a gel material that can expand from a first diameter to a second diameter upon contact with tear fluid.

Embodiment a67 is directed to the drug insert of embodiment a66 wherein the second diameter is about 50% greater than the first diameter.

Embodiment a68 is directed to the drug insert of embodiment a66 wherein the porous material impregnated with the drug is a HEMA hydrophilic polymer.

Embodiment a69 relates to the drug insert of aspect a1, wherein the matrix comprises a polyurethane polymer or copolymer.

Embodiment a70 is directed to the drug insert of embodiment a69 wherein the polyurethane polymer or copolymer comprises an aliphatic polyurethane, an aromatic polyurethane, a hydrogel-forming polyurethane material, a hydrophilic polyurethane, or a combination thereof.

Embodiment a71 is directed to the drug insert of embodiment a69 wherein the polyurethane polymer or copolymer comprises a hydrogel adapted to swell upon contact with an aqueous medium and the sheath body has sufficient elasticity to expand in response to swelling of the hydrogel.

Embodiment a72 is directed to the drug insert of embodiment a71 wherein the expansion is adapted to retain the implant body within a lacrimal duct of a patient.

Embodiment a73 relates to the drug insert of embodiment a69 wherein the therapeutic agent comprises cyclosporine or olopatadine, a prodrug or derivative of cyclosporine or olopatadine, or any combination thereof.

Embodiment a74 is directed to the drug insert of embodiment a73 wherein the weight ratio of cyclosporine or olopatadine, or a cyclosporine prodrug or derivative, or an olopatadine prodrug or derivative, or a combination thereof, to the polyurethane polymer or copolymer is from about 1% to about 70% by weight.

Embodiment a75 is directed to the drug insert of aspect a1 wherein the concentration of drug in the core is similar in the portion of the drug core immediately adjacent to the exposed surface, the portion distal to the exposed surface, and the portion disposed between the proximal portion and the distal portion.

Embodiment a76 is directed to the drug insert of embodiment a75 wherein the proximal portion has a length that is at least about one tenth the length of the drug core.

Embodiment a77 relates to the drug insert of aspect a1, wherein the drug insert or implant is adapted for placement within or adjacent to an eye of a patient.

Embodiment A78 relates to the drug insert of aspect A1, wherein a) the therapeutic agent is uniformly and homogeneously dispersed throughout the matrix; or b) the therapeutic agent forms at least partially a solid or liquid inclusion within the matrix.

The drug insert aspects and embodiments of aspect a1 and embodiments a2 through a76 may be combined in any manner so long as the combinations are not self-contradictory. For example, embodiment a6 can be combined with any one of embodiments a2 to a 5. These combinations are intended to provide the same principles and meanings as the various dependent claims and as the various dependent claims refer to other various dependent claims such that any and all combinations of the foregoing and subsequent subject matter are included in such aspects and embodiment combinations.

Aspect B1 relates to a drug core adapted for disposition into or as a drug insert or implant, comprising a therapeutic drug and a matrix, the drug insert or implant adapted for disposition within or adjacent to a cavity, tissue, duct, or fluid of a patient's body, the matrix comprising a polymer, wherein an amount of the therapeutic drug in a volumetric portion of the drug core is similar to an amount of the therapeutic drug in any other equal volumetric portion of the drug core.

Embodiment B2 relates to the drug core of aspect B1, wherein the drug insert or implant is adapted for placement within or adjacent to the eye of the patient.

Embodiment B3 relates to the core of aspect B1, wherein a) the therapeutic agent is uniformly and homogeneously dispersed throughout the matrix; or b) the therapeutic agent forms at least partially a solid or liquid inclusion within the matrix.

Embodiment B4 is directed to the drug core of aspect B1, wherein the amount of the therapeutic agent within one volumetric portion of the drug core differs from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 30%.

Embodiment B5 is directed to the drug core of aspect B1, wherein the amount of the therapeutic agent within one volumetric portion of the drug core differs from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 20%.

Embodiment B6 is directed to the drug core of aspect B1, wherein the amount of the therapeutic agent within one volumetric portion of the drug core differs from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 10%.

Embodiment B7 is directed to the drug core of aspect B1, wherein the amount of the therapeutic agent within one volumetric portion of the drug core differs from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 5%.

Embodiment B8 is directed to the drug core of aspect B1, wherein the therapeutic agent is uniformly and homogeneously distributed throughout the matrix.

Embodiment B9 relates to the drug core of aspect B1, wherein the therapeutic agent at least partially forms solid or liquid inclusions within the matrix.

Embodiment B10 relates to the drug core of aspect B1, wherein the therapeutic agent at least partially forms solid or liquid inclusions within the matrix, wherein the inclusions have an average diameter of less than about 20 μm.

Embodiment B11 relates to the drug core of embodiment B10 wherein the standard deviation of the inclusion diameter is less than about 8 μm.

Embodiment B12 relates to the drug core of aspect B1, wherein the therapeutic agent at least partially forms solid or liquid inclusions within the matrix, wherein the inclusions have an average diameter of less than about 10 μm.

Embodiment B13 is directed to the drug core of embodiment B12 wherein the standard deviation of the inclusion diameter is less than about 4 μm.

Embodiment B14 is directed to the drug core of aspect B1, wherein the amount of the therapeutic agent in equal volume portions near the proximal portion, near the intermediate portion, and near the distal portion of the drug core are similar.

Embodiment B15 relates to the drug core of embodiment B14 wherein the amounts of the therapeutic agents differ by no more than about 30%.

Embodiment B16 relates to the drug core of embodiment B14 wherein the amounts of the therapeutic agents differ by no more than about 20%.

Embodiment B17 relates to the drug core of embodiment B14 wherein the amounts of the therapeutic agents differ by no more than about 10%.

Embodiment B18 relates to the drug core of embodiment B16, wherein the amounts differ by no more than about 5%.

Embodiment B19 relates to the drug core of aspect B1, wherein the polymer comprises a non-biodegradable silicone or polyurethane, or a combination thereof.

Embodiment B20 relates to the drug core of aspect B1, wherein the therapeutic drug comprises a glaucoma drug, a muscarinic drug, a β blocker, an α agonist, a carbonic anhydrase inhibitor, a prostaglandin or prostaglandin analog, an anti-inflammatory drug, an anti-infective drug, a dry eye drug, or any combination thereof.

Embodiment B21 relates to the drug core of embodiment B20, wherein the anti-inflammatory agent comprises a steroid, a soft steroid, or an NSAID and/or other compound having analgesic properties.

Embodiment B22 is directed to the drug core of embodiment B20, wherein the anti-infective agent comprises an antibiotic, an antiviral, or an antifungal agent.

Embodiment B23 is directed to the drug core of embodiment B20 wherein the dry eye drug comprises cyclosporine, an antihistamine, and a mast cell stabilizer, olopatadine, a demulcent, or sodium hyaluronate.

Embodiment B24 relates to the drug core of aspect B1, wherein the polymer comprises silicone.

Embodiment B25 relates to the drug core of aspect B1, wherein the therapeutic agent comprises cyclosporine and the polymer comprises polyurethane.

Embodiment B26 is directed to the drug core of aspect B1 comprising a release rate modifying material comprising an inert filler material, a salt, a surfactant, a dispersant, a second polymer, an oligomer, or a combination thereof.

Embodiment B27 is directed to the drug core of aspect B1 disposed within the sheath body.

Embodiment B28 is directed to the drug core of aspect B1 formed in the shape of an implant body for disposition in or adjacent to a cavity, tissue, duct, or fluid of a patient's body.

The drug core aspects and embodiments of aspect B1 and embodiments B2 through B28 may be combined in any manner, as long as the combinations are not self-contradictory. For example, embodiment B6 can be combined with any one of embodiments B2 to B5. These combinations are intended to provide the same principles and meanings as the various dependent claims and as the various dependent claims refer to other various dependent claims such that any and all combinations of the foregoing and subsequent subject matter are included in such aspects and embodiment combinations.

Aspect C1 relates to a filled precursor sheath comprising a precursor sheath body comprising a precursor sheath core, the drug core comprising a therapeutic agent and a matrix, the matrix comprising a polymer, the agent being substantially impermeable to the precursor sheath body, wherein an amount of the therapeutic agent in a volumetric portion of the precursor sheath core is similar to an amount of the therapeutic agent in any other equal volumetric portion of the precursor sheath core.

Embodiment C2 is directed to the filled precursor sheath of aspect C1 adapted for producing a plurality of drug inserts by dividing the filled precursor sheath, each drug insert adapted to be disposed within a respective implant adapted to be disposed within or adjacent to a cavity, tissue, duct, or fluid of the body.

Embodiment C3 is directed to the filled precursor sheath of aspect C1 wherein the implant is adapted for placement within or adjacent to an eye of a patient.

Embodiment C4 relates to the precursor sheath of aspect C1 wherein the amount of the therapeutic agent in one volumetric portion of the prodrug core differs from the amount of the therapeutic agent in any other equal volumetric portion of the prodrug core by no greater than about 30%.

Embodiment C5 relates to the precursor sheath of aspect C1 wherein the amount of the therapeutic agent in one volumetric portion of the prodrug core differs from the amount of the therapeutic agent in any other equal volumetric portion of the prodrug core by no greater than about 20%.

Embodiment C6 relates to the precursor sheath of aspect C1 wherein the amount of the therapeutic agent in one volumetric portion of the prodrug core differs from the amount of the therapeutic agent in any other equal volumetric portion of the prodrug core by no greater than about 10%.

Embodiment C7 relates to the precursor sheath of aspect C1 wherein the amount of the therapeutic agent in one volumetric portion of the prodrug core differs from the amount of the therapeutic agent in any other equal volumetric portion of the prodrug core by no greater than about 5%.

Embodiment C8 relates to the precursor sheath of aspect C1, wherein the amount of drug in a first insert of the plurality of inserts is similar to the amount of drug in any other insert of the plurality of inserts.

Embodiment C9 is directed to the precursor sheath of embodiment C8 wherein the amount of drug in the first insert differs by no more than about 30% as compared to the amount of drug in any other insert.

Embodiment C10 is directed to the precursor sheath of embodiment C8 wherein the amount of drug in the first insert differs by no more than about 20% as compared to the amount of drug in any other insert.

Embodiment C11 is directed to the precursor sheath of embodiment C8 wherein the amount of drug in the first insert differs by no more than about 10% as compared to the amount of drug in any other insert.

Embodiment C12 is directed to the precursor sheath of embodiment C8 wherein the amount of drug in the first insert differs by no more than about 5% as compared to the amount of drug in any other insert.

Embodiment C13 is directed to the precursor sheath of aspect C1 wherein the implant comprises a punctal plug and each of the plurality of inserts is adapted to be disposed within a corresponding plurality of punctal plugs.

Embodiment C14 is directed to the precursor sheath of embodiment C13 wherein each exposed surface of each drug insert segmented by the precursor sheath is adapted to release a therapeutic amount of the drug into the tear fluid over a period of at least several days when the insert is disposed within a punctal plug and the punctal plug is disposed in the punctum of the patient.

Embodiment C15 is directed to the precursor sheath of aspect C1 wherein the drug core comprises about 0.1% to about 50% by weight of the drug.

Embodiment C16 relates to the precursor sheath of aspect C1, wherein the matrix comprises a non-biodegradable silicone or polyurethane, or a combination thereof.

Embodiment C17 relates to the precursor sheath of aspect C1, wherein the sheath body comprises a polymer comprising at least one of polyimide, PMMA, PET, wherein the polymer is extruded or cast, or stainless steel, or titanium.

Embodiment C18 relates to the precursor sheath of aspect C1, wherein the drug comprises a glaucoma drug, a muscarinic drug, a β blocker, an α agonist, a carbonic anhydrase inhibitor, a prostaglandin or prostaglandin analog, an anti-inflammatory drug, an anti-infective drug, a dry eye drug, or any combination thereof.

Embodiment C19 is directed to the precursor sheath of embodiment C18 wherein the anti-inflammatory agent comprises a steroid, a soft steroid, or an NSAID and/or other compound having analgesic properties.

Embodiment C20 is directed to the precursor sheath of embodiment C18 wherein the anti-infective agent comprises an antibiotic, an antiviral, or an antifungal agent.

Embodiment C21 is directed to the precursor sheath of embodiment C18 wherein the dry eye drug comprises cyclosporine, an antihistamine, and a mast cell stabilizer, olopatadine, a demulcent, or sodium hyaluronate.

Embodiment C22 relates to the precursor sheath of aspect C1 wherein the drug comprises latanoprost and the amount of drug in each of the plurality of drug inserts is about 10-50 μ g.

Embodiment C23 is directed to the precursor sheath of aspect C1 wherein the drug insert comprises a release rate modifying material comprising an inert filler material, a salt, a surfactant, a dispersant, a second polymer, an oligomer, or a combination thereof.

Embodiment C24 relates to the precursor sheath of aspect C1 adapted for segmentation by cutting with a blade or with a laser.

Embodiment C25 relates to the precursor sheath of aspect C1 wherein the drug is dissolved in a matrix.

Embodiment C26 relates to the precursor sheath of aspect C1 wherein the drug is at least partially present throughout the matrix as a plurality of solid or liquid inclusions comprising droplets of the drug having a diameter of no greater than about 100 μ ι η at a temperature below about 25 ℃ (when the drug is liquid below about 25 ℃), or the inclusions comprising particles of the drug having a diameter of no greater than about 100 μ ι η (when the drug is solid below about 25 ℃).

Embodiment C27 is directed to the precursor sheath of embodiment C26 wherein the inclusions have an average diameter of less than about 20 μm.

Embodiment C28 is directed to the precursor sheath of embodiment C27 wherein the standard deviation of the inclusion diameter is less than about 8 μm.

Embodiment C29 is directed to the precursor sheath of embodiment C26 wherein the inclusions have an average diameter of less than about 10 μm.

Embodiment C30 is directed to the precursor sheath of embodiment C29 wherein the standard deviation of the diameters of the inclusions is less than about 4 μm.

Embodiment C31 is directed to the precursor sheath of embodiment C26 wherein the size distribution of the diameters of the plurality of inclusions is monodisperse.

Embodiment C32 is directed to the precursor sheath of aspect C1 wherein a) the therapeutic agent is uniformly and homogeneously dispersed throughout the matrix; or b) the therapeutic agent forms at least partially a solid or liquid inclusion within the matrix.

The filled precursor sheath aspects and embodiments of aspect C1 and embodiments C2 through C32 may be combined in any manner, so long as the combination is not self-contradictory. For example, embodiment C6 can be combined with any one of embodiments C2 to C5. These combinations are intended to provide the same principles and meanings as the various dependent claims and as the various dependent claims refer to other various dependent claims such that any and all combinations of the foregoing and subsequent subject matter are included in such aspects and embodiment combinations.

Aspect D1 relates to an implant body for disposition in or adjacent to a cavity, tissue, duct, or fluid of a patient's body, the implant body including a channel adapted to receive a drug insert therein such that an exposed surface of the insert is exposed to the cavity, tissue, duct, or fluid of the body when the insert is disposed within the implant and when the implant is disposed in or adjacent to the cavity, tissue, duct, or fluid of the body, the drug insert including a sheath body that is substantially impermeable to a drug, the sheath body including a drug core, the drug core including a therapeutic drug and a matrix, the matrix including a polymer, wherein an amount of the therapeutic drug within a volumetric portion of the prodrug core is similar to an amount of the therapeutic drug within any other equal volumetric portion of the prodrug core.

Embodiment D2 is directed to the implant body of aspect D1, wherein the implant is adapted for placement within or adjacent to an eye of a patient.

Embodiment D3 is directed to the implant body of aspect D1, wherein the amount of the therapeutic agent within one volumetric portion of the drug core differs from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 30%.

Embodiment D4 is directed to the implant body of aspect D1, wherein the amount of the therapeutic agent within one volumetric portion of the drug core differs from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 20%.

Embodiment D5 is directed to the implant body of aspect D1, wherein the amount of the therapeutic agent within one volumetric portion of the drug core differs from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 10%.

Embodiment D6 is directed to the implant body of aspect D1, wherein the amount of the therapeutic agent within one volumetric portion of the drug core differs from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 5%.

Embodiment D7 is directed to the implant of aspect D1, wherein the exposed surface is capable of releasing the therapeutic amount into at least one of the sclera, the cornea, or the vitreous when disposed in or adjacent to the eye of the patient.

Embodiment D8 is directed to the implant of aspect D1 comprising a punctal plug adapted for placement within a punctum of a patient for release of a drug into tear fluid.

Embodiment D9 is directed to the implant of aspect D1, wherein the therapeutic agent is dissolvable in the matrix.

Embodiment D10 is directed to the implant of aspect D1 wherein the therapeutic agent forms an inclusion within the matrix but is sufficiently soluble in or transportable through the matrix such that the exposed surface is capable of releasing a therapeutic amount of the agent into tear fluid for a period of time when the implant is disposed in or adjacent to the eye.

Embodiment D11 is directed to the implant of aspect D1 wherein the release rate of the drug is determined in part by the concentration of the drug dissolved in the matrix.

Embodiment D12 relates to the implant of aspect D1, wherein the matrix comprises a cross-linked, water-insoluble, solid material that comprises inclusions.

Embodiment D13 is directed to the implant of embodiment D12 wherein the crosslinked, water-insoluble solid material comprises silicone or polyurethane.

Embodiment D14 is directed to the implant of aspect D1, wherein the matrix further comprises an effective amount of a release rate modifying material comprising at least one of a cross-linking agent, an inert filler material, a surfactant, a dispersant, a second polymer, or oligomer, or any combination thereof.

Embodiment D15 is directed to the implant of aspect D1 wherein the drug core comprises about 5% to about 50% of the therapeutic agent.

Embodiment D16 relates to the implant of embodiment D10 wherein the inclusions of the drug are liquid or solid in appearance.

Embodiment D17 is directed to the implant of aspect D1, wherein the sheath body comprises a polymer comprising at least one of polyimide, PMMA, PET, wherein the polymer is extruded or cast, or stainless steel, or titanium.

Embodiment D18 is directed to the implant of aspect D1, wherein the implant body comprises at least one of a silicone or a hydrogel.

Embodiment D19 relates to aspect D1 wherein the drug is present throughout the matrix as a plurality of solid or liquid inclusions comprising droplets of the drug having a diameter no greater than about 200 μm at a temperature below about 25 ℃ (when the drug is liquid below about 25 ℃), or comprising particles of the drug having a diameter no greater than about 200 μm (when the drug is solid below about 25 ℃).

Embodiment D20 relates to the implant of embodiment D19 wherein the inclusions have an average diameter of less than about 20 μm.

Embodiment D21 is directed to the implant of embodiment D20 wherein the standard deviation of the diameters of the inclusions is less than about 8 μm.

Embodiment D22 relates to the implant of embodiment D19 wherein the inclusions have an average diameter of less than about 15 μm.

Embodiment D23 is directed to the implant of embodiment D22 wherein the standard deviation of the diameters of the inclusions is less than about 6 μm.

Embodiment D24 is directed to the implant of embodiment D19 wherein the inclusions have an average diameter of less than about 10 μm.

Embodiment D25 is directed to the implant of embodiment D24 wherein the standard deviation of the diameters of the inclusions is less than about 4 μm.

Embodiment D26 is directed to the implant of embodiment D19 wherein the size distribution of the diameters of the plurality of inclusions is monodisperse.

Embodiment D27 is directed to the implant of embodiment D19 wherein the inclusions comprise a cross-sectional size of about 0.1 μm to about 50 μm.

Embodiment D28 is directed to the implant of embodiment D19 wherein the drug forms inclusions in the matrix that are in a liquid physical state at less than about 25 ℃.

Embodiment D29 is directed to the implant of embodiment D19 wherein the drug forms inclusions in the matrix that are in a solid physical state below about 25 ℃.

Embodiment D30 relates to the implant of aspect D1, wherein: a) the therapeutic agent is uniformly and homogeneously dispersed throughout the matrix; or b) the therapeutic agent forms at least partially a solid or liquid inclusion within the matrix.

The implant body aspects and embodiments of aspect D1 and embodiments D2 through D30 may be combined in any manner so long as the combination is not self-contradictory. For example, embodiment D6 can be combined with any one of embodiments D2 to D5. These combinations are intended to provide the same principles and meanings as the various dependent claims and as the various dependent claims refer to other dependent claims such that any and all combinations of the foregoing and subsequent subject matter are included in such aspects and embodiment combinations.

Aspect E1 relates to a method of producing a drug insert for an implant body adapted for disposition within or adjacent to a cavity, tissue, conduit, or fluid of a patient's body, the insert comprising a drug core and a sheath body partially covering the drug core, the drug core comprising a therapeutic drug and a matrix, the matrix comprising a polymer, the sheath body disposed over a portion of the drug core for inhibiting release of the drug from the portion upon insertion of the implant into the patient's body and thereby defining at least one exposed surface of the drug core adapted to release the drug, the method comprising injecting a mixture comprising a matrix precursor and the therapeutic drug into the sheath body at a temperature below about 25 ℃, such that the sheath body is substantially filled; the mixture is then solidified within the sheath body to form a drug core within the sheath body, wherein the amount of the therapeutic agent in one volumetric portion of the drug core is similar to the amount of the therapeutic agent in any other equal volumetric portion of the drug core.

Aspect E2 relates to a method of producing a drug insert for an implant body adapted for placement within or adjacent to a cavity, tissue, duct, or fluid of a patient's body, the method comprising injecting a mixture comprising a therapeutic drug and a precursor matrix into a precursor sheath body at a temperature of less than about 25 ℃ such that the precursor sheath is substantially filled with the drug substantially impermeable to the precursor sheath body, allowing the mixture to solidify in the precursor sheath body so as to provide a solidified, filled precursor sheath body comprising a prodrug core; and segmenting the cured filled precursor sheath to form a plurality of drug inserts, each drug insert being adapted to fit within a respective implant body, wherein each drug insert comprises a drug core and a sheath body disposed over a portion of the drug core for inhibiting release of drug from said portion upon insertion of the implant into a patient and thereby defining at least one exposed surface of the drug core adapted to release drug, and wherein the amount of therapeutic drug in a volumetric portion of the drug core is similar to the amount of therapeutic drug in any other equal volumetric portion of the drug core.

Embodiment E3 is directed to the method of aspect E2 for producing a drug insert, wherein each of the plurality of drug inserts has substantially the same length, and wherein the amount of drug in a first insert of the plurality of inserts is similar to the amount of drug in any other insert of the plurality of inserts.

Embodiment E4 relates to the method of producing a drug insert of aspect E1, aspect E2, or embodiment E3, wherein the implant is adapted for placement in or adjacent to the eye of a patient.

Embodiment E5 relates to the method of aspect E1 or E2, wherein the amount of the therapeutic drug within one volumetric portion of the drug core differs by no greater than about 30% from the amount of the therapeutic drug within any other equal volumetric portion of the drug core.

Embodiment E6 relates to the method of aspect E1 or E2, wherein the amount of the therapeutic drug within one volumetric portion of the drug core differs by no greater than about 20% from the amount of the therapeutic drug within any other equal volumetric portion of the drug core.

Embodiment E7 relates to the method of aspect E1 or E2, wherein the amount of the therapeutic drug within one volumetric portion of the drug core differs by no greater than about 10% from the amount of the therapeutic drug within any other equal volumetric portion of the drug core.

Embodiment E8 relates to the method of aspect E1 or E2, wherein the amount of the therapeutic drug within one volumetric portion of the drug core differs by no greater than about 5% from the amount of the therapeutic drug within any other equal volumetric portion of the drug core.

Embodiment E9 relates to the method of aspect E2, wherein the amount of drug in each of the plurality of drug inserts varies by no more than about 30%.

Embodiment E10 relates to the method of aspect E2, wherein the amount of drug in each of the plurality of drug inserts varies by no more than about 20%.

Embodiment E11 relates to the method of aspect E2, wherein the amount of drug in each of the plurality of drug inserts varies by no more than about 10%.

Embodiment E12 relates to the method of aspect E2, wherein the amount of drug in each of the plurality of drug inserts varies by no more than about 5%.

Embodiment E13 relates to the method of aspect E2, wherein segmenting the precursor insert comprises cutting the precursor insert with a blade or with a laser.

Embodiment E14 relates to the method of aspect E1 or E2, wherein the implant comprises a punctal plug adapted to be disposed within a punctum of a patient.

Embodiment E15 is directed to the method of embodiment E14 wherein the exposed surface is adapted to release a therapeutic amount of a drug into the tear fluid over a period of at least several days when the insert is disposed in the punctal plug and the punctal plug is disposed in the punctum of the patient.

Embodiment E16 relates to the method of aspect E1 or E2, wherein the mixture further comprises a solvent in which the matrix precursor and the drug are soluble, and wherein the curing comprises at least partial removal of the solvent after injection into the sheath body or the precursor sheath body, respectively.

Embodiment E17 relates to the method of embodiment E16, wherein curing comprises heating, vacuum treating, or both.

Embodiment E18 relates to the method of embodiment E16, wherein the solvent comprises a hydrocarbon, an ester, a halogenated hydrocarbon, an alcohol, an amide, or a combination thereof.

Embodiment E19 is directed to the method of embodiment E16 wherein the solvent comprises a halogenated hydrocarbon and the agent comprises cyclosporine.

Embodiment E20 relates to the method of aspect E1 or E2, wherein curing the mixture comprises heating the mixture to a temperature and for a time and at a relative humidity.

Embodiment E21 relates to embodiment E20 wherein the temperature comprises about 20 ℃ to about 100 ℃, the relative humidity comprises about 40% to about 100%, and the period of time comprises about 1 minute to about 48 hours.

Embodiment E22 relates to the method of embodiment E21, wherein the temperature is at least about 40 ℃, the relative humidity is at least about 80%, or both.

Embodiment E23 relates to the method of aspect E1 or E2, wherein the curing comprises a step of polymerization or crosslinking of the matrix precursor, or both.

Embodiment E24 relates to the method of embodiment E23, comprising conducting polymerization or crosslinking, or both, in the presence of a catalyst.

Embodiment E25 relates to the method of embodiment E24 wherein the catalyst comprises a tin compound or a platinum compound.

Embodiment E26 is directed to embodiment E24 wherein the catalyst includes at least one of a platinum and vinyl hydride system or a tin and alkoxy system.

Embodiment E27 relates to the method of aspect E1 or E2, wherein the mixture is prepared by a process comprising sonication.

Embodiment E28 relates to the method of aspect E1 or E2, wherein injecting comprises injecting at a pressure of at least about 40 psi.

Embodiment E29 relates to the method of aspect E1 or E2, wherein the temperature comprises a temperature of about-50 ℃ to about 25 ℃.

Embodiment E30 relates to the method of aspect E1 or E2, wherein the temperature includes a temperature of about-20 ℃ to about 0 ℃.

Embodiment E31 relates to the method of aspect E1 or E2, wherein the mixture is injected such that the sheath body or precursor sheath body, respectively, is filled at a rate of no greater than about 0.5 cm/sec.

Embodiment E32 relates to the method of aspect E1 or E2, wherein each drug insert is sealed at one end thereof, the second end providing an exposed surface.

Embodiment E33 relates to the method of embodiment E32, wherein each drug insert is sealed at one end thereof with a UV-curable adhesive, cyanoacrylate, epoxy, by clamping, welding with heat, or with an end cap.

Embodiment E34 is directed to the method of embodiment E33, further comprising irradiating the drug insert with the UV-curable adhesive with an ultraviolet lamp.

Embodiment E35 is directed to the method of embodiment E33, further comprising inserting each drug insert into a channel of the implant body adapted to receive the insert therein after sealing one end.

Embodiment E36 relates to the method of aspect E1 or E2, wherein the insert comprises about 0.1% to about 50% by weight of the drug.

Embodiment E37 relates to the method of aspect E1 or E2, wherein the matrix comprises a non-biodegradable silicone or polyurethane.

Embodiment E38 relates to the method of aspect E1 or E2, wherein the sheath or precursor sheath comprises at least one of polyimide, PMMA, PET, stainless steel, or titanium.

Embodiment E39 relates to the method of aspect E1 or E2, wherein the drug comprises a glaucoma drug, a muscarinic drug, a β blocker, an α agonist, a carbonic anhydrase inhibitor, or a prostaglandin or prostaglandin analog, an anti-inflammatory drug, an anti-infective drug, a dry eye drug, or any combination thereof.

Embodiment E40 relates to the method of embodiment E39, wherein the anti-inflammatory agent comprises a steroid, a soft steroid, or an NSAID and/or any other compound having analgesic properties.

Embodiment E41 relates to the method of embodiment E39, wherein the anti-infective agent comprises an antibiotic, an antiviral, or an antifungal (antimicotic).

Embodiment E42 relates to the method of embodiment E39 wherein the dry eye drug comprises cyclosporine, olopatadine, a demulcent, or sodium hyaluronate.

Embodiment E43 relates to the method of aspect E1 or E2, wherein the drug comprises latanoprost, the matrix comprises silicone or polyurethane, and the amount of drug in each of the plurality of drug inserts is about 10-50 μ g.

Embodiment E44 relates to the method of aspect E1 or E2 wherein the drug comprises cyclosporin, the matrix comprises silicone or polyurethane, and the relative amount of drug in each of the plurality of drug inserts is from about 1% to about 50% of the core.

Embodiment E45 relates to the method of aspect E1 or E2, wherein the drug insert comprises a release rate modifying material comprising an inert filler material, a salt, a surfactant, a dispersant, a second polymer, an oligomer, or a combination thereof.

Embodiment E46 is directed to the method of aspect E1 or E2, wherein the drug core is substantially cylindrical having an axis, wherein the surface of the drug core not covered by the sheath is disposed on one end of the cylinder and the drug core covered by the sheath is disposed on the remainder of the surface of the cylinder.

Embodiment E47 relates to the method of aspect E1 or E2, wherein the drug is dissolved in a matrix.

Embodiment E48 relates to the method of embodiment E47, wherein the drug comprises cyclosporine and the matrix comprises polyurethane.

Embodiment E49 relates to the method of aspect E1 or E2 wherein the drug is dispersed throughout the matrix as a plurality of solid or liquid inclusions comprising droplets of the drug having a diameter no greater than about 200 μm at a temperature below about 25 ℃ (when the drug is liquid below about 25 ℃), or the inclusions comprising particles of the drug having a diameter no greater than about 200 μm (when the drug is solid below about 25 ℃).

Embodiment E50 relates to the method of embodiment E49, wherein the inclusions have an average diameter of less than about 20 μm.

Embodiment E51 relates to the method of embodiment E50, wherein the standard deviation of the diameters of the inclusions is less than about 8 μm.

Embodiment E52 relates to the method of embodiment E49, wherein the inclusions have an average diameter of less than about 15 μm.

Embodiment E53 relates to the method of embodiment E52, wherein the standard deviation of the diameters of the inclusions is less than about 6 μm.

Embodiment E54 relates to the method of embodiment E49, wherein the inclusions have an average diameter of less than about 10 μm.

Embodiment E55 relates to the method of embodiment E54, wherein the standard deviation of the diameters of the inclusions is less than about 4 μm.

Embodiment E56 relates to the method of embodiment E49, wherein the distribution of diameters of the inclusions is a monodisperse distribution.

Embodiment E57 relates to the method of embodiment E49, wherein the mixture is prepared by a process comprising sonication.

Embodiment E58 relates to the method of embodiment E49, wherein the inclusion comprises a cross-sectional size of about 0.1 μm to about 50 μm.

Embodiment E59 relates to the method of embodiment E49 wherein the drug forms inclusions in the matrix that are in a liquid physical state at less than about 25 ℃.

Embodiment E60 relates to the method of embodiment E59, wherein substantially all of the inclusions are drug droplets having a diameter of less than about 50 μm within the matrix.

Embodiment E61 relates to the method of embodiment E59, wherein the average droplet diameter within the matrix is about 5-50 μm.

Embodiment E62 relates to the method of embodiment E59, wherein the drug is latanoprost.

Embodiment E63 relates to the method of embodiment E49 wherein the drug is in a solid physical state below about 25 ℃.

Embodiment E64 relates to the method of embodiment E63 wherein the drug forms inclusions in the matrix, the inclusions being in a solid physical state below about 25 ℃.

Embodiment E65 relates to the method of embodiment E63, wherein substantially all of the inclusions are drug particles having a diameter of less than about 50 μm within the matrix.

Embodiment E66 relates to the method of embodiment E63, wherein the average particle diameter within the matrix is about 5-50 μm.

Embodiment E67 relates to the method of embodiment E63 wherein the drug is bimatoprost, olopatadine, or cyclosporine.

Embodiment E68 relates to the method of aspect E1 or E2, wherein each drug insert comprises two or more therapeutic drugs.

Embodiment E69 relates to the method of aspect E1 or E2, wherein each drug core comprises a first and a second drug core.

Embodiment E70 is directed to the method of embodiment E69 wherein the first and second drug cores are positioned side-by-side and together form a column, being the drug core within the sheath body.

Embodiment E71 is directed to the method of embodiment E69 wherein the drug core comprises two drug cores, the first drug core comprises a first drug and a first matrix, the second drug core comprises a second drug and a second matrix, wherein the first drug and the second drug are different and the first matrix and the second matrix are the same or different from each other, the implant body comprises an aperture adapted to receive a drug insert comprising the first and second drug cores, the method further comprising disposing the drug cores within the insert prior to disposing the insert within the aperture of the implant body.

Embodiment E72 is directed to the method of embodiment E71, wherein the first substrate and the second substrate differ from each other in at least one of composition, area of exposed surface, surfactant, crosslinker, additive, substrate material, formulation, or stability.

Embodiment E73 is directed to the method of embodiment E71 wherein the first drug core and the second drug core are disposed within the sheath such that the first drug core has a surface exposed directly to tear fluid and the second drug core has a surface exposed to the first drug core.

Embodiment E74 is directed to the method of embodiment E71 wherein the first drug core and the second drug core are disposed side-by-side within a sheath.

Embodiment E75 is directed to the method of embodiment E71 wherein the first drug core and the second drug core are each cylindrical and disposed with the drug cores, the first drug core being positioned near a proximal end of an aperture in an implant body adapted to receive the drug cores and the second drug core being positioned near a distal end of the aperture.

Embodiment E76 is directed to the method of embodiment E71, wherein the first drug core and the second drug core are each cylindrical and are concentrically positioned within an aperture of the implant body adapted to receive the drug cores, the first drug core having a first central opening, the second drug core being configured to fit within the first central opening of the first drug core.

Embodiment E77 is directed to the method of embodiment E71 wherein the first and second drug cores are concentrically positioned within the orifice, the first drug core having a first central opening exposing the first inner surface, the second drug core having a second central opening exposing the second inner surface, the second drug core configured to fit within the first central opening of the first drug core, and wherein the orifice extends distally from the proximal end of the implantable body adapted to allow tear or tear film fluid to pass through the orifice and contact the first and second inner surfaces of the first and second central openings and release the first and second therapeutic agents into the lacrimal duct.

Embodiment E78 relates to the method of embodiment E71, wherein the insert is adapted such that, upon implantation thereof, the first therapeutic agent is released at therapeutic levels throughout a first time period and the second therapeutic agent is released at therapeutic levels throughout a second time period.

Embodiment E79 relates to the method of embodiment E71 wherein the first therapeutic agent is released at therapeutic levels throughout the first time period and the second therapeutic agent is released at therapeutic levels throughout the second time period.

Embodiment E80 relates to the method of embodiment E79, wherein the first period of time and the second period of time are one week to five years.

Embodiment E81 relates to the method of embodiment E79, wherein the first period of time and the second period of time are substantially the same.

Embodiment E82 relates to the method of embodiment E79, wherein the first period of time and the second period of time are different.

Embodiment E83 is directed to the method of embodiment E71, further comprising providing a tip coupled to the implant body and covering the opening, the tip being permeable to the first and second therapeutic agents.

Embodiment E84 relates to the method of embodiment E71, wherein the therapeutic level is a drop administration or less.

Embodiment E85 relates to the method of embodiment E71 wherein the therapeutic level is less than 10% of the amount administered as drops.

Embodiment E86 is directed to the method of embodiment E71, further comprising disposing a drug-impregnated porous material within the first matrix, the second matrix, or both, the drug-impregnated porous material adapted to allow tear fluid to release the first drug, the second drug, or both, at therapeutic levels over a sustained period of time when the implant comprising the drug core is disposed in the punctum, wherein the drug-impregnated porous material is a gel material that can expand from a first diameter to a second diameter.

Embodiment E87 is directed to the method of embodiment E86 wherein the second diameter is about 50% greater than the first diameter.

Embodiment E88 relates to the method of embodiment E86, wherein the porous material impregnated with a drug is a HEMA hydrophilic polymer.

Embodiment E89 is directed to embodiment E71 wherein the implant body comprises a central bore extending from the proximal end to the distal end of the implant body adapted to allow tear fluid to pass through the implant body and release the first and second therapeutic agents into the lacrimal duct.

Embodiment E90 relates to the method of embodiment E71 wherein the first drug provides a first effect and a side effect to the patient and the second drug provides a second effect that alleviates or counteracts the side effect of the first drug.

Embodiment E91 relates to the method of aspect E1 or E2, wherein the matrix comprises a polyurethane polymer or copolymer.

Embodiment E92 is directed to the method of embodiment E91, wherein the polyurethane polymer or copolymer comprises an aliphatic polyurethane, an aromatic polyurethane, a hydrogel-forming polyurethane material, a hydrophilic polyurethane, or a combination thereof.

Embodiment E93 is directed to the method of embodiment E91 wherein the polyurethane polymer or copolymer comprises a hydrogel adapted to swell upon contact with an aqueous medium and the sheath is sufficiently elastic to expand in response to swelling of the hydrogel.

Embodiment E94 relates to the method of embodiment E93, wherein the expanding is adapted to retain the plug within the lacrimal duct.

Embodiment E95 relates to the method of embodiment E91, wherein the therapeutic agent comprises cyclosporine or olopatadine, a prodrug or derivative of cyclosporine or olopatadine, or any combination thereof.

Embodiment E96 is directed to the method of embodiment E95 wherein the weight ratio of cyclosporine or olopatadine, or a cyclosporine prodrug or derivative, or an olopatadine prodrug or derivative, or a combination thereof, to the polyurethane polymer or copolymer is from about 1% to about 70% by weight.

Embodiment E97 relates to the method of embodiment E95 wherein the amounts or concentrations of the polyurethane polymer or copolymer, and the cyclosporin or olopatadine, or a prodrug or derivative of cyclosporin or olopatadine, or a combination thereof, are selected to provide a release profile for the drug into the tear fluid of the patient.

Embodiment E98 relates to the method of embodiment E91, wherein the drug core further comprises a second therapeutic agent.

Embodiment E99 relates to the method of embodiment E91 comprising forming a mixture by melting and mixing the polyurethane polymer or copolymer and the therapeutic agent.

Embodiment E100 relates to the method of embodiment E99, wherein the therapeutic agent is in molten form in the mixture.

Embodiment E101 relates to the method of embodiment E99, wherein the therapeutic agent is in solid form in the mixture.

Embodiment E102 relates to a drug insert prepared by the method of aspect E1 or E2.

Embodiment E103 relates to the methods of aspects E1 or E2, wherein the temperature comprises a temperature of less than about 25 ℃.

Embodiment E104 relates to the methods of aspects E1 or E2, wherein the temperature comprises a temperature of less than about 15 ℃.

Embodiment E105 relates to the methods of aspects E1 or E2, wherein the temperature comprises a temperature of less than about 10 ℃.

Embodiment E106 relates to the methods of aspects E1 or E2, wherein the temperature comprises a temperature of less than about 5 ℃.

Embodiment E107 relates to the methods of aspects E1 or E2, wherein: a) the therapeutic agent is uniformly and homogeneously dispersed throughout the matrix; or b) the therapeutic agent forms at least partially a solid or liquid inclusion within the matrix.

The aspects of the production processes of aspects E1 and E2 and embodiments E3 to E107 and the aspects and embodiments can be combined in any way, as long as the combinations are not contradictory. For example, embodiment E6 can be combined with any one of embodiments E3 to E5. These combinations are intended to provide the same principles and meanings as the various dependent claims and as the various dependent claims refer to other dependent claims such that any and all combinations of the foregoing and subsequent subject matter are included in such aspects and embodiment combinations.

Aspect F1 relates to a method of treating a disorder in a patient in need thereof, comprising disposing in the patient an implant comprising a drug insert of any one of aspect a1 and embodiments a2-a78, or a drug core of any one of aspect B1 and embodiments B2-B28, or a drug core obtained by segmenting a filled precursor sheath of any one of aspect C1 and embodiments C2-C32, or a drug implant of any one of aspect D1 and embodiments D2-D30, or a drug insert of embodiment E102, in or adjacent to the eye of the patient, such that the drug is released into a body tissue or fluid, wherein the therapeutic drug is suitable for treating the disorder.

Embodiment F2 relates to the method of aspect F1, wherein the disorder comprises glaucoma and the drug is a prostaglandin analog.

Embodiment F3 relates to the method of embodiment F2, wherein the matrix comprises a non-biodegradable silicone or polyurethane polymer.

Embodiment F4 relates to the method of embodiment F2, wherein the prostaglandin analog is latanoprost.

Embodiment F5 relates to the method of aspect F1, wherein the disorder comprises dry eye or ocular inflammation and the drug is cyclosporine or olopatadine or a prodrug or derivative of cyclosporine or olopatadine.

Embodiment F6 relates to the method of embodiment F5, wherein the substrate comprises polyurethane.

Aspect G1 relates to a drug insert adapted for placement within a lacrimal implant for providing sustained release of latanoprost to an eye of a patient in need of treatment for glaucoma, the drug insert comprising a drug core and a sheath body partially covering the drug core, the drug core comprising latanoprost and a matrix, the matrix comprising a silicone polymer, the sheath body disposed over a portion of the drug core so as to inhibit release of latanoprost from the portion and thereby define at least one exposed surface of the drug core not covered by the sheath body so as to be adapted for release of latanoprost to the eye, wherein an amount of latanoprost in a volumetric portion of the drug core is similar to an amount of latanoprost in any other equal volumetric portion of the drug core.

Embodiment G2 relates to the drug insert of aspect G1 wherein the amount of latanoprost in one volumetric portion of the drug core differs by no greater than about 30% from the amount of latanoprost in any other equal volumetric portion of the drug core.

Embodiment G3 relates to the drug insert of aspect G1 wherein the amount of latanoprost in one volumetric portion of the drug core differs by no greater than about 20% from the amount of latanoprost in any other equal volumetric portion of the drug core.

Embodiment G4 relates to the drug insert of aspect G1 wherein the amount of latanoprost in one volumetric portion of the drug core differs by no greater than about 10% from the amount of latanoprost in any other equal volumetric portion of the drug core.

Embodiment G5 relates to the drug insert of aspect G1 wherein the amount of latanoprost in one volumetric portion of the drug core differs by no more than about 5% from the amount of latanoprost in any other equal volumetric portion of the drug core.

Embodiment G6 relates to the drug insert of aspect G1, wherein the latanoprost is interspersed as droplets thereof within the silicone.

The drug insert aspects and embodiments of aspect G1 and embodiments G2 through G6 may be combined in any manner, as long as such combinations are not self-contradictory. For example, embodiment G6 can be combined with any one of embodiments G2 to G5. These combinations are intended to provide the same principles and meanings as the various dependent claims and as the various dependent claims refer to other dependent claims such that any and all combinations of the foregoing and subsequent subject matter are included in such aspects and embodiment combinations.

Aspect H1 relates to a drug insert adapted for disposition within a punctal plug for sustained release of cyclosporine for an eye for treating dry eye or inflammation, the insert comprising a drug core and a sheath body partially covering the drug core, the drug core comprising cyclosporine and a matrix comprising a polyurethane polymer, the sheath body disposed over a portion of the drug core so as to inhibit release of cyclosporine from the portion and thereby define at least one exposed surface of the drug core not covered by the sheath body adapted for release of cyclosporine for the eye, wherein an amount of cyclosporine in a volumetric portion of the drug core is similar to an amount of cyclosporine in any other equal volumetric portion of the drug core.

Embodiment H2 relates to the drug insert of aspect H1 wherein the amount of cyclosporin in one volumetric portion of the drug core differs from the amount of cyclosporin in any other equal volumetric portion of the drug core by no more than about 30%.

Embodiment H3 relates to the drug insert of aspect H1 wherein the amount of cyclosporin in one volumetric portion of the drug core differs by no more than about 20% from the amount of cyclosporin in any other equal volumetric portion of the drug core.

Embodiment H4 relates to the drug insert of aspect H1 wherein the amount of cyclosporin in one volumetric portion of the drug core differs by no more than about 10% from the amount of cyclosporin in any other equal volumetric portion of the drug core.

Embodiment H5 relates to the drug insert of aspect H1 wherein the amount of cyclosporin in one volumetric portion of the drug core differs by no more than about 5% from the amount of cyclosporin in any other equal volumetric portion of the drug core.

Embodiment H6 relates to the drug insert of aspect H1 wherein the cyclosporine is dissolved within the polyurethane.

The drug insert aspects and embodiments of aspect H1 and embodiments H2 through H6 may be combined in any manner, as long as such combinations are not self-contradictory. For example, embodiment H6 can be combined with any one of embodiments H2 to H5. These combinations are intended to provide the same principles and meanings as the various dependent claims and as the various dependent claims refer to other dependent claims such that any and all combinations of the foregoing and subsequent subject matter are included in such aspects and embodiment combinations.

Additional aspects and embodiments include the following.

A drug insert of any one of aspects a1 and embodiments a1-a78, or a drug core of any one of aspects B1 and embodiments B2-B28, or a drug core obtained by segmenting a filled precursor sheath of any one of aspects C1 and embodiments C2-C32, or a drug implant of any one of aspects D1 and embodiments D2-D30, or a drug insert of embodiment E102, adapted to provide sustained release of a therapeutic drug to the eye or surrounding tissue, or to provide sustained release of a therapeutic drug systemically, or to provide sustained release of a therapeutic drug in any combination thereof.

The drug core of any of aspects a1 and embodiments a2-a78 formed in the shape of an implant body for disposition in or adjacent to a cavity, tissue, conduit, or fluid of a patient's body.

Another aspect of the invention relates to the use of a drug insert of any one of aspect a1 and embodiments a1-a78, or a drug core of any one of aspect B1 and embodiments B2-B28, or a drug core obtained by dividing a filled precursor sheath of any one of aspect C1 and embodiments C2-C32, or a drug implant of any one of aspect D1 and embodiments D2-D30, or a drug insert of embodiment E102, for the manufacture of an implant suitable for treating a condition in a patient in need thereof.

Another aspect of the invention relates to an implant comprising a polymer and a therapeutic agent disposed therein, wherein an amount of the therapeutic agent in one volumetric portion of the implant is similar to an amount of the therapeutic agent in any other equal volumetric portion of the implant.

Another aspect of the invention relates to a method of producing an implant comprising a polymer and a therapeutic agent disposed therein, wherein an amount of the therapeutic agent in a volumetric portion of the implant is similar to an amount of the therapeutic agent in any other equal volumetric portion of the implant, wherein the method comprises injecting a mixture comprising the polymer and the therapeutic agent into a mold, the method comprising injecting the mixture at a temperature of less than about 25 ℃.

Brief Description of Drawings

FIG. 1A shows a top cross-sectional view of a sustained release implant for treating an optical defect of the eye according to one embodiment of the present invention.

Fig. 1B illustrates a side cross-sectional view of the sustained release implant of fig. 1A.

Fig. 1C shows a perspective view of a sustained release implant having a coil indwelling structure according to an embodiment of the present invention.

FIG. 1D shows a perspective view of a sustained release implant with an indwelling structure comprising a strut, according to one embodiment of the present invention.

FIG. 1E shows a perspective view of a sustained release implant with a caged retention structure in accordance with one embodiment of the present invention.

FIG. 1F shows a perspective view of a sustained release implant including a core and a sheath according to one embodiment of the present invention.

Figure 1G schematically illustrates a perspective view of a sustained release implant including a flow-restricting indwelling element, according to one embodiment of the present invention.

FIG. 2A shows a cross-sectional view of a sustained release implant of one embodiment of the present invention having a core that includes an increased exposed surface area.

FIG. 2B shows a cross-sectional view of a sustained release implant of one embodiment of the present invention having a core that includes an increased exposed surface area.

Fig. 2C and 2D show perspective and cross-sectional views, respectively, of a sustained release implant having a core that includes a reduced exposed surface area, according to an embodiment of the present invention.

FIG. 2E illustrates a cross-sectional view of a sustained release implant having a core including an increased exposed surface area with indentations and battlements (castellations) according to one embodiment of the present invention.

Fig. 2F shows a perspective view of a sustained release implant including a core having a bend, according to one embodiment of the present invention.

Fig. 2G shows a perspective view of a sustained release implant of one embodiment of the present invention having a core including a channel having an inner surface.

Fig. 2H shows a perspective view of a sustained release implant of one embodiment of the present invention having a core including fenestrated channels to enhance drug migration.

Fig. 2I shows a perspective view of a sustained release implant having a convex exposed drug core surface according to an embodiment of the present invention.

Fig. 2J shows a side view of a sustained release implant of one embodiment of the present invention having a core including an exposed surface area with several soft brush members extending therefrom.

Fig. 2K shows a side view of a sustained release implant according to an embodiment of the present invention having a drug core including a convex exposed surface and an indwelling structure.

FIG. 2L shows a side view of a sustained release implant according to one embodiment of the present invention having a drug core with a concave indented surface to increase the exposed surface area of the core.

Fig. 2M shows a side view of a sustained release implant according to one embodiment of the present invention having a drug core with a concave surface in which channels are formed to increase the exposed surface area of the core.

Fig. 3A and 3B illustrate an implant including a silicone body, a drug core, and an indwelling structure, according to one embodiment of the present invention.

Fig. 3C shows the implant of fig. 3A inserted into the upper lacrimal duct of the eye.

Fig. 3D shows the implant of fig. 3A in an expanded configuration after implantation into the lacrimal duct of the eye.

Fig. 4A shows a drug core insert suitable for use with an implant according to one embodiment of the present invention.

Figure 4B illustrates an implant suitable for use with a drug core insert according to one embodiment of the present invention.

Figure 4C illustrates a ring-shaped drug core insert suitable for use with an implant for systemic delivery of a therapeutic agent in accordance with an embodiment of the present invention.

Fig. 4D shows an implant suitable for use with the drug core insert described in fig. 4C.

Fig. 4E and 4F show side cross-sectional and end views, respectively, of a drug core insert having two drug cores, according to embodiments of the present invention.

Fig. 5A to 5C schematically illustrate the replacement of the drug core and sheath body according to an embodiment of the present invention.

Fig. 5D and 5E illustrate an implant according to an embodiment of the present invention comprising a filament extending from a drug core insert for removal of the drug core insert from the implant.

Fig. 5F shows an implant according to an embodiment of the present invention including a filament extending along the drug core insert, which is bonded to the distal end of the drug core insert for removal of the drug core insert from the implant body.

Fig. 6A illustrates a method of producing a punctal plug according to an embodiment of the invention.

Fig. 6B shows a method of producing a hydrogel rod according to the method of fig. 6A.

Fig. 6C illustrates a method of molding a silicone stopper according to the method of fig. 6A.

Fig. 6D illustrates a method of assembling a punctal plug member according to the method of fig. 6A.

Fig. 6E illustrates a method of producing a drug core insert according to the method of fig. 6A.

Fig. 6F shows a method 690 of final assembly according to the method 600 of fig. 6A.

Figures 7A and 7B show latanoprost elution data at day 1 and 14 for three core diameters of 0.006, 0.012, and 0.025 inches, and three latanoprost concentrations of approximately 5%, 11%, and 18%, according to embodiments of the invention.

Figure 7C shows elution data for latanoprost from 0.32mm diameter, 0.95mm long drug cores at concentrations of 5, 10, and 20% and drug weights of 3.5, 7, and 14 μ g, respectively, according to embodiments of the present invention.

Fig. 7D and 7E show graphs showing the dependence of latanoprost elution rates at day 1 and day 14 for three core diameters and three concentrations in fig. 7A and 7B on the exposed surface area of the drug core, according to embodiments of the present invention.

Fig. 8 shows elution profiles of cyclosporine from a drug core into a surfactant-free buffer solution and a surfactant-containing buffer solution, according to an embodiment of the present invention.

Figure 9 shows a normalized elution profile in nanograms per day per device over a 100 day period for a bulk sample of silicone containing 1% bimatoprost, according to an embodiment of the invention.

Figure 10 shows a graph of elution of latanoprost from the core of four formulations of latanoprost according to an embodiment of the invention.

Figure 11A shows the effect of material and cross-linking on elution of a drug core with 20% latanoprost, according to an embodiment of the invention.

Figure 11B shows the effect of drug concentration on latanoprost elution, according to an embodiment of the invention.

Fig. 11C illustrates the effect of capping one end of a drug core insert according to an embodiment of the present invention.

Figure 12 shows elution of fluorescein and the effect of a surfactant on fluorescein elution, according to an embodiment of the invention.

Figure 13 illustrates elution of sterile and non-sterile drug cores, according to an embodiment of the present invention.

Figure 14 illustrates the effect of salt on the elution of therapeutic drugs, according to an embodiment of the present invention.

15A-D show scanning electron micrographs of longitudinal sections of silicone/latanoprost drug inserts prepared by the method of the present invention; a, B, = extrusion at and above ambient temperature, C, D = extrusion below ambient temperature.

Fig. 16 shows a plot of latanoprost content per 1mm section of a filled precursor sheath prepared by an extrusion process performed at about 0 ℃, about-25 ℃, about 40 ℃, and room temperature.

Fig. 17 shows an implant including a silicone body, a drug core, and an indwelling structure, in accordance with an embodiment of the present invention.

Fig. 18A illustrates a cross-sectional view of a sustained release implant having a first drug core with a first therapeutic agent and a second drug core with a second therapeutic agent for treating an eye, the first and second drug cores being concentrically arranged, in accordance with an embodiment of the present invention.

Fig. 18B illustrates a side cross-sectional view of the sustained release implant of fig. 18A.

Fig. 19A shows a cross-sectional view of a sustained release implant for treating an eye having a first drug core with a first therapeutic agent and a second drug core with a second therapeutic agent, the first and second drug cores being arranged side-by-side, in accordance with an embodiment of the present invention.

Fig. 19B illustrates a side cross-sectional view of the sustained release implant of fig. 19A.

Fig. 20A shows a cross-sectional view of a sustained release implant having a first drug core with a first therapeutic agent and a second drug core with a second therapeutic agent for treating an eye, the first and second drug cores being concentrically arranged with a hollow center to allow fluid flow through the implant, according to an embodiment of the present invention.

Fig. 20B illustrates a side cross-sectional view of the sustained release implant of fig. 20A.

Fig. 21 schematically illustrates a lacrimal insert in the shape of a punctal plug for use in a therapeutic implant.

Fig. 22 illustrates one embodiment of a therapeutic implant for treating an eye, the therapeutic implant having a punctal plug and a sustained release implant having a drug core containing a first therapeutic agent and a second therapeutic agent.

Fig. 23-25 illustrate different embodiments of therapeutic implants for treating an eye having a punctal plug and a sustained release implant having a first drug core comprising a first therapeutic agent and a second drug core comprising a second therapeutic agent.

Fig. 26A-26C illustrate different embodiments of therapeutic implants for treating an eye that include a punctal plug made of a porous material that is impermeable to drugs, with two therapeutic drugs.

Fig. 27 shows a therapeutic implant containing first and second therapeutic agents when applied to an eye.

Fig. 28 shows a plurality of core elements that may be combined into a cylindrical drug core.

Fig. 29A-29D illustrate different embodiments of cylindrical drug cores using the core member of fig. 28.

Fig. 30A and 30B illustrate other embodiments of cylindrical drug cores resulting from combinations of differently shaped core elements.

Fig. 31 illustrates a cross-sectional view of a sustained release implant for treating an eye having a first drug core comprising a first therapeutic agent and a second drug core comprising a second therapeutic agent, the first and second drug cores being in a stacked arrangement, in accordance with an embodiment of the present invention.

Fig. 32 illustrates one embodiment of a therapeutic implant for treating an eye having a punctal plug and a sustained release implant having a first drug core comprising a first therapeutic agent and a second drug core comprising a second therapeutic agent, the first and second drug cores being in a stacked arrangement, according to an embodiment of the invention.

Fig. 33 illustrates one embodiment of a therapeutic implant for treating a body condition, the implant having a first therapeutic agent and a second therapeutic agent.

Figures 34 and 35 illustrate the anatomical structure of an eye suitable for use with an implant, in accordance with an embodiment of the present invention.

Fig. 36 shows one embodiment of an implant having a curved design.

Detailed Description

Definition of

Unless otherwise indicated, words and phrases in this document have the ordinary meaning as understood by those skilled in the art. Such a general meaning can be obtained by referring to their use in the art and to general and scientific dictionaries such as, for example,Webster’sThird NewInternationalDictionary，Merriam-WebsterInc，Springfield，MA，1993；TheAmericanHeritageDictionaryoftheEnglish Languagehoughton Mifflin, Boston MA, 1981; andHawley’s CondensedChemicalDictionary，14^thedition，WileyEurope，2002。

the following explanation of certain terms is intended to be illustrative and not exhaustive. These terms have the ordinary meanings assigned to their use in the art, and additionally include the following explanations.

As used herein, the term "about" refers to a deviation of 10% of the specified numerical value, e.g., about 50% means a deviation from 45% to 55%.

As used herein, the term "and/or" refers to any one, any combination, or all of the items with which this term is associated.

As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.

As used herein, "subject" or "patient" includes mammals such as humans, non-human primates, rats, mice, dogs, cats, horses, cows, and pigs.

"therapeutic agent" refers to a pharmaceutical compound or mixture thereof that is effective and medically indicated for use in treating a condition in a patient.

By "treating" or "treatment" is meant herein the alleviation of symptoms associated with a disorder or disease, or the inhibition of further progression or worsening of those symptoms, or the prevention or prophylaxis of the disease or disorder. Similarly, as used herein, an "effective amount" as used in the context of a therapeutic drug, or a "therapeutically effective amount" of a therapeutic drug, refers to an amount of drug that completely or partially alleviates the symptoms associated with a disorder or condition, or stops or delays further progression or worsening of those symptoms, or prevents the disorder or condition. In particular, an "effective amount" refers to an amount effective, at dosages and for durations necessary, to achieve the desired therapeutic result. A therapeutically effective amount is also an amount in which any toxic or adverse effects are outweighed by the therapeutically beneficial effects of the compounds of the invention. When the term "effective amount" is used in the context of a functional material, e.g., an effective amount of a dispersant, it is meant that the amount of functional material used is effective to achieve the desired result.

The term "implant" as used herein refers to a physical device adapted to be inserted into or adjacent to a portion of a patient's body, not necessarily surgically placed. For example, insertion of an implant such as a punctal plug through the punctum and into the lacrimal finger of the eye of a patient need not involve surgery, and similarly, placement of a device adapted to remain in contact with the eyeball under the eyelid. The implants are formed of biocompatible materials because the materials actually come into contact with body tissue or fluids as they are propagated to the site of action. As defined herein, an implant is adapted to receive a "drug insert," i.e., a structure containing a therapeutic agent, for administration to a particular patient to treat a particular condition, and to release the therapeutic agent to a target tissue or organ over a period of time. The therapeutic amount of drug released over a period of time is referred to as "sustained release" or "controlled release" as is well known in the art.

The term "eye and surrounding tissue" is meant to include not only the eyeball, but also the surrounding conjunctiva, lacrimal gland, lacrimal duct (a channel that drains tears to the sinuses), eyelids, and related bodily structures.

The term "polymer" as used herein refers to an organic macromolecule comprising one or more repeating units, as is well known in the art. "copolymer" refers to a polymer comprising at least two repeating units. The copolymer may be a block copolymer in which a segment comprising a plurality of a certain type of repeating unit is bonded to a segment comprising a plurality of a second type of repeating unit. The "polymer" or "polymeric material" may be silicone, polyurethane, polyamide, polyester, polysaccharide, polyimide, etc., or any copolymer thereof. The polymeric material is biocompatible when the polymeric material is to contact bodily tissue or fluid.

A "matrix" is a material comprising an organic polymer in which a therapeutic drug is dispersed, the composition of the material, referred to as a "core", serves as a reservoir for the drug, from which the drug is released over a period of time.

The term "precursor" as used and applied to any particular item in the context of the present invention refers to an intermediate or precursor or preceding article, device, item or compound that is subsequently manipulated to form the final article, device, item or compound, etc. For example, a "precursor sheath" is an elongated tube that, after being filled with a matrix and cut, forms a sheath for an insert. In another example of the term as used herein, a "matrix precursor" is "cured" to form a matrix. The matrix precursor may itself be a polymer and may be cured, for example by cross-linking. Alternatively, the matrix precursor may be a polymer dissolved in a solvent, and curing includes removing the solvent to provide the polymer matrix material. Alternatively, the matrix precursor may be a monomer, and curing may involve polymerization of the monomer, and may also involve removal of solvent, and crosslinking of the polymer formed by polymerization. In another example, a prodrug core is a solidified matrix containing the therapeutic drug, which may be cut to an appropriate length to form the drug core. A typical application of a prodrug core is a filled precursor sheath. The filled precursor sheath is a precursor sheath body containing a prodrug core that can be cut to the appropriate length to produce the drug insert of the present invention.

The terms "drug," "therapeutic agent," "drug" as used herein refer to a pharmaceutical substance, compound, or mixture thereof that is suitable and medically useful for treating a condition in a patient. The drug may be in the physical form of a solid or in the physical form of a liquid at about room temperature or at about body temperature, depending on the melting point of the material. Examples of therapeutic drugs are provided herein, and specific examples of the type or kind of drug that may be included in the insert of the present invention for treating disorders of the eye include glaucoma drugs, muscarinic drugs, beta blockers, alpha agonists, carbonic anhydrase inhibitors, or prostaglandins or prostaglandin analogs; an anti-inflammatory agent, an anti-infective agent, a dry eye agent, or any combination thereof. More specifically, examples of glaucoma drugs are prostaglandins or prostaglandin analogs. An example of a muscarinic drug is pilocarpine. An example of a beta blocker is betaxolol. An example of an alpha agonist is brimonidine. Examples of carbonic anhydrase inhibitors are dorzolamide or brinzolamide. Examples of anti-inflammatory agents include steroids, soft steroids, non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen. Examples of analgesics include salicylic acid and acetaminophen. The antibiotic (antibacterial) may be a beta-lactam antibiotic, a macrocyclic antibiotic such as erythromycin, fluoroquinolone, or the like. The antiviral drug compound may be a reverse transcriptase inhibitor or a viral protease inhibitor. The antifungal agent may be a triazole antifungal compound. The dry eye drug may be cyclosporine, olopatadine, a demulcent, or sodium hyaluronate.

In various embodiments, the therapeutic agent is contained in the matrix such that the amount of therapeutic agent in one volumetric portion of the drug core is similar to the amount of therapeutic agent in any other equal volumetric portion of the drug core. For example, the amount of the therapeutic agent within one volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 30%. For example, the amount of the therapeutic agent within one volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 20%. For example, the amount of the therapeutic agent within one volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 10%. For example, the amount of the therapeutic agent within one volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 5%. In addition, the concentration of the therapeutic agent in one volumetric portion of the drug core may be the same as any other equal volumetric portion of the drug core, including in certain embodiments those embodiments in which the agent is present as a homogeneous, homogeneous dispersion and embodiments in which the agent is present as solid or liquid inclusions throughout the matrix.

In some embodiments, the drug may be dissolved in the matrix when the chemical properties of the drug and matrix and the concentration of the drug in the matrix are such that dissolution is achieved. For example, as is known in the art, certain lipophilic steroid derivatives may be dissolved in silicone at significant concentrations. In this case, the drug is said to be "dissolved" in the polymer, either uniformly and homogeneously dispersed throughout the matrix, or "molecularly dispersed" in the polymer (as the compound may be dissolved in the solvent) to form a "solid solution" of the drug in the polymeric material of the matrix.

In other embodiments, the drug is not completely soluble in the matrix, but is present as domains or "inclusions" of the drug in the polymer matrix. The inclusion may be a liquid or a solid at about room temperature or at about the temperature of the human body. After the matrix precursor has cured to form the matrix, the inclusions are unevenly distributed, either in the now solid or in proximity to the solid matrix, and thereby at least to some extent prevent re-association with each other, such as by droplet growth. This form is referred to as "heterogeneous" distribution of the drug in the matrix. Where inclusions of drug are present, it is believed that a certain proportion of the drug may also be dissolved in the matrix. However, dissolution is not necessary for the operation and function of the present invention. Furthermore, the inhomogeneous distribution of the drug with the matrix may be understood at a macroscopic level, as discussed in the following definitions relating to the terms "concentration" and "similar".

The term "concentration" of a therapeutic drug as used herein refers to the concentration of the drug in the macroscopic portion of the matrix-drug core, i.e., it is controlled so as to achieve a degree of reproducibility between different samples of the core. The concentration of the drug in the macroscopic portion of the core may vary, but only to a limited extent, with respect to the concentration in any other equal macroscopic portion of the core. The term does not refer to concentrations at the molecular level in which discrete and/or irregular domains or inclusions of the drug may be present in concentrated form, but rather refers to concentrations greater than at least about 0.1mm³The volume concentration of the drug in the core volume of (a), for example, a cubic core sample having one side of about 100 μm, or a cross-sectional area of about 1mm²0.1mm thick flakes of (a).

The term "similar", as in "similar" concentrations of therapeutic agents, refers to the indicated amount (such as in units of μ g/mm) within the defined tolerance³The concentration of the drug) differ only to some extent between the different measurements. The degree of variation is controlled or adjusted to provide a degree of uniformity of the core material, making multiple cores or inserts medically appropriate in that tissue may be organized between their different samples Providing a dose of the drug within a certain limit. For example, the concentration of "similarity" between two equal volumes of core material, or between two inserts prepared from a filled precursor sheath, may vary by no more than about 30%, or may vary by no more than about 20%, or may vary by no more than about 10%, or may vary by no more than about 5%. The term "similar" also includes solid solutions and homogeneous, homogeneous dispersions as defined herein. These relate to situations where the therapeutic drug concentration is the same in different parts of the core or between cores. This is a subclass of the more general class of "similar".

The inclusions may be of different sizes, and multiple inclusions may have different particle size distributions, as defined herein. By the expression inclusion diameter of no more than about 100 μm, it is meant that the largest inclusion observed within the drug insert of the present invention has a largest dimension of no more than about 100 μm. When a particular size distribution of inclusions is recited, it is meant that a substantial portion of all inclusions have the stated dimensions. When referring to the average size or "average diameter" of inclusions within a population of inclusions, it is meant to refer to the numerical average of the largest dimension of all inclusions. When the expression population of inclusions refers to a "standard deviation" of the distribution of inclusion diameters, it is meant that the distribution of inclusion diameters is normal or near normal, and the standard deviation is a measure of the numerical distribution, as is well known in the art. Small standard deviations from the mean diameter indicate a tight distribution of inclusion diameters, which is a feature of various embodiments of the present invention.

In various embodiments, the inclusions can have a mean diameter of less than about 20 μm, and a standard deviation of the diameters of the inclusions is less than about 8 μm. Alternatively, the inclusions can have a mean diameter of less than about 15 μm and a standard deviation of the diameters of the inclusions of less than about 6 μm. Alternatively, the inclusions can have an average diameter of less than about 10 μm, and a standard deviation of the diameters of the inclusions is less than about 4 μm. The relative uniformity of the distribution of the inclusion size, and the relative uniformity of the amount of drug dispersed per unit volume of the core within the insert, are features of different embodiments of the present invention.

The size distribution of the inclusion diameters may be monodisperse and may be closely monodisperse. By "monodispersity" is meant that the size distribution of the diameters of the plurality of inclusions is relatively tightly centered around the average inclusion diameter, even if the distribution is not a normal distribution. For example, the distribution may have a relatively sharp upper size boundary of inclusions larger than the average diameter, but the distribution of inclusions smaller than the average diameter may be tapered. However, the size distribution may be tightly concentrated or monodisperse.

"polyurethane" refers to various polymers or copolymers comprising repeating units covalently bonded by urethane, i.e., urethane linkages-N-C (O) -O-, where the N and O atoms are attached to organic groups. The organic groups may be aliphatic, aromatic, or mixed, and may contain other functional groups. Each of the atomic groups other than the atomic group at the end of the molecular chain is linked to the other atomic groups through a di (or more) urethane group. The polyurethane polymer contains only urethane-type groups linking the repeating units. Polyurethane copolymers, such as polyurethane-silicone copolymers or polyurethane-carbonate copolymers, contain urethane and other types of groups linking the repeating units, i.e., groups of the silicone and carbonate types, respectively.

The polyurethane-silicone copolymer comprises segments of polyurethane chains and segments of silicone chains, as is well known in the art. The polyurethane-carbonate copolymer comprises urethane segments and carbonate (-O-C (O) O-) segments. An example of a polyurethane-carbonate copolymer is Carbothane(Lubrizol)。

The term 'hydrogel' as used herein refers to a polymeric material that adsorbs more than 100% by weight, for example up to 500-2000% by weight, of water within the polymer structure and thereby swells significantly in physical dimension. Hydrogels have physical integrity, have tensile strength, and are not substantially fluid. A "hydrogel-forming polymer" is a polymeric material that is capable of forming a hydrogel upon contact with water. Examples include TG-500 and TG-2000.

"TG-500" and "TG-2000" are hydrogel-forming polyurethane-type polymers produced by ThermedisPolymer products division of Lubrizol advanced materials, Inc., of Wilmington, MA. They are described by the manufacturer as aliphatic polyether-based thermoplastic polyurethanes capable of forming hydrogels. Such hydrogel-forming polymers can absorb more than 100% by weight, for example up to 500-2000% by weight, of water and thereby swell in physical size.

A "hydrophilic polymer" is a polymer that can be wetted by water, i.e., does not have a water-repellent surface. Hydrophilic polymers can absorb water to a small extent, for example about 0-100% by weight, but do not swell as much in volume as hydrogel-forming polymers.

"Cyclosporin" is an immunosuppressant drug widely used after allogeneic organ transplantation to reduce the activity of the patient's immune system and thereby reduce the risk of organ rejection. It has been studied in the transplantation of skin, heart, kidney, lung, pancreas, bone marrow and small intestine. Cyclosporine (cyclosporine a) originally isolated from norway soil samples is the main form of the drug, an 11 amino acid cyclic non-ribosomal peptide (undecapeptide) produced by the fungus tolypocladium unflatum gams. The structure of cyclosporine is:

The structure of "olopatadine" is shown below, being an NSAID that can be administered as the hydrochloride salt:

a "prodrug" is a substance that, for example, when administered to a mammal, releases a therapeutic drug such as cyclosporine or olopatadine (olopatadine), or a biologically active derivative of any of these substances. Prodrugs may be chemical derivatives comprising a bond that is cleavable by an enzyme endogenous to the mammalian circulatory system, such as an esterase or phosphatase. For example, the amide NH of cyclosporin may be substituted with an ester group to give the carbamate of ROC (O) N-cyclosporin. Endogenous esterases can cleave ester bonds to give N-carboxamides, which can spontaneously decarboxylate to yield cyclosporine. Esters of olopatadine that can be cleaved by endogenous esterases to yield olopatadine are examples of prodrugs of olopatadine. The polarity (hydrophobic/hydrophilic) of cyclosporine or olopatadine can be altered by forming a prodrug.

A "derivative" is a substance that is chemically closely related to a therapeutic agent, which retains at least some of the biological activity of the therapeutic agent, but does not need to be metabolized in a mammalian subject to the agent itself to provide the desired beneficial results.

"release profile" as used in "defined release profile" refers to the release rate of a therapeutic agent from a plug of the present invention into the eye as a function of time, which can be defined or determined by selecting a particular polyurethane polymer or copolymer for a particular therapeutic agent. The release profile, in turn, controls the concentration of the drug in the eye and surrounding tissues over the period of time that the plug releases the drug.

Detailed Description

The present invention relates to various embodiments of a drug insert and drug core comprising a therapeutic drug for use in an implant body adapted for placement in a tissue, fluid, cavity, or passage of a body. The implant body may be adapted to be disposed in or adjacent to an eye of a patient. The implant releases a drug to the body over a period of time, e.g., into the eye or surrounding tissue or both, for treating a patient's medical condition for which the therapeutic drug is applicable. The present invention also relates to various embodiments of methods of producing a drug insert, and to various embodiments of methods of treating a patient using an implant comprising a drug insert.

In various embodiments, the present invention provides a drug core adapted to be disposed within a sheath and thereby within an implant. The implant is adapted for placement in or adjacent to the eye of a patient for providing sustained release of a therapeutic agent to the eye or surrounding tissue or both.

The drug core includes a therapeutic agent and a matrix, wherein the matrix includes a polymer, wherein an amount of the therapeutic agent in a volumetric portion of the drug core is similar to an amount of the therapeutic agent in any other equal volumetric portion of the drug core.

The insert includes a drug core and a sheath body partially covering the drug core. For example, the amount of the therapeutic agent in the volumetric portion of the drug core differs from the amount of the therapeutic agent in any other equal volumetric portion of the drug core by less than about 30%. For example, the amount of the therapeutic agent in the volumetric portion of the drug core differs from the amount of the therapeutic agent in any other equal volumetric portion of the drug core by less than about 20%. For example, the amount of the therapeutic agent in the volumetric portion of the drug core differs from the amount of the therapeutic agent in any other equal volumetric portion of the drug core by less than about 10%. For example, the amount of the therapeutic agent in the volumetric portion of the drug core differs from the amount of the therapeutic agent in any other equal volumetric portion of the drug core by less than about 5%.

The sheath body is disposed over a portion of the drug core for inhibiting release of the drug from the portion upon insertion of the implant into a patient and thereby defines at least one exposed surface of the drug core adapted to release the drug to the eye or surrounding tissue or both.

In various embodiments, the present invention provides a plurality of drug inserts as described above, wherein each of the plurality of inserts includes a similar amount of drug dispersed therebetween, respectively. For example, similar amounts of drug dispersed therein, respectively, may differ by no more than about 30%. For example, similar amounts of drug dispersed therein, respectively, may differ by no more than about 20%. For example, similar amounts of drug dispersed therein, respectively, may differ by no more than about 10%. For example, similar amounts of drug dispersed therein, respectively, may differ by no more than about 5%.

The exposed surface of the core is adapted to release a therapeutic amount of the drug to body tissue or fluid, such as into tear fluid, over a period of at least several days upon insertion of the implant into a patient. The drug impermeable sheath is used to at least partially block exposure of non-target tissue to the drug. For example, when a drug insert is disposed within an implant inserted into the lacrimal duct of an eye, the sheath serves to inhibit release of the drug to a therapeutic target (e.g., the eye) while blocking release to non-target tissues, such as the interior of the lacrimal duct, or the paranasal sinuses.

In one embodiment, the drug core may be substantially cylindrical with an axis, wherein the exposed surface of the drug core is disposed on one end of the cylinder, and the surface of the drug core covered by the sheath body comprises the remainder of the cylindrical surface.

In the multiple drug inserts of the present invention, the therapeutic amount of drug released by each drug insert is similar between different inserts. For example, in a plurality of drug inserts of the present invention, the therapeutic amount of drug released by each of the plurality of inserts may differ by no more than about 30% therebetween, or by no more than about 20% therebetween, or by no more than about 10% therebetween, or by no more than about 5% therebetween. In some embodiments, in the plurality of drug inserts of the present invention, the therapeutic amount of drug released by each of the plurality of inserts may be the same.

The drug core or drug insert may have different relative amounts of therapeutic drug therein. For example, the drug core may include about 0.1% to about 50% by weight of the drug. The drug is dispersed within a matrix (the matrix including a polymer) to form a composite material that can be disposed within the sheath. For example, the matrix may be formed of a non-biodegradable silicone or polyurethane or a combination thereof. The sheath is formed of a substantially drug impermeable substance so as to block release of the drug other than through the exposed surface. It may be formed of any suitable biocompatible material, such as a polymer comprising at least one of polyimide, PMMA, or PET, wherein the polymer is extruded or cast, and a metal comprising stainless steel or titanium.

Therapeutic agents for use in the insert or core of the invention may include anti-glaucoma drugs (e.g., adrenergic agonists, adrenergic antagonists (beta blockers), carbonic anhydrase inhibitors (CAI, systemic and topical), parasympathomimetics, prostaglandins such as latanoprost and hypotensives, lipids, and combinations thereof), antimicrobials (e.g., antibiotics, antivirals, antiparasitics, antifungals, etc.), corticosteroids or other anti-inflammatory drugs (e.g., NSAIDs or other analgesics and compounds that treat pain) such as cyclosporine or oloridine (olopatidine), decongestants (e.g., vasoconstrictors), drugs that prevent or modify allergic responses (e.g., antihistamines, cytokine inhibitors, leukotriene inhibitors, IgE inhibitors, immunomodulators such as cyclosporine), mast cell stabilizers, Cycloplegic, mydriatic, etc.

Examples of drugs additionally include, but are not limited to, coagulation inhibitors; antithrombotic agents, thrombolytic agents; a fibrinolytic agent; an inhibitor of vasospasm; a vasodilator; anti-hypertensive agents; antimicrobial agents, such as antibiotics (such as tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, cephalexin, oxytetracycline, chloramphenicol, rifampin, ciprofloxacin, tobramycin, gentamicin, erythromycin, penicillin, sulfonamide, sulfadiazine, sulfacetamide, sulfamethoxazole, sulfisoxazole, nitrofurazone, sodium propionate), antifungal agents (such as amphotericin B and miconazole), and antiviral agents (such as idoxuridine, acyclovir, ganciclovir (ganciclovir), interferon); surface glycoprotein receptor inhibitors; anti-platelet agents; an anti-mitotic agent; a microtubule inhibitor; an antisecretory agent; an activity inhibitor; a remodeling inhibitor; an antisense nucleotide; an antimetabolite; antiproliferative agents (including anti-angiogenic agents); chemotherapeutic agents for cancer; anti-inflammatory agents (such as cyclosporin, olopatadine, hydrocortisone acetate, dexamethasone 21-phosphate, fluocinolone, medrysone, methylprednisolone, prednisolone 21-phosphate, prednisolone acetate, fluoromethalone, betamethasone, triamcinolone acetonide); non-steroidal anti-inflammatory drugs (NSAIDs) (such as salicylates, indomethacin, ibuprofen, diclofenac, flurbiprofen, piroxicam, indomethacin, ibuprofen, naproxen (naxopren), piroxicam, and nabumetone). Examples of such anti-inflammatory steroids contemplated for use in the punctal plugs of the invention include triamcinolone acetonide and corticosteroids, including, for example, triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone, fluorometholone, and derivatives thereof); anti-allergic agents (such as cromolyn sodium, antazoline, methapyriline, chlorpheniramine, cetirizine, mepyramine, pheniramine); antiproliferative agents (such as 1, 3-cis retinoic acid, 5-fluorouracil, paclitaxel, rapamycin, mitomycin C, and cisplatin); decongestants (such as phenylephrine, naphazoline, tetrahydrozoline); miotics and anticholinesterases (such as pilocarpine, salicylate, carbachol, chloroacetylcholine, physostigmine, diisopropylfluorophosphoric acid, diethoxyphosphorylthiocholine iodide, dimethomonium bromide); antineoplastic agents (such as carmustine, cisplatin, fluorouracil); immunological agents (such as vaccines and immunostimulants); hormonal agents (such as estrogen, estradiol, progestagen (progestational), progesterone, insulin, calcitonin, parathyroid hormone, peptide and vasopressin hypothalamic releasing factor); immunosuppressants, growth hormone antagonists, growth factors (such as epidermal growth factor, fibroblast growth factor, platelet derived growth factor, transforming growth factor beta, growth hormone (somatotripin), fibronectin); angiogenesis inhibitors (such as angiostatin, anecortavacetate, thrombospondin, anti-VEGF antibodies); a dopamine agonist; a radiotherapeutic agent; a peptide; a protein; an enzyme; an extracellular matrix; compounding agent; an ACE inhibitor; a free radical scavenger; a chelating agent; an antioxidant; (ii) resistance to polymerase; a photodynamic therapeutic agent; a gene therapy drug; and other therapeutic agents such as prostaglandins, anti-prostaglandins, prostaglandin precursors, including anti-glaucoma agents including beta-blockers such as timolol, betaxolol, levobunolol, atenolol, and prostaglandin analogs such as bimatoprost, travoprost, latanoprost, and the like; carbonic anhydrase inhibitors such as acetazolamide, dorzolamide, brinzolamide, methazolamide, dichlorfenamide, acetazolamide; and neuroprotective agents such as lubezole, nimodipine, and related compounds; and parasympathetic function-like drugs such as pilocarpine, carbachol, physostigmine, and the like.

Additional drugs that may be used with the implants of the present invention include, but are not limited to, drugs that have been approved in accordance with the Section505 of the United states Federal food, Drug, and clinical laboratory service or in accordance with the public health service Act, some of which may be at the U.S. Food and Drug Administration (FDA) sitehttp://www.accessdata.fda.gov/scripts/cder/drugsatfda /indexAnd finding. The punctal plugs of the invention can also be used with drugs listed on OrangeBook (paper or electronic) which can be found at the FDAOrangeBook website (http:// www.fda.gov/cder/ob /), which can have the same date as the filing date of this patent document, or have an earlier or later date. For example, these drugs may include dorzolamide, olopatadine, travoprost, bimatoprost, cyclosporine, brimonidine, moxifloxacin, tobramycin, brinzolamide, acyclovir, timolol maleate, ketorolac tromethamine, prednisolone acetate, sodium hyaluronate, nepafenac, bromfenac, diclofenac, flurbiprofen, suprofnac, binoxan, patanol, dexamethasone/tobramycin compositions, moxifloxacin, or acyclovir, among others.

In various embodiments, the drug may be cyclosporine or a prodrug or derivative thereof, or olopatadine or a prodrug or derivative thereof, and optionally the second drug is selected from the list of therapeutic drugs listed above.

In various embodiments, the drug may be a prostaglandin analog, such as latanoprost, bimatoprost, or travoprost, and the amount of drug in the drug insert may be about 10-50 μ g.

In various embodiments, the therapeutic agent is contained in the matrix such that the amount of therapeutic agent in one volumetric portion of the drug core is similar to the amount of therapeutic agent in any other equal volumetric portion of the drug core. For example, the amount of the therapeutic agent within one volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 30%. For example, the amount of the therapeutic agent within one volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 20%. For example, the amount of the therapeutic agent within one volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 10%. For example, the amount of the therapeutic agent within one volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 5%. In addition, the concentration of the therapeutic agent in one volumetric portion of the drug core may be the same as any other equal volumetric portion of the drug core, including in certain embodiments those embodiments in which the agent is present as a homogeneous, homogeneous dispersion and embodiments in which the agent is present as solid or liquid inclusions throughout the matrix.

In various embodiments, the drug may be dissolved in the matrix within the drug core used with the implant, i.e., at an effective concentration, wherein the drug is sufficiently soluble in the polymer such that no inclusions or concentrated domains of the drug are present. This is known in the art as a solid solution, i.e. a homogeneous, homogeneous dispersion on the molecular level, in which the solid polymer acts as a solvent and no liquid solvent is present. For example, where the drug comprises cyclosporin and the matrix comprises polyurethane, a solid solution is formed at a useful concentration of cyclosporin in the insert. This solubility is believed to result, at least in part, from the interaction of a large number of amide linkages in the cyclosporine (which is a cyclic peptide) molecule with the amide-like urethane linkages of the polyurethane polymer.

In various embodiments, the drug is not sufficiently soluble in the matrix to form a solid solution. In these embodiments, the drug may be distributed at least partially throughout the matrix as a plurality of solid or liquid inclusions, the inclusions comprising droplets of the drug having a diameter of no greater than about 100 μm (when the drug is liquid at about 20 ℃), or particles of the drug having a diameter of no greater than about 100 μm (when the drug is solid at about 20 ℃); wherein the inclusions of drug are dispersed throughout each drug core.

As discussed above, the size and size distribution of the inclusions can have an effect on the release rate of the drug from the drug core to the patient. For example, smaller, more uniform inclusions can be used to more effectively infuse large quantities of matrix and drug at higher rates due to the more favorable surface area to volume ratio. Thus, the method of the present invention provides for controlling or adjusting the average diameter of the inclusions or the distribution of the diameters of the inclusions. For example, the inclusions have an average diameter of less than about 20 μm. Such average diameter inclusions may have a standard deviation of diameters of inclusions of less than about 8 μm. For example, the inclusions have an average diameter of less than about 15 μm. Such average diameter inclusions may have a standard deviation of diameters of inclusions of less than about 6 μm. Alternatively, the inclusions have an average diameter of less than about 10 μm. Such average diameter inclusions may have a standard deviation of diameters of inclusions of less than about 4 μm. In various embodiments, the distribution of diameters of the inclusions can be a monodisperse distribution. In various embodiments, the inclusions comprise predominantly a cross-sectional size of about 0.1 μm to about 50 μm. A close distribution or monodisperse distribution of inclusion diameters is considered advantageous from a therapeutic perspective for drug cores or drug inserts comprising cores.

Various embodiments of the present invention also provide a drug core or an insert comprising a drug core, wherein the drug forms inclusions in the matrix that are in a liquid physical state at about 20 ℃. For example, substantially all of the inclusions are droplets of the drug within the matrix having a diameter of less than about 30 μm. Also, the droplets may have an average diameter of less than about 10 μm, or may have a standard deviation of inclusion diameters of less than about 4 μm. An example of a drug that is in a liquid physical state at about 20 ℃ is latanoprost.

Various embodiments of the present invention also provide a drug core or an insert comprising a drug core, wherein the drug forms an inclusion in the matrix that is in a solid physical state at about 20 ℃. For example, substantially all of the inclusions are drug particles having a diameter of less than about 30 μm within the matrix. For example, the average particle diameter within the matrix is about 5-50 μm. Examples of drugs that are in a solid physical state at about 20 ℃ include bimatoprost, olopatadine, or cyclosporine.

In various embodiments, the drug insert or drug core may include two or more therapeutic drugs, or may include multiple drug cores. Such a multi-drug core may also be referred to as multiple drug sub-cores, which together form an overall drug core. In this case, for clarity, the first and second drug cores may also be referred to as first and second drug sub-cores. For example, a drug insert of the present invention may include two drug cores disposed within a sheath body, the first drug core including a first drug and a first matrix, the second drug core including a second drug and a second matrix, wherein the first drug and the second drug are different, the first matrix and the second matrix being the same or different from each other; the implant body includes an aperture adapted to receive first and second cores disposed within the sheath body, and the drug core is adapted to be disposed within the aperture of the implant body within the sheath. The first matrix and the second matrix may differ from each other in at least one of composition, area of exposed surface, surfactant, cross-linking agent, additive, matrix material, formulation, release rate modifying agent, or stability. The first drug core and the second drug core may be disposed within the sheath body such that, upon disposing the drug insert within the implant body and disposing the implant body in or adjacent to the eye of the patient, the first drug core has a surface that is directly exposed to tear fluid and the second drug core does not have a surface that is directly exposed to tear fluid. Alternatively, the first drug core and the second drug core may be disposed side-by-side within the sheath body. Alternatively, the first drug core and the second drug core may each be cylindrical and provided with a sheath body, the first drug core being positioned near a proximal end of an aperture in the implant body and the second drug core being positioned near a distal end of the aperture when the drug insert is disposed within the implant body. Alternatively, the first drug core and the second drug core may each be cylindrical, provided that the first drug core has a first central opening, the drug core within the sheath body being concentrically positioned within the aperture of the implant body adapted to receive the drug insert, and the second drug core being configured to fit within the first central opening of the first drug core. Alternatively, the first and second drug cores may be concentrically positioned within an orifice of the implant body, the first drug core having a first central opening exposing the first inner surface, the second drug core having a second central opening exposing the second inner surface, the second drug core being configured to fit within the first central opening of the first drug core, and wherein the orifice extends from the proximal end to the distal end of the implant body and is adapted to allow tear fluid to pass through the orifice and contact the first and second inner surfaces of the first and second central openings and release the first and second therapeutic agents into the lacrimal duct of the patient upon insertion of the implant body into the patient.

In various embodiments, the first therapeutic agent can have a release profile in which the first agent is released at therapeutic levels over a first time period, and the second therapeutic agent has a second release profile in which the second agent is released at therapeutic levels over a second time period. For example, the first time period and the second time period may be one week to five years. The first and second release characteristics may be substantially the same, or may be different.

In various embodiments, a first drug provides a first effect and a side effect to a patient, and a second drug can provide a second effect that alleviates or counteracts the side effect of the first drug.

In various embodiments, any inclusions in the first drug core and the second drug core, respectively, have an average diameter of less than about 20 μm, and may have a standard deviation of diameters of less than about 8 μm.

In various embodiments, the implant body can include a central bore extending from the proximal end to the distal end of the implant body so as to be adapted to allow tear fluid to pass through the implant body when the implant body is disposed in or adjacent the eye such that the first and second therapeutic agents are released into the tear fluid into the lacrimal duct of the patient.

In various embodiments, the drug insert or drug core can additionally comprise a drug-impregnated porous material within the first matrix, the second matrix, or both, the drug-impregnated porous material adapted to allow tear fluid to release the first drug, the second drug, or both, at therapeutic levels over a sustained period of time when the implant comprising the drug core is disposed within the punctum or lacrimal canaliculus, wherein the drug-impregnated porous material is a gel material that can expand from a first diameter to a second diameter upon contact with tear fluid. The second diameter is about 50% larger than the first diameter. An example of a suitable material for the drug impregnated porous material is hydroxyethyl methacrylate (HEMA) hydrophilic polymer.

In various embodiments, the drug insert or drug core may comprise a polyurethane polymer or copolymer. For example, the polyurethane polymer or copolymer can be an aliphatic polyurethane, an aromatic polyurethane, a hydrogel-forming polyurethane material, a hydrophilic polyurethane, or a combination thereof. In various embodiments, the polyurethane polymer or copolymer may include a hydrogel adapted to swell upon contact with an aqueous medium, and the sheath body has sufficient elasticity to expand in response to swelling of the hydrogel. For example, the expansion may be adapted to retain the implant body within a channel of the patient, such as within the lacrimal duct.

In various embodiments, where the matrix comprises polyurethane, the therapeutic agent comprises cyclosporine or olopatadine, a prodrug or derivative of cyclosporine or olopatadine, or any combination thereof. For example, cyclosporine or olopatadine, or a cyclosporine prodrug or derivative, or an olopatadine prodrug or derivative, or a combination thereof, may be present in a weight ratio to the polyurethane polymer or copolymer of about 1% to about 70% by weight. The concentration of cyclosporine in the core in the portion of the drug core proximal to the exposed surface, the portion distal to the exposed surface, and the portion disposed between the proximal portion and the distal portion may be similar. For example, the proximal portion may have a length of one tenth of the length of the drug core.

In various embodiments, the present invention provides a drug core comprising a therapeutic drug and a matrix for disposition in a drug insert or implant, wherein the matrix comprises a polymer. The drug insert or implant is adapted for placement in or adjacent to the eye of a patient for providing sustained release of a therapeutic drug to the eye or surrounding tissue or both. The therapeutic agent is contained in the matrix such that the amount of therapeutic agent in one volumetric portion of the drug core is similar to the amount of therapeutic agent in any other equal volumetric portion of the drug core. For example, the therapeutic agent may be uniformly and homogeneously dispersed throughout the matrix, such as in a solid solution, or the therapeutic agent may at least partially form solid or liquid inclusions within the matrix. For example, the amount of the therapeutic agent within one volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 30%. For example, the amount of the therapeutic agent within one volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 20%. For example, the amount of the therapeutic agent within one volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 10%. For example, the amount of the therapeutic agent within one volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 5%. For example, the amount of therapeutic agent within a volumetric portion of the drug core may be the same as the amount of therapeutic agent in any other equal volumetric portion of the drug core.

In various embodiments of the drug insert of the present invention for placement in or adjacent to an eye of a patient, the implant can be a lacrimal implant insertable into a lacrimal duct, commonly referred to as a lacrimal plug, i.e., an implant adapted to be inserted through a punctum into an eye so as to reside within a lacrimal duct of the eye, wherein the drug insert can contact a tear fluid and thereby release a therapeutic drug in contact with the eye or surrounding tissue or both.

In various embodiments, an insert core comprising a drug and a matrix is surrounded by the sheath body, the matrix comprising a polymeric material. The drug is substantially impermeable to the sheath body such that the drug is only released through the exposed surface of the core that contacts the tear fluid. The drug contained within the core acts as a reservoir to release a therapeutic amount or concentration of the drug over a period of time, which may range from days to months. For example, in the treatment of glaucoma, the drug insert may comprise a prostaglandin analog, such as latanoprost.

The drug core is adapted to be disposed in a larger structure (implant), which in turn is adapted to be disposed within a tissue, cavity, or passage of the body. In various embodiments, the implant may be a lacrimal plug adapted to be positioned within a lacrimal canaliculus of an eye, i.e., within a channel that drains tears from a surface of the eye.

For example, different embodiments of the drug core may be used in implants, such as punctal plugs, which are adapted for placement near the eye to treat a patient suffering from an ocular disorder by releasing one or more drugs from the core within the implant onto the surface of the eye, such as by diffusion into the tear fluid. Although specific reference is made to a punctal plug having drug delivery capabilities for use in the lacrimal duct of an eye, different embodiments of the implant can be used for sustained release of drugs and treatment of other structures near and/or within the eye (e.g., sclera, conjunctiva, cul-de-sac of the eyelids, trabecular meshwork, ciliary body, cornea, choroid, suprachoroidal space, sclera, vitreous humor, aqueous humor, and retina). In addition, the implants of the present invention having a core may be used to release therapeutic agents into tissues, body cavities, or passageways other than the eye or adjacent structures. In various embodiments, the drug core may be used to provide sustained release of the therapeutic agent into the ear and/or eustachian tube, nasal and/or sinus cavities, urethra, skin, gastrointestinal tract (including colon, intestinal tract, etc.) and in or near joints such as knee, finger or toe and intervertebral joints.

In various embodiments, a drug core comprising a therapeutic drug complex and a matrix is partially contained within or partially surrounded by a sheath that is substantially impermeable to the drug. The sheath may cover a portion, but not all, of the surface of a core that includes the drug and the matrix material and has an exposed surface such that the therapeutic drug may be released through the exposed surface. The drug core and its sheath together are adapted to be included within an implant structure that is itself adapted to be implanted within a patient, such as within a body cavity, tissue, conduit, or fluid. For example, the implant may be an ocular implant, adapted to be disposed in or around an eye, such as a punctal plug; adapted for placement within the lacrimal duct of the eye such that the drug may be released through the punctum of the eye to contact the eyeball and surrounding tissues.

The sheath may be composed of any suitable biocompatible material that is substantially impermeable to the therapeutic agent. For example, the sheath may be an impermeable polymeric material such as polyimide, polymethylmethacrylate, or a polyester such as PET, or a biocompatible metal such as stainless steel or titanium, or an inorganic glass such as an inorganic glass formed from silica. The drug may be any therapeutic substance that is capable of diffusing through the matrix, at least to some extent, the matrix including a polymer, such that the drug may be released into the tissues or fluids of the body. The matrix may comprise a polymeric material, for example, the matrix may comprise silicone, polyurethane, or any non-biodegradable polymer in which the drug has at least sufficient solubility to diffuse through the matrix. The matrix may comprise other materials including, but not limited to, other types of polymers such as polyolefins, polyamides, polyesters, polyvinyl alcohol, or polyvinyl alcohol or acetate, ethylene-vinyl acetate copolymers, polysaccharides such as cellulose or chitin, and the like, provided that the materials are biocompatible. Thus, the selection of materials for the matrix may be based at least in part on the selected drug for the intended particular application, such that sufficient solubility of the drug in the matrix may be achieved so that therapeutic levels of the drug in the target tissue may be maintained over a period of time.

Other substances may be included in the core along with the matrix, such as release rate modifying substances, such as surfactants, dispersants, fillers, other polymers and oligomers, and the like.

The substantially impermeable sheath prevents the drug from diffusing through. Therefore, the drug diffuses into the surrounding body fluid, tissue, and the like mainly through the core portion not covered by the sheath. The rate of diffusion of the drug into the surrounding body fluids, tissues, etc. is determined at least in part by the rate of diffusion of the drug through the matrix. When the drug molecules reach the exposed surface of the complex and come into contact with the environment, they can diffuse into the surrounding fluid or tissue. In certain embodiments, the therapeutic agent may be initially released into tissue structures adjacent to the target, for example into the punctum of the patient in the vicinity of the target eye tissue, and may thereby diffuse to the site of action.

In various embodiments, the drug is soluble or substantially insoluble in the polymeric matrix material. In embodiments in which the drug is soluble in the polymeric matrix material at the concentration used, the drug core comprises a homogeneous complex in which the drug is dispersed within the polymeric matrix material at the molecular level. For example, highly lipophilic drugs such as norethindrone diacetate can be dissolved in silicone polymers at significant concentrations so that the core can be a homogeneous dispersion of the drug in the matrix at the molecular level. For example, the cyclopeptide analog cyclosporin can be dissolved in significant concentrations in polyurethanes, which are polymers containing linker units similar to amide linkages. In the presence of a homogeneous dispersion of the drug in the matrix, the rate of release of the drug from the exposed surface of the core into the body's fluid or tissue can be controlled by the rate of diffusion or transport of the drug through the matrix. In embodiments where the drug is soluble in the polymeric matrix material, the rate of release of the drug into the tissue or fluid of the body may be determined at least in part by the concentration of the drug dissolved in the matrix of the core. In various embodiments, the concentration of the therapeutic agent dissolved in the matrix may be a saturation concentration. The kinetics of this release may be zero order, first order, or at a fractional order between zero and first order.

In embodiments where the drug is only partially soluble or sparingly soluble or insoluble in the matrix at the concentrations used, the core comprises a heterogeneous composition in which the drug substance is dispersed throughout the polymeric matrix material as solid or liquid inclusions. In the presence of some solubility, but very low solubility, a certain amount of drug will dissolve in the matrix. In various embodiments, the inclusions can have a size of about 0.1 μm to about 100 μm. In the presence of inclusions of the drug in the matrix, the drug may be at least sparingly soluble in the matrix, such that there is at least some diffusion of the drug from the inclusions to the exposed surface of the drug core, such that the drug may diffuse further into the body's fluids or tissues, e.g., the drug may diffuse into tear fluid. Where the drug is insoluble in the matrix, the drug acts as a separate phase-forming domain or inclusion within the matrix, which may cooperate to form microchannels that allow the drug to be transported to the surface of the matrix. In various embodiments, the drug may be transported through channels or pores in the matrix that are permeable to body fluids. In various embodiments, the drug may be transported through pores or channels present in the matrix.

The drug is present in the core at a concentration dispersed in the matrix. The concentration is the concentration of the drug within the macroscopic portion of the matrix-drug core, which is controlled so that there is a similar concentration between different samples of the core. Similar concentrations of the drug in macroscopic portions of the core may vary, but only to a limited extent, with respect to the concentration in any other equal macroscopic portion of the core. The term does not relate to concentrations at the molecular level, where domains or inclusions of the drug may be present in concentrated form, but refers to concentrations greater than at least about 0.1mm³The volume concentration of the drug in the core volume of (a), for example, a cubic core sample having one side of about 100 μm, or a cross-sectional area of about 1mm²0.1mm thick flakes of (a). The concentrations may differ by no more than about 30%, or no more than about 20%, or no more than about 10%, or no more than about 5%.

In various embodiments, the inclusions can have an average diameter of less than about 20 μm, or less than about 15 μm, or less than about 10 μm. The distribution of diameters of the inclusions may be monodisperse, i.e. relatively tightly concentrated around a mean diameter. If the distribution of the diameter of the inclusions is normal or near normal, the monodispersity can be expressed as the standard deviation, and the standard deviation of the diameter of the inclusions can be less than about 8 μm, or less than about 6 μm, or less than about 4 μm.

While not intended to limit the invention, it is believed that factors controlling the release rate of a drug from a substrate into a patient, such as the release of an ophthalmic drug into the tear fluid, are complex and depend on a number of variables. For example, the drug and matrix material may together define the saturation concentration of the drug in the matrix. For some drug-matrix compositions, high concentrations of the drug can be dissolved in the matrix. For other compositions, the saturation concentration is lower. For other compositions, solubility is not present and the release rate is often controlled by a separate domain phase. Another possible factor is the rate of mass transfer of the inclusion to the surface of the substrate. Yet another possible factor is the diffusion rate of the drug from the matrix into body fluids such as tears.

The release rate of the therapeutic amount of the therapeutic agent may be determined, at least in part, by the concentration of the therapeutic agent in the matrix of the drug core. The therapeutic agent may be sufficiently dissolved from the inclusion (if present) in the matrix to maintain the concentration of therapeutic agent dissolved in the matrix such that the release rate remains within the therapeutic window for an extended period of time. This may result in a zero order release rate of the desired drug, as would be the case if there were a true reservoir of drug in the inclusion, while the limited solubility of the matrix of the drug is rate critical in allowing the drug to reach the exposed surface of the core where it can be released into the tear fluid or other medium. In embodiments where the drug is insoluble in the matrix material and forms inclusions, the rate of release of the drug into the body tissue or fluid may be determined at least in part by the concentration of the drug as it diffuses from the inclusions through the discrete domains in the matrix material to the location of exposure to the body tissue or fluid.

In various embodiments, the matrix comprises a release rate modifying material in an amount sufficient to release the therapeutic agent from the drug core in therapeutic amounts over an extended period of time upon implantation. The release rate modifying material may include an inert filler material, a salt, a surfactant, a dispersant, a second polymer, an oligomer, or a combination thereof. For example, the core may include a surfactant or dispersant material, or a filler, oligomer, another polymer, etc., in addition to the one or more drugs and the polymer matrix material. Examples include polymers such as polyethylene glycol (PEG), sodium alginate, low molecular weight silicones or polyurethanes, and the like. Non-polymeric additives may include hydrophilic solvents such as ethylene glycol or glycerol.

In various embodiments, the core comprises from about 5% to about 50% of the drug. Depending on the drug, and the rate of release of the drug from the polymer selected for the matrix, the concentration may control the period of time that the drug is released in therapeutic amounts into a bodily fluid, such as tear fluid.

In various embodiments, as discussed above, the core may include two or more drugs. In certain embodiments, both drugs are substantially soluble in the matrix material. In other embodiments, the first agent is substantially soluble in the matrix material and the second agent forms inclusions within the matrix material. In some embodiments, the implant includes a single drug core with two therapeutic agents mixed within a matrix. In other embodiments, the implant includes two drug cores, each with a separate therapeutic agent.

In some embodiments, the second drug may be a counter-acting drug (counter-active) to avoid side effects of the first therapeutic drug. In one example, the first drug may be a cycloplegic drug, i.e., a drug that blocks accommodation (focusing) of the eye, e.g., atropine or scopolamine, and the second therapeutic drug may be at least one of an anti-glaucoma drug or a miotic drug selected to reduce known cycloplegic drug-induced glaucoma side effects or to cause pupil constriction to counter known mydriatic effects of atropine or scopolamine. The anti-glaucoma agent may include at least one of a sympathomimetic agent, a parasympathetic function-like agent, a beta blocker, a carbonic anhydrase inhibitor, or a prostaglandin analog. In another example, the first therapeutic agent may be a steroid and the second therapeutic agent may be an antibiotic, where the steroid impairs the immune response but the antibiotic provides protection against infection. In another example, the first therapeutic agent may be pilocarpine and the second therapeutic agent may be a non-steroidal anti-inflammatory drug (NSAID). Analgesics may be good companion (compliance) for treatment.

In particular embodiments, the core insert comprises a single drug-matrix complex comprising two drugs therein. In other embodiments, the core insert comprises two separate drug-matrix complexes ("sub-cores" or first and second cores) disposed adjacent to each other within a sheath. The two separate composites may be arranged in concentric spatial configurations, fan-shaped structures, or other forms, provided that when arranged in a tissue, cavity, or passage of a patient's body, the exposed surfaces of both composites are exposed to the tissue or fluid of the body.

In some embodiments, the therapeutic agent may be released with a characteristic that follows the kinetic progression of the release of the therapeutic agent, and the progression is in the range of about zero to about 1. In particular embodiments, the range is from about zero to about 0.5, such as from about zero to about 0.25. The therapeutic agent may be released in a profile that corresponds to a kinetic progression of therapeutic agent release, and the progression is from about zero to about 0.5, with release lasting for at least about one month after structure insertion, e.g., the progression is within the range and release lasts for at least about 3 months after structure insertion.

In various embodiments, the present invention provides a filled precursor sheath adapted to produce a plurality of drug inserts by dividing the filled precursor sheath, each drug insert adapted to be disposed within a respective implant adapted to be disposed within or adjacent to an eye of a patient for sustained release of a therapeutic drug to the eye or surrounding tissue or both. The filled precursor sheath includes a precursor sheath body and a precursor drug core contained therein, the precursor drug core including a therapeutic agent and a matrix, wherein the matrix includes a polymer and a therapeutic agent. In the prodrug core, the amount of therapeutic agent in one volumetric portion of the prodrug core is similar to the amount of therapeutic agent in any other equal volumetric portion of the prodrug core. The drug is substantially impermeable to the precursor sheath body. Each of the plurality of inserts resulting from its division is adapted to release a drug to the eye or surrounding tissue, or both, upon contact with tear fluid. The respective sheath body of each of the plurality of inserts segmented from the filled precursor sheath is disposed over a portion of the respective drug core of each of the plurality of inserts for defining at least one exposed surface of the drug core adapted to release the drug to the eye or surrounding tissue or both when the insert is disposed in the implant and the implant is inserted into the patient. For example, the amount of therapeutic agent in one volumetric portion of the prodrug core may differ from the amount of therapeutic agent in any other equal volumetric portion of the prodrug core by no greater than about 30%. For example, the amount of therapeutic agent in one volumetric portion of the prodrug core may differ from the amount of therapeutic agent in any other equal volumetric portion of the prodrug core by no greater than about 20%. For example, the amount of therapeutic agent in one volumetric portion of the prodrug core may differ from the amount of therapeutic agent in any other equal volumetric portion of the prodrug core by no greater than about 10%. For example, the amount of therapeutic agent in one volumetric portion of the prodrug core may differ from the amount of therapeutic agent in any other equal volumetric portion of the prodrug core by no more than about 5%.

In various embodiments, the filled precursor sheath may be adapted to provide any of the above-described drug inserts by segmenting the filled precursor sheath. In various embodiments, the precursor sheath may be divided by cutting with a blade or with a laser or the like.

In various embodiments, the present invention provides an implant body for placement in or adjacent to an eye of a patient for releasing a therapeutic agent to the eye or surrounding tissue, or both, over a period of time. The implant body includes a channel therein adapted to receive the drug insert such that an exposed surface of the insert is exposed to tear fluid when the insert is disposed within the implant and the implant is disposed in or adjacent the eye. The drug insert includes a substantially drug impermeable sheath body containing a drug core including a therapeutic agent and a matrix including a polymer, wherein an amount of the therapeutic agent in a volumetric portion of the drug core is similar to an amount of the therapeutic agent in any other equal volumetric portion of the drug core. The implant body comprises a biocompatible material and is adapted to be held within or adjacent the eye for a period of time. For example, the amount of the therapeutic agent within one volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 30%. For example, the amount of the therapeutic agent within one volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 20%. For example, the amount of the therapeutic agent within one volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 10%. For example, the amount of the therapeutic agent within one volumetric portion of the drug core may differ from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 5%.

In various embodiments, the exposed surface of the drug core contained within the implant is capable of releasing the therapeutic amount into at least one of the sclera, cornea, or vitreous when the implant is disposed in or adjacent to the eye of the patient. For example, the implant may be a punctal plug adapted to be disposed within a punctum of a patient for release of a drug into tear fluid.

In various embodiments of the inventive method described above, the mixture may additionally include a solvent in which the matrix precursor and the drug are soluble, and the curing may include at least partially removing the solvent after injection into the sheath body or the precursor sheath body, respectively. Curing may involve heating, vacuum treatment, or both. The solvent may be a hydrocarbon, an ester, a halogenated hydrocarbon, an alcohol, an amide, or a combination thereof. For example, where the drug is cyclosporine, the solvent may be a halogenated hydrocarbon.

In various embodiments, curing the mixture may include heating the mixture to a temperature and for a period of time at a relative humidity. For example, the temperature may comprise from about 20 ℃ to about 100 ℃, the relative humidity may comprise from about 40% to about 100%, and the time period may comprise from about 1 minute to about 48 hours. More specifically, the temperature may be at least about 40 ℃, the relative humidity may be at least about 80%, or both. In various embodiments, curing may include the step of polymerizing or crosslinking, or both, the matrix precursor, or both. For example, the polymerization or crosslinking, or both, may be carried out in the presence of a catalyst. For example, the catalyst may be a tin compound or a platinum compound, such as a platinum and vinyl hydride catalyst system or a tin and alkoxy catalyst system.

In various embodiments, the mixture can be prepared by methods including sonication. The matrix precursor and drug may be mixed to provide a well-dispersed emulsion-like complex in which the drug (if insoluble or slightly soluble in the matrix precursor) may be dispersed as small particles or droplets.

In various embodiments, the step of injecting the mixture into the sheath can be performed at a pressure of at least about 40 psi. The mixture can be injected such that the sheath body or the precursor sheath body, respectively, is filled at a rate of no greater than about 0.5 cm/sec.

The injection or extrusion of the mixture comprising the drug and the matrix precursor or matrix may be carried out at room temperature (20 deg.C), or above, or may be carried out at a temperature below room temperature, below 20 deg.C. For example, the injection can be performed wherein the temperature below room temperature includes a temperature of about-50 ℃ to about 20 ℃, or wherein the temperature below room temperature includes a temperature of about-20 ℃ to about 0 ℃.

As discussed below, fig. 15 and 16 provide graphical demonstration of the advantages of sub-ambient extrusion in terms of uniformity of inclusion diameter, and uniformity of distribution of the therapeutic drug throughout the length of the filled precursor sheath. Fig. 15 shows an electron micrograph of a low temperature segment portion (cryogenicology section) of a drug core in which extrusion was performed at different temperatures. As can be seen, the average diameter of the droplets of latanoprost included in the extrusion at 0 ℃ or-25 ℃ is smaller compared to the extrusion at 25 ℃ or at 40 ℃.

In parallel tests described in examples 12 and 13, the average inclusion diameter and diameter size distribution of the latanoprost-silicone mixture was determined at room temperature and when extruded at-5 ℃:

cold extrusion (-5 ℃): 0.006 ± 0.002mm (n =40 inclusions),

room temperature (22 ℃): 0.019 ± 0.019mm (n =40 inclusion),

it is shown that the cold extrusion technique produces inclusions of smaller average diameter and more uniform size than extrusion at ambient temperature.

Fig. 16 graphically shows the latanoprost content in a 10cm precursor sheath filled with latanoprost-silicone mixture as discussed in examples 12 and 13. As can be seen, cold extrusion at-25 ℃ and 0 ℃ (squares) unexpectedly resulted in a more uniform distribution of the therapeutic drug latanoprost in the silicone matrix along the entire length of the 10cm precursor sheath after curing, followed by dividing the precursor sheath into 1mm segments and determining the latanoprost content in each segment (drug insert). Extrusion at room temperature (circles) and at 40 ℃ (triangles) has significantly more variation. This result is significant for the production of medically useful devices in that it is desirable to maintain a uniform content of therapeutic drug in the plurality of drug inserts produced by this method.

In various embodiments, each drug insert may be sealed at one end thereof such that the second end provides an exposed surface for release of the drug when the insert is disposed within the implant and the implant is inserted into the patient. Each drug insert may be sealed at one end thereof using UV-curable adhesives, cyanoacrylates, epoxies, by clamping, using heat welding, or using end caps. In the case of UV-curable adhesives, curing is carried out by irradiation with ultraviolet lamps.

In various embodiments, the method of the present invention additionally comprises inserting each drug insert into the channel of the respective implant body adapted to receive the insert therein after sealing one end of the drug insert.

In various embodiments, where the drug core comprises two drug cores, the first drug core comprises a first drug and a first matrix, the second drug core comprises a second drug and a second matrix, wherein the first drug and the second drug are different and the first matrix and the second matrix are the same or different from each other, the implant body comprises an aperture adapted to receive a drug insert comprising the first and second drug cores, the method can further comprise disposing the drug cores within the insert prior to disposing the insert comprising the drug cores within the aperture of the implant body.

In various embodiments, where the therapeutic agent comprises cyclosporine or olopatadine, a prodrug or derivative of cyclosporine or olopatadine, or any combination thereof, the matrix comprises a polyurethane, and the weight ratio of cyclosporine or olopatadine, or a prodrug or derivative of cyclosporine, or a prodrug or derivative of olopatadine, or a combination thereof to the polyurethane polymer or copolymer is from about 1% to about 70% by weight, the method can comprise forming a mixture by melting and mixing the polyurethane polymer or copolymer and the therapeutic agent. The therapeutic agent may be in molten form in the mixture or may be in solid form in the mixture.

In some embodiments, the matrix includes an inert filler material mixed with the therapeutic agent such that the exposed surface releases the therapeutic agent in a therapeutic amount for a sustained period of time.

In some embodiments, the salt is mixed with the matrix precursor such that, after curing, the exposed surface of the matrix releases the therapeutic agent in therapeutic amounts for a sustained period of time.

In some embodiments, a surfactant is mixed with the matrix precursor such that, after curing, the exposed surface of the matrix releases the therapeutic agent in therapeutic amounts for a sustained period of time.

In some embodiments, the presence of the second polymer or oligomer may be sufficient to alter the release rate of the therapeutic agent after mixing the second polymer or oligomer with the matrix precursor and curing to form the matrix.

Various embodiments of the present invention provide a lacrimal plug for insertion into a lacrimal duct of a patient, the plug comprising a drug core having a distal end and a proximal end, at least the distal end of the drug core having a cross-section suitable for insertion through a punctum, the drug core comprising a polyurethane polymer or copolymer comprising a therapeutic drug deliverable into an eye or surrounding tissue; and a substantially impermeable sheath is disposed over a portion of the drug core to define at least one exposed surface of the drug core, the at least one exposed surface of the drug core being located near the proximal end to contact tear or tear film fluid of the patient and release the therapeutic agent at therapeutic levels for a sustained period of time when the plug is implanted for use within a lacrimal canaliculus of the patient. The stopper of the present invention comprises a core containing a therapeutic agent therein, which is formed from a polyurethane polymer or copolymer. The polyurethane polymer or copolymer of the core may be an aliphatic polyurethane, an aromatic polyurethane, a hydrogel-forming polyurethane material, a hydrophilic polyurethane, or a combination thereof. For example, the core may be formed from the hydrogel-forming polyurethane material TG-500 or TG-2000 aliphatic, polyether-based thermoplastic polyurethane capable of forming a hydrogel. Such hydrogel-forming polymers can absorb more than 100% by weight, for example up to 500-2000% by weight, of water and thereby swell in physical size. Alternatively, the core may be formed from a hydrophilic polyurethane such as Pursil which swells in a much smaller proportion, about 20-100%, on contact with an aqueous medium. Other examples include Lubrizol products, including Tecophilic grades, such as HP-60D20, HP-60D35, HP-60D60, or HP-93A 100.

In various embodiments, the therapeutic agent may comprise cyclosporine, or a prodrug or derivative of cyclosporine. As is well known in the art, cyclosporine is an immunomodulator and is useful in the treatment of dry eye and inflammation of the eye, such as those caused by allergy. The weight ratio of cyclosporin or a cyclosporin prodrug or derivative to the polyurethane polymer or copolymer, respectively, can range from about 1% up to about 70% by weight, and even greater. The release rate of cyclosporine or prodrug or derivative thereof may be controlled by selecting the particular type of polyurethane used for the core and by adjusting the polarity (hydrophobic/hydrophilic) of the therapeutic drug. Cyclosporine is a fairly hydrophobic compound, but may be made more hydrophilic by the incorporation of functional groups, such as groups that can be cleaved in vivo by endogenous enzymes such as esterases, where the incorporated functional groups may include hydrophilic moieties.

In various embodiments, the therapeutic agent may be olopatadine (olopatadine), or a prodrug or derivative of olopatadine. For example, the drug may be the hydrochloride salt of olopatadine, also known as patanol. When used to treat allergic conjunctivitis (itchy eye), olopatadine inhibits histamine release from mast cells. It is a relatively selective histamine H1 antagonist that inhibits type 1 immediate hypersensitivity reactions in vivo and in vitro, including histamine-induced effects on human conjunctival epithelial cells.

The plug additionally includes a substantially impermeable sheath such that the area for release of the therapeutic agent is defined on at least one exposed surface of the drug core disposed proximate to a punctum of the eye such that the therapeutic agent readily contacts tear fluid and thereby diffuses at the surface of the eye. For example, cyclosporine may be released into tear fluid to help treat dryness or inflammation of the eye, such as inflammation caused by allergy. The sheath may also be adapted to provide a second exposed surface of the drug core near the distal end of the plug for release of the therapeutic drug into the lacrimal duct, if so desired. For example, a second therapeutic agent may be included, such as an antibiotic for treating a lacrimal infection.

The sheath can have sufficient elasticity or flexibility such that the sheath can expand in response to expansion of the hydrophilic polyurethane polymer or copolymer or hydrogel-forming polyurethane polymer or copolymer when the core is expanded in contact with an aqueous medium, such as when the core is constructed from the hydrophilic polyurethane polymer or copolymer or hydrogel-forming polyurethane polymer or copolymer. The expansion is adapted to retain the plug within the lacrimal duct.

The core may additionally comprise a second bioactive agent, such as those described below, such as for use in the treatment of a secondary condition or for use in assisting in the treatment of a condition, for example those for which ciclosporin or olopatadine is medically indicated.

The lacrimal implant may be any suitable shape suitable for insertion into the lacrimal duct of the eye. For example, the implant may be substantially cylindrical when inserted into a canal (canal) prior to expansion of any hydrogel-forming core of the plug. Alternatively, the implant may be tapered in shape, or may be curved in an "L" shape, or may have any other shape that may be disposed within the lacrimal canaliculus of a patient's eye such that the therapeutic agent may be released from the core into the tear fluid that rinses the eye. Thus, when the implant is placed in the lacrimal duct, the core of the implant has an outlet opening to the punctal opening so that the drug can diffuse into the tear fluid and thereby rinse the surface of the eye. In various embodiments, the core has an outlet to the interior of the lacrimal duct for releasing the drug into the interior of the lacrimal duct.

For example, the implant may be in a shape referred to as a "bent-design," as disclosed in a patent application filed concurrently with the present application. For example, the implant may be a structure referred to as an "H-design," as disclosed in a patent application filed concurrently with the present application. Alternatively, the implant may be a structure referred to as a "skeleton" (skeletons), as disclosed in patent applications filed concurrently with the present application.

In various embodiments, a method of producing the implant of the present invention is provided, comprising melting and mixing a polyurethane polymer or copolymer and adding a therapeutic agent to form a mixed melt, and then either casting the mixed melt within a sheath or casting the mixed melt to form a core and then disposing the sheath around the core.

The polyurethane selected to form the core of the implant may be thermoplastic, such that the implant may be produced by a melt extrusion or casting process. For example, a melt of the core polyurethane can be prepared and the therapeutic drug can be incorporated therein. In various embodiments, the drug may be melted at a temperature near the melting point of the suitable polyurethane polymer or copolymer, and the drug may be incorporated in the molten state itself, provided that the melting point is at or below the decomposition temperature of the polyurethane, and the melting point of the polyurethane is below the temperature at which significant thermal decomposition of the drug occurs. For example, cyclosporin melts at about 135 deg.C, TG-500 melts at about 170 deg.C, and TG-2000 melts at about 115 deg.C. Thus, when using TG-2000, a mixed melt can be prepared at a temperature of about 135 ℃ or higher, with both the cyclosporine and the polyurethane core material in a molten state. Higher melting point materials, such as TG-500, may be used if the cyclosporin is stable when it is held at the elevated temperature for a period of time in the process used.

In various embodiments, the drug is not melted in the melted polyurethane, but dispersed therein as a solid in a fine powder form, such as a particulate form. For example, olopatadine, which melts above 200 ℃, can be dispersed in solid form in the melt of the polyurethane. The polyurethane melt containing the solid drug is then cast, optionally within a sheath, to provide the stopper of the invention.

Thus, the implant of the present invention may be formed by a melt-mixing process. For example, the mixed melt may be cast into a mold that has been lined with a higher melting sheath material, which may be a polyurethane that is substantially impermeable and diffusible to cyclosporine. In this way, an implant with a sheath can be prepared. Alternatively, the core may be received in a mold and then coated with a sheath material and cast onto the surface of the implant, except for the areas of the core material that are to remain exposed. Alternatively, the sheath material may be cast to cover the entire implant and then a portion removed to expose the core material at least one location adjacent the proximal end, where the cyclosporin may readily contact tear fluid and thus diffuse into the eye.

In various embodiments, a method of producing the implant of the present invention is provided, comprising dissolving and mixing a polyurethane polymer or copolymer in a solvent containing a therapeutic agent to form a mixed solution, and then either casting the mixed solution within a sheath and then removing the solvent, or casting the mixed solution to form a core and then removing the solvent and then disposing the sheath around the core.

The polyurethane selected to form the core of the implant may be dissolved in an organic solvent, such as methylene chloride or tetrahydrofuran. Many therapeutic agents, such as cyclosporine, are also soluble in many organic solvents, including dichloromethane or tetrahydrofuran. In this way, a mixed solution can be prepared. This solution can then be used to cast the core of the implant by removing the solvent. The solvent may be removed by evaporation, which may be done at ambient conditions, or may involve heating, reduced pressure, or both. After removal of the solvent, the jacket can be coated or cast around the core, either leaving exposed areas of the core or removing a portion of the jacket to provide exposed areas.

In various embodiments, the method of producing the implant of the present invention comprises dissolving the polyurethane polymer or copolymer in a solvent, then adding the therapeutic agent in solid form, the agent being substantially insoluble in the solvent, and then removing the solvent to cast the core. The solid form of the drug may be a fine powder, such as in the form of microparticles, to provide an advantageous surface area to mass ratio. In various embodiments, the implant comprises a dispersion of the drug in solid form in a polyurethane polymer or copolymer.

The polyurethane polymer or copolymer comprising the core may be an aliphatic polyurethane, an aromatic polyurethane, a hydrogel-forming polyurethane material, a hydrophilic polyurethane, or a combination thereof. The particular polyurethane used for the therapeutic drug may be selected so as to control the release profile of the drug over time.

The implants of the invention are useful for treating disorders of the eye or surrounding tissues. For example, implants comprising cyclosporine or olopatadine, or both, may be used to treat ocular disorders involving dry eye or ocular inflammation. The therapeutic agent may be released into the eye and into surrounding tissue, such as the lacrimal canaliculus, over a period of time. The period of time may be from about 1 week to about 6 months. Where expanded polyurethane is used, the expansion of the implant may be used to secure the plug within the lacrimal canaliculus for the entire period of time suitable for drug release.

In various embodiments, the present invention provides a drug insert prepared by the methods of the present invention.

In various embodiments, the present invention provides methods of treating a condition in a patient in need thereof, comprising disposing an implant comprising a drug insert of the present invention, or a drug core obtained by dividing a filled precursor sheath of the present invention, or a drug implant of the present invention, or a drug insert prepared by a method of the present invention, in or adjacent to an eye of a patient such that the drug is released into body tissue or fluid, wherein the therapeutic drug is suitable for treating the condition.

In various embodiments, the present invention provides the use of a drug insert of the present invention, or a drug core obtained by dividing a filled precursor sheath of the present invention, or an implant of the present invention, or a drug insert prepared by a method of the present invention, for the manufacture of an implant suitable for treating a condition in a patient in need thereof.

In various embodiments, the present invention provides a drug insert adapted for placement within a punctal plug for sustained release of latanoprost for the eye to treat glaucoma, the insert comprising a drug core and a sheath body partially covering the drug core, the core comprising latanoprost and a matrix, wherein the matrix comprises a silicone polymer, the latanoprost being dispersed as droplets thereof within the silicone, wherein the amount of latanoprost in a volumetric portion of the drug core is similar to the amount of latanoprost in any other equal volumetric portion of the drug core, the sheath body being disposed over a portion of the drug core so as to inhibit release of latanoprost from the portion, an exposed surface of the core not covered by the sheath body being adapted to release latanoprost to the eye.

In various embodiments, the present invention provides a drug insert adapted for disposition within a punctal plug for sustained release of cyclosporine for the eye to treat dry eye or inflammation, the insert comprising a core and a sheath body partially covering the core, the core comprising a cyclosporine and a matrix, wherein the matrix comprises a polyurethane polymer, the cyclosporine dissolved within the polyurethane, wherein the amount of cyclosporine in one volumetric portion of the drug core is similar to the amount of cyclosporine in any other equal volumetric portion of the drug core, the sheath body disposed over a portion of the core so as to inhibit release of cyclosporine from the portion, an exposed surface of the core not covered by the sheath body being adapted to release cyclosporine to the eye.

Discussion of the figures

FIG. lA illustrates a top cross-sectional view of a sustained release implant for treating an optical defect of an eye according to an embodiment of the present invention. The implant 100 includes a drug core 110. The drug core 110 is an implantable structure that holds a therapeutic drug. The drug core 110 includes a matrix 170 containing inclusions 160 of the therapeutic drug. The inclusions 160 typically include the therapeutic drug in a concentrated form, such as a crystalline form, and the therapeutic drug may dissolve in the matrix 170 of the drug core 110 over time. The matrix 170 may comprise a silicone matrix or the like, and the therapeutic drug mixture within the matrix 170 may be non-homogeneous. In many embodiments, the heterogeneous mixture includes a silicone matrix portion saturated with the therapeutic drug and an inclusion portion including therapeutic drug inclusions such that the heterogeneous mixture includes a heterogeneous mixture of phases. In some embodiments, the inclusions 160 comprise droplets of a therapeutic drug oil, for example, latanoprost oil. In some embodiments, the inclusions 160 may include particles of a therapeutic drug, such as solid bimatoprost particles in crystalline form. In many embodiments, the matrix 170 encapsulates the inclusions 160, and the inclusions 160 may include microparticles having a size of about 1 μm to about 100 μm. The encapsulated inclusions are dissolved in a surrounding solid matrix (e.g., silicone) that encapsulates the microparticles such that the matrix 170 is substantially saturated with the therapeutic drug upon release of the therapeutic drug from the core.

The drug core 110 is surrounded by a sheath body 120. The sheath body 120 may be substantially impermeable to the therapeutic agent such that the therapeutic agent is often released from exposed surfaces on the end of the drug core 110 not covered by the sheath body 120. The indwelling structure 130 is connected to the drug core 110 and the sheath body 120. The shape of the retention structure 130 is such as to retain the implant in a hollow tissue structure, such as the punctum of the lacrimal duct as described above.

Occlusion element 140 is disposed over indwelling structure 130 and around indwelling structure 130. Occlusive element 140 is impermeable to tear flow and occludes hollow tissue structures and may also serve to protect the tissue of the tissue structure from the influence of indwelling structure 130 by providing a more favorable tissue-binding surface. The sheath body 120 includes a sheath body portion 150 connected to the indwelling structure 130 to hold the sheath body 120 and the drug core 110. The sheath body portion 150 may include a stop to limit movement of the sheath body 120 and the drug core 110. In many embodiments, the sheath body portion 150 can be formed with a bulbous tip 150B. Bulbous tip 150B may include a convex rounded outer portion that provides atraumatic access when introduced into the lacrimal duct. In many embodiments, the sheath body portion 150B can be integral with the occlusion element 140.

Fig. 1B illustrates a side cross-sectional view of the sustained release implant of fig. 1A. The drug core 110 is cylindrical and is shown as having a circular cross-section. The sheath body 120 includes an annular portion disposed over the drug core 110. Indwelling structure 130 includes several longitudinal struts 131. Longitudinal struts 131 are connected together near the ends of the indwelling structure. Although longitudinal struts are shown, annular struts may also be used. Occlusion element 140 is supported by longitudinal struts 131 of indwelling structure 130 and is disposed over longitudinal struts 131, and occlusion element 140 may comprise a radially expandable membrane or the like.

Fig. 1C shows a perspective view of a sustained release implant 102 with a coil retention structure 132 according to one embodiment of the present invention. The indwelling structure 132 comprises a coil and retains the drug core 112. A lumen (e.g., channel 112C) may extend through the drug core 112 to allow tears to flow through the lumen for delivering the therapeutic drug for nasal and systemic application of the therapeutic drug. In addition to, or in conjunction with, channel 112C, the size of the retention structure 132 and core 112 may allow tears to flow around the drug core and sheath body, while the retention element holds the tear duct tissue away from the drug core. The drug core 112 may be partially covered. The sheath body includes a first component 122A covering the first end of the drug core and a second component 122B covering the second end of the drug core. The occlusive element may be placed over the indwelling structure, and/or the indwelling structure may be dip coated, as described above.

Figure 1D shows a perspective view of a sustained release implant 104 having an indwelling structure 134 which includes a strut, according to one embodiment of the present invention. The retention structure 134 includes longitudinal struts and retains the drug core 114. The drug core 114 is covered with a sheath body 124 over a substantial portion of the drug core 114. The drug core releases the therapeutic drug through the exposed tip and the sheath body 124 is annular over a substantial portion of the drug core, as described above. The occlusive element may be placed on the indwelling structure, or the indwelling structure may be dip coated, as described above. A projection that can engage an instrument such as a hook, loop, suture, or loop 124R extends from the sheath body 124 to allow the drug core and sheath body to be removed together to facilitate replacement of the sheath body and drug core while the indwelling structure remains implanted in the lacrimal duct. In some embodiments, protrusions, which may be engaged with a device including hooks, loops, sutures, or loops, may extend from the retention structure 134 to allow for removal of the sustained release implant by removal of the retention structure, drug core, and sheath body via the protrusions.

Fig. 1E shows a perspective view of a sustained release implant 106 with a caged retention structure 136 in accordance with one embodiment of the present invention. The retention structure 136 comprises several connected metal strands and holds the drug core 116. The drug core 116 is covered with a sheath body 126 over a substantial portion of the drug core 116. The drug core releases the therapeutic drug through the exposed tip and the sheath body 126 is annular over a substantial portion of the drug core, as described above. The occlusive element may be placed over the indwelling structure, and/or the indwelling structure may be dip coated, as described above.

FIG. 1F shows a perspective view of a sustained release implant including a core and a sheath according to one embodiment of the present invention. The drug core 118 is covered with a sheath body 128 over a substantial portion of the drug core 118. The drug core releases the therapeutic drug through the exposed tip and the sheath body 128 is annular over a substantial portion of the drug core, as described above. The therapeutic drug release rate is controlled by the exposed drug core surface area and the materials included within the drug core 118. In many embodiments, the elution rate of the therapeutic drug is strongly and significantly correlated with the area of the exposed surface of the drug core and weakly correlated with the concentration of the drug disposed in the inclusions of the drug core. For a circular exposed surface, the elution rate strongly depends on the diameter of the exposed surface, e.g., the diameter of the exposed drug core surface near the end of the cylindrical drug core. Such implants may be implanted into eye tissue, for example, below the conjunctival tissue layer 9 of the eye, and either above the scleral tissue layer 8, as shown in fig. 1F, or only partially within the scleral tissue layer so as not to penetrate the scleral tissue. It is noted that the drug core 118 may be used with any of the indwelling structures and occlusive members described herein.

In one embodiment, the drug core is implanted between the sclera 8 and conjunctiva 9 without the sheath body 128. In such embodiments without a sheath body, the physical properties of the drug core can be adjusted to compensate for the increase in exposed surface of the drug core, e.g., to reduce the concentration of dissolved therapeutic drug in the drug core matrix, as described herein.

Figure 1G schematically illustrates a perspective view of a sustained release implant 180 including a flow restricting indwelling structure 186, a core 182 and a sheath 184, according to one embodiment of the present invention. The sheath body 184 may at least partially cover the drug core 182. The drug core 182 may contain inclusions of the therapeutic agent therein to provide sustained release of the therapeutic agent. The drug core 182 may include an exposed convex surface region 182A. The exposed convex surface region 182A may provide an increased surface area for the release of the therapeutic agent. An occlusion element 188 may be disposed on the retention structure 186 to block the flow of tears through the lacrimal duct. In many embodiments, an indwelling structure 186 may be located within an occlusive structure 188 to provide an occlusive element integral with the indwelling structure. Flow-restricting retention structure 186 and occlusion element 188 are sized to block tear flow through the lacrimal duct.

The core and sheath bodies described herein can be implanted into various tissues in a variety of ways. Many of the cores and sheaths described herein, particularly the structures described with reference to fig. 2A-2J, may be implanted separately as punctal plugs. Alternatively, many of the cores and sheath bodies described herein may include drug cores, sheath bodies, and the like, for implantation with the indwelling structures and occlusive elements described herein.

Fig. 2A shows a cross-sectional view of a sustained release implant 200 having a core that includes an increased exposed surface area, according to one embodiment of the present invention. The drug core 210 is covered by a sheath body 220. The sheath body 220 includes an opening 220A. The diameter of the opening 220 is close to the maximum cross-sectional diameter of the drug core 210. The drug core 210 includes an exposed surface 210E, which is also referred to as an active surface. The exposed surface 210E includes 3 surfaces: an annular surface 210A, a cylindrical surface 210B, and an end face 210C. The annular surface 210A has an outer diameter that approximates the maximum cross-sectional diameter of the core 210 and an inner diameter that approximates the outer diameter of the cylindrical surface 210B. The end face 210C has a diameter that matches the diameter of the cylindrical surface 210B. The surface area of the exposed surface 210E is the sum of the areas of the annular surface 210A, the cylindrical surface 210B, and the end face 210C. The surface area may be increased by the dimension of the cylindrical surface region 210B extending longitudinally along the axis of the core 210.

Fig. 2B shows a cross-sectional view of a sustained release implant 202 having a core 212 that includes an increased exposed surface area 212A according to one embodiment of the present invention. The sheath body 222 extends over the core 212. The therapeutic agent may be released from the core, as described above. The exposed surface area 212A is generally conical, may be elliptical or spherical, and may extend outwardly from the sheath body to increase the exposed surface area of the drug core 212.

Fig. 2C and 2D show perspective and cross-sectional views, respectively, of a sustained release implant 204 having a drug core 214 that includes a reduced exposed surface area 214A, in accordance with an embodiment of the present invention. The drug core 214 is packaged within the sheath body 224. The sheath body 22 includes an annular end portion 224A defining an opening through which the drug core 214 may extend. The drug core 214 includes an exposed surface 214A for release of the therapeutic agent. The diameter 214D of the exposed surface 214A is less than a maximum dimension, e.g., a maximum diameter, across the drug core 214.

Fig. 2E shows a cross-sectional view of a sustained release implant 206 having a drug core 216 according to one embodiment of the present invention, the 216 comprising an increased exposed surface area with a battlement extending from the drug core. The battlement includes several spaced apart fingers 216F to provide an increased surface area for the exposed surface 216A. In addition to the increased surface area provided by the battlement, the drug core 216 may also include indentations 216I. The indentation 216I may have the shape of an inverted cone. The core 216 is covered by a sheath body 226. The sheath body 226 is open at one end to provide an exposed surface 216A on the drug core 216. The sheath body 226 also includes fingers and has a battlement (nesting) pattern that matches the core 216.

Fig. 2F shows a perspective view of a sustained release implant 250 including a core having a crimp, according to one embodiment of the present invention. Implant 250 includes a core 260 and a sheath body 270. The core 260 has an exposed surface 260A on the end of the core that allows the drug to migrate into the surrounding tear or tear film fluid. The core 260 also includes a bend 260F. The bend 260F increases the surface area of the core that is exposed to the surrounding tear or tear film fluid. By this increase in exposed surface area, the bend 260F increases the migration of the therapeutic agent from the core 260 into the tear or tear film fluid and the targeted treatment area. The bend 260F is formed such that a channel 260C is formed in the core 260. Channel 260C is connected to the end of the core and connects to an opening in exposed surface 260A for the migration of therapeutic agents. Thus, the total exposed surface area of the core 260 includes the exposed surface 260A that is directly exposed to tear or tear film fluid and the surfaces of the folds 260F that are exposed to tear or tear film fluid through the connection of the channels 260C with the exposed surface 260A and tear or tear film fluid.

Fig. 2G shows a perspective view of a sustained release implant of one embodiment of the present invention having a core including a channel having an inner surface. The implant 252 includes a core 262 and a sheath body 272. The core 262 has an exposed surface 262A on the end of the core that allows the drug to migrate into the surrounding tear or tear film fluid. The core 262 also includes a channel 262C. The channel 262C increases the surface area of the channel by forming an inner surface 262P on the inner side of the channel that abuts the core. In some embodiments, the inner exposed surface may also be porous. The channel 262C extends to the end of the core proximate the exposed surface 262A of the core. The surface area of the core exposed to the surrounding tear or tear film fluid may include the inner side of the core 262 exposed to the channel 262C. This increase in exposed surface area may increase the migration of the therapeutic agent from the core 262 into the tear or tear film fluid and the targeted treatment area. Thus, the total exposed surface area of the core 262 includes the exposed surface 262A that is directly exposed to tear or tear film fluid and the inner surface 262P that is exposed to tear or tear film fluid through the connection of the channel 262C with the exposed surface 262A and the tear or tear film fluid.

Fig. 2H shows a perspective view of a sustained release implant 254 having a core 264 according to one embodiment of the invention, the core 264 including channels to enhance drug migration. The implant 254 includes a core 264 and a sheath body 274. The exposed surface 264A is located on the end of the core 264, but the exposed surface may be located elsewhere. Exposed surface 264A allows the drug to migrate to the surrounding tear or tear film fluid. The core 264 also includes a channel 264C. The channel 264C extends to the exposed surface 264. The channel 264C is sufficiently large so that tear or tear film fluid can enter the channel and thereby increase the surface area of the core 264 that is in contact with the tear or tear film fluid. The surface area of the core exposed to the surrounding tear fluid or tear film fluid may include an inner surface 264P of the core 262 defining the channel 264C. By this increase in exposed surface area, channel 264C increases the migration of the therapeutic agent from core 264 into the tear or tear film fluid and the target treatment area. Thus, the total exposed surface area of the core 264 includes the exposed surface 264A that is directly exposed to tear or tear film fluid and the inner surface 264P that is exposed to tear or tear film fluid through the connection of the channels 262C with the exposed surface 264A and tear or tear film fluid.

Fig. 2I shows a perspective view of a sustained release implant 256 having a drug core 266 with a convex exposed surface 266A according to one embodiment of the present invention. The drug core 266 is partially covered with a sheath body 276, the sheath body 276 extending at least partially over the drug core 266 to define a convex exposed surface 266A. The sheath body 276 includes a shaft portion 276S. The convex exposed surface 266A provides an increased exposed surface area over the jacket body. The convex exposed surface 266A has a larger cross-sectional area than the shaft portion 276S of the sheath body 276. In addition to a larger cross-sectional area, the convex exposed surface 266A has a greater surface area due to the convex shape extending outwardly from the core. Sheath body 276 includes several fingers 276F that support drug core 266 in the sheath body, fingers 276F providing support to the drug core to hold drug core 266 in place in sheath body 276. Fingers 276F are spaced apart to allow drug to migrate from the core to tear or tear film fluid between the fingers. The projections 276P extend outwardly on the sheath body 276. The protrusions 276P may be pressed inward to push the drug core 266 out of the sheath body 276. Drug core 266 may be replaced with another drug core after an appropriate time, such as after drug core 266 has released the majority of the therapeutic drug.

Fig. 2J shows a side view of a sustained release implant 258 having a core 268 according to one embodiment of the invention, the core 268 including an exposed surface area having several soft brush-like members 268F. The drug core 268 is partially covered with a sheath body 278, the sheath body 278 extending at least partially over the drug core 268 to define an exposed surface 268A. The sheath body 278 includes a shaft portion 278S. The soft brush members 268F extend outwardly from the drug core 268 and provide an increased exposed surface area for the drug core 268. The soft brush-like members 268F are also soft and resilient and easily flex so that these members do not cause irritation to the adjacent tissue. Although the drug core 268 may be formed from any number of materials as defined above, silicone is a suitable material for producing the drug core 268, and includes materials for producing the soft brush member 268F. Exposed surface 268A of drug core 268 also includes a notch 268I such that at least a portion of exposed surface 268A is concave.

Fig. 2K shows a side view of a sustained release implant 259 having a drug core 269 having a convex exposed surface 269A according to one embodiment of the invention. The drug core 269 is partially covered with a sheath body 279, the sheath body 279 extending at least partially over the drug core 269 to define a convex exposed surface 269A. The sheath body 279 includes a shaft portion 279S. The convex exposed surface 269 provides increased exposed surface area above the jacket body. The convex exposed surface 269A has a larger cross-sectional area than the shaft portion 279S of the sheath body 279. In addition to a larger cross-sectional area, the convex exposed surface 269A has a greater surface area due to the convex shape extending outward from the core. Indwelling structure 289 may be connected to sheath body 279. Indwelling structure 289 may comprise any indwelling structure described herein, for example a coil comprising a superelastic shape memory alloy such as Nitinol. Indwelling structure 289 can be dip coated to make the indwelling structure biocompatible.

Fig. 2L shows a side view of a sustained release implant 230 according to one embodiment of the present invention having a drug core 232 with a concave indented surface 232A to increase the exposed surface area of the core. The sheath body 234 extends at least partially over the drug core 232. A concave indented surface 232A is formed on the exposed end of the drug core 232 to provide an increased exposed surface area for the drug core.

Fig. 2M shows a side view of a sustained release implant 240 according to one embodiment of the present invention having a drug core 242 with a concave surface 242A in which channels 242C are formed to increase the exposed surface area of the core. The sheath body 244 extends at least partially over the drug core 242. A concave indented surface 242A is formed on the exposed end of the drug core 232 to provide an increased exposed surface area for the drug core. Channels 242C are formed in the drug core 242 to provide an increased exposed surface area for the drug core. The channel 242C may extend to the concave indented surface 242A such that the channel 242C provides increased core surface area exposed to the tear or tear film.

Referring now to fig. 3A-3B, an implant, such as a punctal plug 300, is shown, according to one embodiment of the invention, including a silicone body 310, a drug core 320, and an indwelling structure 330. The body 310 includes a proximal channel 314 sized to receive a drug core insert 320. The body 310 includes a distal passage 318. The distal channel 318 may be sized to receive the hydrogel rod 332. The septum 319 may separate the proximal channel from the distal channel. The filament 334 may be embedded in the body 310 and wound around the hydrogel rod 332 to secure the hydrogel rod 332 to the body 310.

The drug core insert 320 may include a sheath 322 that is substantially impermeable to the drug so as to direct the drug toward the exposed surface 326 of the drug core. The drug core 320 may include a silicone matrix 328 in which the inclusions 324 of the drug are encapsulated. Drug core inserts and the production of drug core inserts are described in U.S. patent applications 11/695,537 and 11/695,545. In some embodiments, the body 310 may include an annular rim 315 near the exposed surface 326 that extends into the proximal passageway 314 and bears against the sheath body 322 to retract the sheath body and reduce the exposed surface area of the drug core near the proximal end of the body. In some embodiments, an optional annular rim 315 may bear against the sheath body to retain the drug core in the channel without retracting the sheath body.

Indwelling structure 330 may include hydrogel rod 332, hydrogel coating 336, protuberance 312, and protuberance 316. The hydrogel rod may be inserted through the punctum into the canalicular lumen (canaliculus) in a narrow profile configuration. After insertion into the lumen, hydrogel rod 332 and hydrogel cover 336 may be hydrated and expanded into a wide profile configuration. The protrusions 312 and 316 may hold and/or stabilize the implant 300 within the inner cavity, such as when the hydrogel coating and stem are expanded.

Fig. 3C shows insertion of the lacrimal plug 300 of fig. 3A into an upper lacrimal duct of an eye. The punctal plug 300 can be positioned in the superior lacrimal duct with a hydrogel rod 332 for placement in alignment. The punctal plug 300 can be advanced into the upstanding portion of the lacrimal duct 10V such that the exposed surface of the drug core and the proximal end of the implant are substantially aligned with the exterior of the punctal opening.

Fig. 3D shows the punctal plug of fig. 3A in an expanded configuration after implantation into the lacrimal duct of the eye. Hydrogel rod 332 and hydrogel cover 336 are shown in an expanded, contoured configuration.

Fig. 4 illustrates a drug core insert 400 suitable for use with an implant according to one embodiment of the present invention. The drug core insert includes a first proximal end 402 and a distal end 404. The drug core insert 400 includes a sheath body 410, such as a polyimide tube. The sheath body 410 may comprise a material that is substantially impermeable to the therapeutic agent such that the sheath body may inhibit the flow of the therapeutic agent. Examples of materials that are substantially impermeable to therapeutic agents include polyimide, Polymethylmethacrylate (PMMA), and polyethylene terephthalate (PET). The sheath body 410 includes a first proximal end 412 and a second distal end 414. The drug core insert 400 includes a drug core 420 that includes an inclusion 424 encapsulated in a matrix material 426. The exposed surface 422, including the area on the proximal end of the drug core, is capable of sustained release of the therapeutic drug at therapeutic levels, e.g., therapeutic amounts. In many embodiments, the therapeutic agent is at least partially dissolvable in the matrix material 426 such that the therapeutic agent from the inclusions can penetrate the matrix material, e.g., by diffusion, and be released from the matrix material into the tissue surface and/or body fluid in contact with the exposed surface 422. The material 430 includes the distal end 404 of the drug core insert. In many embodiments, the polyimide tube comprises a cut length of tube, wherein both ends of the tube are cut to expose the drug core. The material 430 may be attached to the distal end of the inserted drug core to inhibit the flow of the therapeutic drug. In many embodiments, material 430 includes an adhesive that is substantially impermeable to the therapeutic agent, such as acrylic, cyanoacrylate, epoxy, urethane, hot melt adhesive, and loctit (tm), using UV curing.

The sheath body 410 is sized to fit within the passage of the implant. The distal end of the drug core insert 404 may be inserted into the implant such that the exposed surface 422 remains exposed as the drug core insert is inserted into the implant.

Fig. 4B shows an implant 450 suitable for use with the drug core insert 400, as in one embodiment of the invention in fig. 4A. Implant 450 includes a proximal end 452 and a distal end 454. Implant 450 includes an indwelling structure 460 including a setback to hold implant 450 in the punctum of the eye. Implant 450 includes a passage 456, passage 456 extending from the interior of the implant to an opening formed in proximal end 452. The channel 456 is sized to receive the drug core insert 400. Drug core insert 400 may be inserted into channel 456 such that distal end 404 of drug core insert 400 is embedded within implant 450, while proximal end 402, including surface 422, is exposed. When implant 450 is placed in the punctum, surface 422 is exposed to the tear fluid of the eye so that a therapeutic agent can be delivered to the eye. In many embodiments, the lacrimal plug has a length of about 2mm and a width of about 1 mm.

A number of implants may be used for drug core insert 400. Some embodiments may use commercially available implants such as SoftPlug silicone punctum plugs available from oasis medical of glendora california, teraapolpunctill plugs available from Medtronic, para pulctill occluder system available from odysseyof memphis, TN, and/or eaglevision plug available from eaglevision of memphis, TN. In some embodiments, the lacrimal plug may comprise a custom-made lacrimal plug, such as a plug sized according to a measurement data selection of the patient. In some embodiments, implants for use with a drug core insert may include implants as described in the following U.S. patent applications: 11/695,537 entitled "DRUGDELIVERY ETHODS, STRUCTURES, ANDCOMPOSITIONS FORNASOLACIMALSYSTEM" filed on 2.4.2007 (attorney docket number SLW2755.001US1); 11/695,545 entitled NASOLCRIMALDAINAGESYSTEMS MIMPLANTSFORDRUGTHERAPY filed on 2.4.2007 (attorney docket number SLW2755.003US1); and 60/871,867 entitled "DRUGDELIVERY IMPLANTSFUNIBINIONOFOPTICADEFECTS", filed on 26.12.2006 (attorney docket number 2755.024PRV), the priority of which is claimed in PCT application PCT/US 2007/088701; and 10/825,047 entitled "DRUGDELIVERY VIAPUNCTALPLUG" filed on 15.4.2004 (attorney docket number SLW2755.025US1).

In some embodiments, the implant may be inserted through the lacrimal punctum and into an associated lacrimal duct, such as shown in fig. 36 and discussed in U.S. patent application _________ (attorney docket No. SLW2755.044US1) entitled "lacrimemplastration enhanced methods," filed concurrently herewith. Insertion of the implant through the lacrimal punctum and into the associated lacrimal duct may allow for one or more of the following: inhibiting or blocking tear flow, for example, for treating dry eye) or for sustained delivery of drugs or other therapeutic agents to the eye (e.g., for treating infection, inflammation, glaucoma, or other ocular diseases or disorders), for sustained delivery of drugs or other therapeutic agents to the nasal passages (e.g., for treating sinus or allergic disorders), or for sustained delivery of drugs or other therapeutic agents to the inner ear system (e.g., for treating vertigo or migraine). The implant may include an implant body including first and second portions, and the implant may extend from a proximal end of the first portion to a distal end of the second portion. In various examples, the proximal end may define a longitudinal proximal axis and the distal end may define a longitudinal distal axis. The implant body can be configured such that, when implanted in a lacrimal punctum and an associated lacrimal duct, there is an included angle of at least 45 ° between the proximal axis and the distal axis for biasing at least a portion of the lacrimal duct against at or more distal of a flexion of the lacrimal duct against at least a portion of the implant body. In some examples, the implant body may be configured such that the included angle is about 45 ° to about 135 °. In such an example, the implant body is configured such that the included angle is about 90 ° (i.e., the included angle is about a right angle). In various examples, the distal end of the first portion may be integrally formed with the second portion at or near the proximal end of the second portion.

In some instances, the implant body may include an angularly disposed cylindrically shaped structure including one or both of a first lumen disposed near the proximal end or a second lumen disposed near the distal end. In such an example, the first lumen extends inwardly from the proximal end of the first portion and the second lumen extends inwardly from the distal end of the second portion. A first drug-releasing drug core insert or other drug-releasing drug core insert may be disposed in the first lumen to provide sustained release of the drug or other therapeutic agent to the eye, while a second drug core insert may be disposed in the second lumen to provide sustained release of the drug or other therapeutic agent to, for example, the nasal passages or inner ear system. The implant body membrane may be positioned between the first lumen and the second lumen and may be used to inhibit or prevent communication of a substance (e.g., a drug) between the first drug core insert and the second drug core insert. In some instances, the implant body is solid and does not include one or more cavities or other pores.

Fig. 4C shows a ring-shaped drug core insert 470 suitable for use with an implant for systemic delivery of a therapeutic drug. The drug core insert 470 includes a sheath body 472 that is substantially impermeable to the therapeutic agent so as to inhibit the flow of the therapeutic agent through the sheath body. The drug core insert 470 includes a solid drug core 474. The drug core 474 includes a matrix material having inclusions of a therapeutic drug dispersed therein, as described above. The drug core 474 includes an exposed surface 478. The drug core 474 includes a generally annular shape with a channel 476 formed therein such that the exposed surface 478 is directed inwardly and exposed to bodily fluids, such as tear fluid, when implanted in the channel. A therapeutic amount (or level) of therapeutic agent can be released from the inner exposed surface 478 to the bodily fluid within the channel.

Fig. 4D shows an implant 480 suitable for use with the drug core described in fig. 4C. Implant 480 includes a body 484 (e.g., a molded silicone body) and a retention structure 482. The passages 486 in the body 484 are sized to receive the drug core insert 470. Implant 480 may include a hydrogel coating 488 on the outside. A hydrogel coating 488 can be positioned adjacent to the retention structure 488. In some embodiments, the hydrogel coating 488 can be positioned distal to the end of the implant 480 such that the hydrogel does not inhibit flow through the channel 476 of the drug core when implanted in a patient. In some embodiments, the indwelling structure may comprise an inflatable coil or stent-like structure having a proximal portion embedded in the body 484 and an exposed distal portion that expands to allow flow through the coil between the punctum and the lacrimal sac, e.g., a shape memory member that can be inflated to secure an implant in the lacrimal duct.

Fig. 4E and 4F show side cross-sectional and end views, respectively, of a drug core insert 490 that includes a first drug core 494 and a second drug core 496. The first drug core 494 comprises an inclusion 494I of a first therapeutic agent and the second drug core 496 comprises an inclusion 496I of a second therapeutic agent. A therapeutic quantity of a first therapeutic agent is released through exposed surface 494S of first drug core 494 and a therapeutic quantity of a second therapeutic agent is released through exposed surface 496S of second drug core 496.

The insert 490 includes an outer sheath body 492 surrounding the drug cores 496 and an inner sheath body 498 disposed between the drug cores 494 and the drug cores 496 to inhibit release of one drug core to the other. Sheath body 492 and sheath body 498 may comprise a substantially impermeable material to the therapeutic agent so as to inhibit the release of the therapeutic agent except on exposed surfaces. In some embodiments, the sheath body can comprise a thin-walled tube.

In some embodiments, the drug core insert may be used with an implant for insertion into tissue in or near the eye, such as the sclera, conjunctiva, cul-de-sac of the eyelids, trabecular meshwork, ciliary body, cornea, choroid, suprachoroidal space, sclera, vitreous humor, aqueous humor, and retina.

In some embodiments, the drug core insert may be produced with a structure that facilitates removal of the drug core insert, such as the filaments described in the following U.S. patent applications: 60/970,696 filed on 9/7/2007 and filed on 9/21/2007 under the title "expandabellanstaolacolorimalidigen mimplaynts" (attorney docket numbers SLW2755.004PRV and 2755.005PRV, respectively) claim priority from said patent application in U.S. patent application ____ filed concurrently herewith.

Fig. 5A to 5C schematically illustrate the replacement of the drug core 510 and the sheath body 520 according to an embodiment of the present invention. The implant 500 includes a drug core 510, a sheath body 520, and an indwelling structure 530. Implant 500 may include an occlusive element supported by indwelling structure 530 and movable with indwelling structure 530. In general, the indwelling structure 530 may assume a first, low profile configuration prior to implantation and a second, high profile configuration after implantation. The retention structure 530 is shown in a high profile configuration and implanted in the lacrimal duct lumen. The sheath body 520 includes an extension portion 525A and an extension portion 525B to connect the sheath body and the drug core to the indwelling structure 530 such that the sheath body and the drug core are retained by the indwelling structure 530. The drug core 510 and sheath body 520 may be removed together by pulling the drug core 510 proximally, as indicated by arrow 530. After drug core 510 and sheath body 520 have been withdrawn, retention structure 530 may remain implanted in the lacrimal tissue, as shown in fig. 5B. A replacement core 560 and replacement sheath body 570 may be inserted together as shown in fig. 5C. Such replacement may be required after the drug core 510 has released an effective amount of the therapeutic drug such that the supply of the therapeutic drug in the drug core is diminished and the release rate of the therapeutic drug approaches a minimally effective level. The replacement sheath body 570 includes an extension portion 575A and an extension portion 575B. The replacement drug core 560 and replacement sheath body 570 may be advanced distally as indicated by arrow 590 to insert the replacement drug core 560 and replacement sheath body 570 into the retention structure 530. The indwelling structure 530 remains in substantially the same location as the replacement drug core 560 and the replacement sheath body 570 are inserted into the resilient member 530.

Fig. 5D and 5E illustrate an implant 800 including a filament 810 according to an embodiment of the present invention, the filament 810 extending from a drug core insert 808 for removing the drug core insert 808 from the implant 800. Implant 800 includes main body 805 and expandable retention structure 820, as described above. The body 810 includes a proximal end 802 and a distal end 803. Implant 800 extends from proximal end 802 to distal end 804 of indwelling structure 820. Implant 800 includes a channel for receiving a drug core insert, as described above. The filaments 810 extend from the proximal end of the drug core insert to the distal end of the drug core insert. The filaments 810 may be molded into the drug core insert. The filaments 840 may include any number of filaments described above, such as sutures, thermoset polymers, shape memory alloys, and the like.

Fig. 5F shows an implant 830 according to an embodiment of the present invention, including a filament 840 extending along a drug core insert 831, which is attached to the distal end of the drug core insert for removal of the drug core insert from body 832. Implant 830 includes a proximal end 833. The filaments 840 may be bonded to the distal end of the drug core insert 831 with an adhesive 842. The filaments 840 may be bonded to the distal end of the drug core insert 831 in a variety of ways, such as with cyanoacrylate, acrylic, epoxy, urethane, hot melt adhesive, and the like.

Sheath body

The sheath body includes suitable shapes and materials to control migration of the therapeutic drug from the drug core. The sheath body houses the core and may fit closely with the core. The sheath body is made of a substantially impermeable material to the therapeutic agent such that the rate of migration of the therapeutic agent can be controlled to a large extent by the exposed surface area of the drug core not covered by the sheath body. In many embodiments, the migration of the therapeutic agent through the sheath body may be about one tenth or less, often one hundredth or less, of the migration of the therapeutic agent through the exposed surface of the drug core. In other words, the migration of the therapeutic agent through the sheath body is at least one order of magnitude less than the migration of the therapeutic agent through the exposed surface of the drug core. Suitable jacket body materials include polyimide, polyethylene terephthalate (hereinafter PET), polymethyl methacrylate (PMMA), stainless steel (e.g., type 316 stainless steel, tube size 25XX), or titanium. The wall thickness of the sheath body is about 0.00025 "to about 0.0015". In some embodiments, the wall thickness may be defined as the distance from the surface of the sheath adjacent the core to the surface of the sheath on the opposite side from the core. The overall diameter of the sheath extending across the core is from about 0.2mm to about 1.2 mm. The core may be formed by dip coating the core in a jacket material. Alternatively or in combination, the sheath body may comprise a tube and a core that are introduced into the sheath, for example as a bodily fluid or solid that may be slid, injected and/or extruded into the sheath body tube. The sheath body may also be dip-coated around the core, such as around a pre-formed core.

The sheath body may be provided with additional features to facilitate clinical application of the implant. For example, the sheath may receive a replaceable drug core, while the indwelling structure and the sheath body remain implanted in the patient. The sheath body may be rigidly attached to an indwelling structure, as described above, the core being replaceable while the indwelling structure remains implanted in the patient. In particular embodiments, the sheath body may have external protrusions that, when squeezed, exert a force on the sheath body and push the core out of the sheath body. Another drug core may then be positioned in the sheath body. In many embodiments, the sheath body and/or the indwelling structure may have a distinguishing feature to show placement, such as a distinguishing color, so that placement of the sheath body and/or indwelling structure in the lacrimal duct or other bodily tissue structure may be easily detected by the patient. The indwelling element and/or sheath body can include at least one marker to indicate a depth of placement in the lacrimal duct such that the indwelling element and/or sheath body can be positioned at a predetermined depth in the lacrimal duct based on the at least one marker.

Indwelling structure

The retention structure comprises a suitable material sized and shaped so that the implant can be easily positioned in a desired tissue location, such as in the lacrimal duct. The indwelling structure may be mechanically stretched and typically expanded to the desired cross-sectional shape, for example, the indwelling structure comprises a superelastic shape memory alloy such as Nitinol. Other materials besides nitinol may also be used, such as elastic metals or polymers, plastically deformable metals or polymers, shape memory polymers, etc., to provide the desired stretch. In some embodiments, fibers of polymers and coatings from Biogeneral, inc. of san diego, California may be used. Many metals may be used, such as stainless steel and non-shape memory alloys and provide the desired stretch. This ability to stretch allows the implant to fit into hollow tissue structures of different sizes, such as 0.3mm to 1.2mm sized lacrimal canaliculus (i.e., one size fits all application sizes). Although individual retention structures may be produced to fit the 0.3-1.2mm canaliculi, a number of alternative retention structures may be used to fit this range, if desired, such as a first retention structure for a 0.3-about 0.9mm canaliculi and a second retention structure for a 0.9-1.2 mm canaliculi. The indwelling structure has a length suitable for the anatomical structure to which it is attached, for example a length of about 3mm for an indwelling structure positioned near the punctum of the lacrimal duct. The length may be adapted to provide sufficient retention for different anatomical structures, for example, 1mm to 15mm in length as desired.

Although the sheath body and the drug core may be attached to one end of the indwelling structure, as described above, in many embodiments, the other end of the indwelling structure is not attached to the drug core and the sheath body, so that the indwelling structure can slide over the sheath body and the drug core as the indwelling structure expands. This ability to slide on one end is desirable because the length of the indwelling structure can contract as it expands to a width exhibiting the desired cross-sectional width. It is noted, however, that many embodiments may use a sheath body that does not slide relative to the core.

In many embodiments, the indwelling structure may be withdrawn from the tissue. There may be protrusions (e.g., hooks, loops, or loops) extending from the indwelling structure to facilitate removal of the indwelling structure.

Occlusion element

The occlusion element comprises a suitable material sized and shaped such that the implant can at least partially inhibit, or even block, the flow of fluid through the hollow tissue structure, such as the flow of lacrimal fluid through the lacrimal duct. The occluding material shown is a thin-walled film of biocompatible material (e.g., silicone) that can expand and contract with the indwelling structure. The occlusive element is formed as a separate thin-walled tube of material that is slid over the end of the indwelling structure and secured to one end of the indwelling structure, as described above. Alternatively, the occlusive element may be formed by dip coating the indwelling structure in a biocompatible polymer (e.g., a silicone polymer). The thickness of the occlusive element can be about 0.01mm to about 0.15mm, often about 0.05mm to 0.1 mm.

Therapeutic agents

The therapeutic agent may include a drug, and may be any one of or their equivalents, derivatives, or analogs, including anti-glaucoma drugs (e.g., adrenergic agonists, adrenergic antagonists (beta blockers), carbonic anhydrase inhibitors (CAI, systemic and topical), parasympathetic function drugs, prostaglandins, prostaglandin analogs, and hypotensive lipids and combinations thereof), antimicrobial agents (e.g., antibiotics, antivirals, antiparacytics, antifungals, etc.), corticosteroids or other anti-inflammatory agents such as olopatadine (e.g., NSAIDs), decongestants (e.g., vasoconstrictors), drugs that prevent or modify allergic responses (e.g., cyclosporine, antihistamines, cytokine inhibitors, leukotriene inhibitors, IgE inhibitors, immunomodulators), mast cell stabilizers, Cycloplegic and the like. Examples of conditions that may be treated with therapeutic drugs include, but are not limited to, glaucoma, pre-and post-surgical treatment, dry eye, and allergy. In some embodiments, the therapeutic agent may be a lubricant or surfactant, such as a lubricant for the treatment of dry eye.

Exemplary therapeutic agents include, but are not limited to, coagulation inhibitors; anti-thrombotic agents; dissolving the blood suppository; a fibrinolytic agent; an inhibitor of vasospasm; a vasodilator; anti-hypertensive agents; antimicrobial agents, such as antibiotics (such as tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, cephalexin, oxytetracycline, chloramphenicol, rifampin, ciprofloxacin, tobramycin, gentamicin, erythromycin, penicillin, sulfonamide, sulfadiazine, sulfacetamide, sulfamethoxazole, sulfisoxazole, nitrofurazone, sodium propionate), antifungal agents (such as amphotericin B and miconazole), and antiviral agents (such as idoxuridine, acyclovir, ganciclovir (ganciclovir), interferon); surface glycoprotein receptor inhibitors; anti-platelet agents; an anti-mitotic agent; a microtubule inhibitor; an antisecretory agent; an activity inhibitor; a remodeling inhibitor; an antisense nucleotide; an antimetabolite; antiproliferative agents (including anti-angiogenic agents); chemotherapeutic agents for cancer; anti-inflammatory agents (such as cyclosporin, olopatadine, hydrocortisone acetate, dexamethasone 21-phosphate, fluocinolone, medrysone, methylprednisolone, prednisolone 21-phosphate, prednisolone acetate, fluoromethalone, betamethasone, triamcinolone acetonide); non-steroidal anti-inflammatory drugs (NSAIDs) (such as salicylates, indomethacin, ibuprofen, diclofenac, flurbiprofen, piroxicam, indomethacin, ibuprofen, naproxen (naxopren), piroxicam, and nabumetone). Such anti-inflammatory steroids contemplated for use in the methods of the present invention include triamcinolone acetonide and corticosteroids, including, for example, triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone, fluorometholone, and derivatives thereof); anti-allergic agents (such as cromolyn sodium, antazoline, methapyriline, chlorpheniramine, cetirizine, mepyramine, pheniramine); antiproliferative agents (such as 1, 3-cis retinoic acid, 5-fluorouracil, paclitaxel, rapamycin, mitomycin C, and cisplatin); decongestants (such as phenylephrine, naphazoline, tetrahydrozoline); miotics and anticholinesterases (such as pilocarpine, salicylate, carbachol, chloroacetylcholine, physostigmine, escein, diisopropylfluorophosphate, diethoxyphosphorylthiocholine iodide, dimethomorph); antineoplastic agents (such as carmustine, cisplatin, fluorouracil); immunological agents (such as vaccines and immunostimulants); hormonal agents (such as estrogen, estradiol, progestagen (progestational), progesterone, insulin, calcitonin, parathyroid hormone, peptide and vasopressin hypothalamic releasing factor); immunosuppressants, growth hormone antagonists, growth factors (such as epidermal growth factor, fibroblast growth factor, platelet derived growth factor, transforming growth factor beta, growth hormone (somatotripin), fibronectin); angiogenesis inhibitors (such as angiostatin, anecortavacetate, thrombospondin, anti-VEGF antibodies); a dopamine agonist; a radiotherapeutic agent; a peptide; a protein; an enzyme; an extracellular matrix; compounding agent; an ACE inhibitor; a free radical scavenger; a chelating agent; an antioxidant; (ii) resistance to polymerase; a photodynamic therapeutic agent; a gene therapy drug; and other therapeutic agents such as prostaglandins, anti-prostaglandins, prostaglandin precursors, including anti-glaucoma agents including beta-blockers such as timolol, betaxolol, levobunolol, atenolol, and prostaglandin analogs such as bimatoprost, travoprost, latanoprost, and the like; carbonic anhydrase inhibitors such as acetazolamide, dorzolamide, brinzolamide, methazolamide, dichlorfenamide, acetazolamide; and neuroprotective agents such as lubezole, nimodipine, and related compounds; and parasympathetic function-like drugs such as pilocarpine, carbachol, physostigmine, and the like.

For ophthalmic applications, some specific therapeutic drugs that may be used include glaucoma drugs (muscarinic drugs, beta blockers, alpha agonists, carbonic anhydrase inhibitors, prostaglandins, and their analogs); anti-inflammatory agents (steroids, soft steroids, NSAIDs); anti-infectives, including antibiotics such as beta lactams, fluoroquinolones, and the like), antiviral agents, and antifungal agents; dry eye drugs (CsA, demulcent, sodium hyaluronate); or a combination thereof.

The amount of drug associated with the drug delivery device may vary depending on the particular drug, the desired therapeutic benefit, and the time over which the device is to deliver the therapeutic drug. Because the devices of the present invention take on a variety of shapes, sizes, and delivery mechanisms, the amount of drug incorporated into the device will depend on the particular disease or condition being treated, as well as the dosage and duration of time over which it is desired to achieve a therapeutic effect. Typically, the amount of drug is at least that amount of drug effective to achieve the desired physiological or pharmacological effect when released from the device.

Embodiments of the drug delivery device of the present invention may be adapted to deliver drugs at a daily rate significantly lower than therapeutically effective, prolonged drops, in order to provide a large therapeutic window with a wide margin of safety. For example, many embodiments treat the eye at therapeutic levels for extended periods of time that do not exceed 5% or 10% of the daily dose of drops. Thus, over an initial period of about seven days, more typically about 1-3 days, the implant may elute the therapeutic agent at a significantly higher rate than the sustained release level, but still below the daily dosage of a drop form. For example, at an average sustained release level of 100ng per day and an initial release rate of 1000-1500ng per day, the amount of drug initially released is less than 2500ng of drug that may be present in one drop of drug delivered to the eye. The use of a sustained release level significantly lower than the amount of drop drug administered per day allows the device to release a therapeutically beneficial amount of drug over a wide safety window to achieve the desired therapeutic benefit while avoiding insufficient or excessive amounts of drug at predetermined locations or areas.

An extension of time may refer to a relatively short period of time, e.g., minutes or hours (such as with anesthetic), days or weeks (such as with pre-or post-operative antibiotics, steroids, or NSAIDs, etc.), or longer (such as in the case of glaucoma treatment), e.g., months or years (repeated use of the device).

For example, a drug such as timolol maleate is a β 1 and β 2 (non-selective) adrenergic receptor blocker and is useful in devices that release over an extended period of time, such as 3 months. Three months is a relatively typical elapsed time between visits to a doctor by glaucoma patients treated with topical drops of glaucoma medication, although the device may provide treatment of longer or shorter duration. In the three month example, a 0.25% concentration of timolol is converted to 2.5-5 mg/1000. mu.L, typically 2.5 mg/1000. mu.L. Drops of timolol for topical administration are usually 40-60. mu.L, typically 50. mu.L. Thus, there may be between.08 and 0.15mg, typically 0.125mg of timolol in one drop. There may be about 8% (e.g. 6-10%) of the drops left in the eye after 5 minutes, so that about 10 μ g of the drug is available at that time. Timolol can have a bioavailability of 30-50% This means that 1.5-7.5. mu.g, e.g. 4. mu.g, of drug is available to the eye. Timolol is typically used twice daily, so the eye can utilize 8 (or 3-15) μ g per day. Thus, the delivery device may contain 270-. The drug is contained within the device and elution is based on the structure of the device, including the polymer used and the surface area available for drug elution. Similarly, a drug may be included on the device and elute olopatadine hydrochloride in a manner similar to timololAnd other drugs.

Commercially available timolol maleate solutions are available as 0.25% and 0.5% preparations, and the initial dose may be 1 drop of the 0.25% solution twice daily. Timolol at a concentration of 0.25% equals 2.5 mg/1000. mu.l. The sustained release of timolol from the drug core per day may be from about 3 to about 15 μ g/day. Although the sustained release amount released from the device per day may vary, a sustained release delivery amount of about 8 μ g per day corresponds to about 3.2% of 0.250mg timolol administered as two drops of a 0.25% solution.

For example, in the case of latanoprost (Xalatan), a prostaglandin F2 alpha analog, the concentration of this glaucoma drug is about one-fiftieth the concentration of timolol. Thus, depending on bioavailability, the amount of drug on the implantable device is significantly less, on the order of 5-135 μ g, typically 10-50 μ g, for latanoprost and other prostaglandin analogs. This also translates into a device that can be smaller than for beta blocker delivery, or can hold more drug for a longer release period.

One drop of Xalatan contained about 2.5 μ g of latanoprost in a drop volume of 50 μ L. Thus, if about 8% of 2.5 μ g were present 5 minutes after instillation, only about 200ng of drug remained on the eye. Based on a clinical trial of latanoprost, this amount is effective in lowering IOP for at least 24 hours. Pfizer/Pharmacia performed several dose-response studies to support the NDA of Xalatan. Latanoprost at a dose of 12.5 μ g/mL to 115/mL. The current dose of latanoprost (50pg/mL once daily) proved to be optimal. However, even with the lowest dose of 12.5. mu.g/mLQD or 15. mu.g/mLBID, IOP reduction of about 60-75% of the 50. mu.g/mLQD dose is constantly administered. Based on the above assumptions, a 12.5 μ g/mL concentration provided 0.625 μ g of latanoprost in 50 μ L drops, with only about 50ng (8%) of drug remaining in the eye after 5 minutes.

In many embodiments, the concentration of latanoprost is about one hundredth (or, 1%) of the concentration of timolol, and in particular embodiments, the concentration of latanoprost may be about one fiftieth (or, 2%) of the concentration of timolol. For example, commercially available latanoprost solution preparations are obtained at a concentration of 0.005%, often delivered in one drop per day. In many embodiments, the therapeutically effective concentration released from the device per day may be about one percent of timolol, from about 30 to 150ng per day, for example about 80ng per day, assuming tear irrigation and bioavailability similar to timolol. For example, for latanoprost and other prostaglandin analogs, the amount of drug on the implantable device can be significantly less, about 1% -2% of timolol, e.g., 2.7-13.5 μ g, and can be about 3-20 μ g. Although the sustained release of latanoprost released per day may vary, a sustained release of 80ng per day corresponds to about 3.2% of 2.5 μ g of latanoprost administered as one drop of 0.005% solution.

For example, in the case of bimatoprost (Lumigan), a synthetic prostamide (prostamide) prostaglandin analog, the concentration of this glaucoma drug is about one twentieth or less of the concentration of timolol. Thus, for bimatoprost and analogues and derivatives thereof, the amount of drug loaded on the delayed release device for 3-6 months delayed release may be significantly less, on the order of 5-30 μ g, typically 10-20 μ g, depending on bioavailability. In many embodiments, the implant can hold more drug for a longer sustained release period, for example 20-40 μ g of bimatoprost and its derivatives for a sustained release period of 6-12 months. This reduction in drug concentration may also translate into a device that may be smaller than that required for beta blocker delivery.

The solution concentration of commercially available bimatoprost is 0.03% by weight, often delivered once per day. Although the sustained release of bimatoprost released per day may vary, a sustained release of 300ng per day corresponds to about 2% of 15 μ g of bimatoprost administered as one drop of 0.03% solution. Work in relation to the present invention suggests that even lower sustained release doses of bimatoprost may provide at least some reduction in intraocular pressure, for example 20-200ng bimatoprost and daily sustained release doses of 0.2-2% of the daily drop dose.

For example, in the case of Travatan (a prostaglandin F2 alpha analog), the concentration of such glaucoma medication may be about 2% or less of the concentration of timolol. For example, commercial solutions are available at concentrations of 0.004%, often delivered once per day. In many embodiments, the therapeutically effective concentration of drug released from the device per day may be about 65ng, assuming tear irrigation and bioavailability similar to timolol. Thus, depending on bioavailability, the amount of drug on the implantable device can be significantly lower. This also translates into a device that can be smaller than for beta blocker delivery, or can hold more drug for a longer release period. For example, for travoprost, latanoprost, and other prostaglandin F2 alpha analogs, the amount of drug on the implantable device can be significantly less, being about 1/100, e.g., 2.7-13.5 μ g, and, typically, about 3-20 μ g of timolol. Although the sustained release of latanoprost released per day may vary, a sustained release of 65ng per day corresponds to about 3.2% of 2.0 μ g latanoprost administered as one drop of 0.004% solution.

In some embodiments, the therapeutic agent may include a corticosteroid, such as fluocinolone acetonide, for treating a target tissue of the eye. In particular embodiments, fluocinolone acetonide may be released from the lacrimal duct and delivered to the retina for the treatment of Diabetic Macular Edema (DME).

It is also within the scope of the present invention to modify or adapt the device to deliver a high release rate, a low release rate, a concentrated release, a burst release, or a combination thereof. Concentrated release of the drug can be achieved by forming an erodible polymeric end cap that dissolves immediately in the tear or tear film. When the polymer end cap contacts the tear or tear film, the solubility properties of the polymer allow the end cap to erode and immediately release all of the drug. Burst release of the drug may be performed using a polymer that is also eroded in the tear or tear film based on the solubility of the polymer. In such an example, the drug and polymer may be layered along the length of the device such that the drug is released immediately as the outer polymer layer dissolves. High or low release rates of the drug can be achieved by changing the solubility of the erodable polymer layer, allowing for rapid or slow release of the drug layer. Other methods of drug release may be achieved by porous membranes, micro-or nano-particle encapsulation of drugs by soluble gels (such as those in typical ophthalmic solutions), depending on the size of the drug molecule.

Drug core

The drug core includes a therapeutic agent and a matrix material for providing sustained release of the therapeutic agent. The matrix material may include a polymer, such as silicone or polyurethane. The therapeutic agent migrates from the drug core to the target tissue (e.g., the ciliary body of the eye). The therapeutic agent may optionally be only sparingly soluble in the matrix, such that a small amount of the therapeutic agent is dissolved in the matrix and available for release from the surface of the drug core 110, and the additional agent is present in the form of inclusions, which may be in a solid or liquid physical state within the matrix. As the therapeutic agent diffuses from the exposed surface of the core to the tear or tear film, the rate of migration from the core to the tear or tear film may be related to the concentration of the therapeutic agent dissolved in the matrix. Additionally or in combination, the rate of migration of the therapeutic agent from the core to the tear or tear film may be related to the nature of the matrix in which the therapeutic agent is dissolved. In particular embodiments, the rate of migration from the drug core to the tear or tear film may be based on a silicone formulation. In some embodiments, the concentration of therapeutic drug dissolved in the drug core can be controlled to provide a desired therapeutic drug release rate. The therapeutic agent included in the core may include a liquid, solid gel, solid crystalline, amorphous solid, solid particulate, and/or dissolved form of the therapeutic agent. In one embodiment, the drug core comprises a silicone matrix comprising the therapeutic drug. The therapeutic agent may comprise liquid or solid inclusions dispersed in a silicone matrix, such as liquid latanoprost droplets or solid bimatoprost particles, respectively. The average diameter and diameter distribution of the droplets or particles can be used to control the elution rate of the drug from the drug core into, for example, the tear fluid of the eye.

In another embodiment, the therapeutic agent may be dissolved in the matrix at a higher level such that inclusions are not formed when the agent is present at a therapeutically useful concentration. For example, cyclosporine may be dissolved in a polyurethane matrix at high concentrations and dispersed at the molecular level throughout the polyurethane matrix, i.e., a "solid solution" of cyclosporine in a polyurethane matrix may be achieved.

Where the inclusion is a solid, various comminuted forms of the solid material may be used to achieve a particular average particle diameter and particle size distribution. Such solid powders may be obtained by any suitable method known in the art. See, for example, the machine manufactured by glatt gmbh for the pharmaceutical industry,http://www.glatt.com/e/00_home/00.htm. During the comminution process, a range of sizes are produced. Fluidized beds and coaters can be used to increase the particle size to a desired size. Particle size affects surface area and may affect dissolution. The inclusion size and associated size distribution can be used to control the rate of elution of the drug from the drug core in both cases, where the inclusion is a solid (such as bimatoprost) and where the inclusion is a liquid (such as latanoprost oil).

The drug core may include one or more biocompatible materials capable of providing sustained release of the therapeutic agent. Although the above references includeEmbodiments of the matrix of the substantially non-biodegradable silicone matrix of dissolved forms of drug inclusions positioned therein describe a drug core, but the drug core may include structures that provide sustained release of the therapeutic drug, such as biodegradable matrices, porous drug cores, liquid drug cores, and solid drug cores. The matrix containing the therapeutic agent may be formed from biodegradable or non-biodegradable polymers. The non-biodegradable drug core may include silicones, acrylates, polyethylenes, polyurethanes, hydrogels, polyesters (e.g., available from e.i. dupont DE nemours and company, Wilmington, DE)) Polypropylene, Polytetrafluoroethylene (PTFE), expanded PTFE (eptfe), Polyetheretherketone (PEEK), nylon, extruded collagen, polymeric foam, silicone rubber, polyethylene terephthalate, very high molecular weight polyethylene, polycarbonate urethane, polyurethane, polyimide, stainless steel, nickel-titanium alloys (e.g., Nitinol), titanium, stainless steel, cobalt-chromium alloys (e.g., mElginSpecialtymetals, Elgin, IL; obtained from CarpentermetalsCorp, Wyomissing, Pa). The biodegradable drug core may include one or more biodegradable polymers such as proteins, hydrogels, polyglycolic acid (PGA), polylactic acid (PLA), poly (levolactic acid) (PLLA), poly (L-glycolic acid) (PLGA), polyglycolide, poly L-lactide, poly D-lactide, poly (amino acids), polydioxanone (polydioxanone), polycaprolactone, polygluconate, polylactic acid-polyethylene oxide copolymers, modified celluloses, collagen, polyorthoesters, polyhydroxybutyrates, polyanhydrides, polyphosphoesters, poly (alpha-hydroxy acids), and combinations thereof. In some embodiments, the drug core may include at least one hydrogel polymer.

Release of therapeutic agents at effective levels

The release rate of the therapeutic agent may be related to the concentration of the therapeutic agent in the drug core. In many embodiments, the drug core includes a non-therapeutic drug substance selected to provide a desired solubility of the therapeutic drug in the drug core. The non-therapeutic drug substance of the drug core may include polymers and additives as described herein. The polymer of the core may be selected to provide the desired solubility and/or dispersibility of the therapeutic agent in the matrix. For example, the core may include a hydrogel that may promote the solubility or dispersibility of a hydrophilic therapeutic agent. In some embodiments, functional groups may be added to the polymer to provide the desired solubility or dispersibility of the therapeutic agent in the matrix. For example, functional groups can be attached to the silicone polymer.

In some embodiments, release rate modifying additives may be used to control the release kinetics of the therapeutic agent. For example, additives may be used to control the concentration of the therapeutic agent by increasing or decreasing the solubility of the therapeutic agent in the drug core, in order to control the release kinetics of the therapeutic agent. Solubility can be controlled by providing the matrix with suitable molecules and/or substances that increase and/or decrease the solubility of the therapeutic agent in the matrix. The solubility of the therapeutic agent may be related to the hydrophobic and/or hydrophilic properties of the matrix and the therapeutic agent. For example, surfactants, benzotriazole cresols, salts, and water can be added to the matrix and enhance the solubility of the hydrophilic therapeutic agent in the matrix. The salt may be water soluble, such as sodium chloride, or water insoluble, such as titanium dioxide. Additionally, oils and hydrophobic molecules may be added to the matrix and may enhance the solubility of the hydrophobic therapeutic agent in the matrix. Alternatively, various oligomers and polymers may be added, for example polysaccharides (such as alginate) or proteins (such as albumin). Solvents such as glycerol may be used to modify the release rate of the drug from the matrix into the tear fluid.

Instead of or in addition to controlling the migration rate based on the concentration of therapeutic drug dissolved in the matrix, the surface area of the drug core may be controlled to obtain a desired rate of drug migration from the core to the target site. For example, a larger exposed surface area of the core may increase the migration rate of the therapeutic agent from the drug core to the target site, while a smaller exposed surface area of the drug core decreases the migration rate of the therapeutic agent from the drug core to the target site. The area of the exposed surface of the drug core may be increased in a number of ways, such as by any of a battlement (entrapment) of the exposed surface, a surface having an exposed channel in communication with a tear or tear film, an indentation of the exposed surface, a protrusion of the exposed surface. The exposed surface may be increased by adding a salt that dissolves and leaves a cavity after the salt dissolves. Hydrogels may also be used that can expand to provide a greater exposed surface area.

In addition, drug impregnated porous materials, such as meshes, such as those disclosed in U.S. patent publication 2002/0055701 or layers of biostable polymers as described in U.S. patent publication 2005/0129731, may be used. Certain polymer methods may be used to incorporate drugs into the devices of the present invention, such as so-called "self-delivering drugs" or PolymerDrugs (polymerxcorporation, Piscataway, NJ) designed to degrade only into therapeutically useful compounds and physiologically inert connector molecules, with additional details in U.S. patent publication 2005/0048121 (East). Such delivery polymers may be used in the devices of the present invention to provide a release rate equal to the polymer erosion and degradation rate and constant over the course of treatment. Such delivery polymers may be used as device coatings or in the form of microspheres for injectable drug depots, such as the depots of the present invention. Additional polymer delivery technologies are also suitable for the devices of the present invention, such as those described in U.S. patent publication 2004/0170685(Carpenter), and technologies available from Medivas (san diego, CA).

In particular embodiments, the drug core matrix comprises a solid material, such as silicone, encapsulating the drug inclusions. Drugs include molecules that are very insoluble in water and sparingly soluble in the drug core matrix used for encapsulation. The inclusions encapsulated by the drug core may be microparticles of a size of about 1 μm to about 100 μm. The drug inclusions may comprise crystals (e.g., bimatoprost crystals) and/or oil droplets (e.g., oil droplets of latanoprost oil). The drug inclusions can be dissolved into a solid drug core matrix and substantially saturate the drug core with drug, e.g., latanoprost oil, dissolved into the solid drug core matrix. Drug dissolved in the drug core matrix is transported from the exposed surface of the drug core into the tear film, often by diffusion. Since the drug core is substantially saturated with drug, in many embodiments, the rate limiting step of drug delivery is transport of the drug from the surface of the drug core matrix exposed to the tear film. Since the drug core is substantially saturated with drug, the drug concentration gradient within the matrix is minimal and does not significantly affect the drug delivery rate. Since the surface area of the drug core exposed to the tear film is nearly constant, the rate of transport of the drug from the drug core into the tear film can be substantially constant. Work in connection with the present invention suggests that the solubility of therapeutic drugs in water and the molecular weight of the drug may affect the transport of the drug from the solid matrix to the tears. In many embodiments, the therapeutic agent is practically insoluble in water and has a solubility in water of about 0.03 wt% to 0.002 wt% and a molecular weight of about 400 g/mol to about 1200 g/mol.

In many embodiments, the therapeutic agent has very low solubility in water, e.g., from about 0.03 wt% to about 0.002 wt%, a molecular weight of from about 400 grams/mole (g/mole) to about 1200 g/mole and is readily soluble in organic solvents. Cyclosporin (CsA) is a solid with a solubility in water at 25 ℃ of 27.67. mu.g/mL, or about 0.0027% by weight, and a molecular weight (M.W.) of 1202.6 g/mol. Latanoprost (Xalatan) is a prostaglandin F2 alpha analog that is a liquid oil at room temperature and has a solubility in water at 25 ℃ of 50 μ g/mL, or about 0.005 wt%, with a m.w. of 432.6 g/mol.

Bimatoprost (Lumigan) is a synthetic prostamide (prostamide) analog that is solid at room temperature and has a solubility in water at 25 ℃ of 300 μ g/mL, or about 0.03 wt%, and a m.w. of 415.6 g/mol.

Work in connection with the present invention indicates that naturally occurring surfactants in the tear film, such as surfactant D and phospholipids, can affect the transport of a drug dissolved in a solid matrix from the core to the tear film. The drug core can be modified in response to surfactants in the tear film to provide sustained delivery of the drug at therapeutic levels into the tear film. For example, empirical data may be generated from a population of patients, e.g., tears collected from 10 patients and analyzed for surfactant content. The elution profile of collected tears for drugs that are slightly soluble in water (e.g., cyclosporine) can also be measured and compared to the elution profile in buffers and surfactants to develop an in vitro model of tear surfactants. In vitro surfactant-containing solutions based on this empirical data can be used to modulate the drug core with respect to the surfactant of the tear film.

The drug core may also be altered to utilize carrier media, such as nano-or micro-particles, such as potentially reactive nanofiber compositions and nano-textured surfaces for composites (innovative surface technologies, LLC, st. paul, MN), nano-structured porous silicon (referred to as nano-structured porous silicon) depending on the size of the molecule to be deliveredIncluding micron-sized particles, membranes, non-woven fabrics (wovenfilvers)) or micro-mechanical implant devices (pSividia, Limited, UK), and protein nanocage systems (Chimeracore) that target selective cells for drug delivery.

In many embodiments, the drug insert comprises a thin-walled polyimide tubing sheath with a drug core comprising latanoprost dispersed in Nusil6385(MAF970), a matrix for drug delivery, Nusil6385 being a medical grade solid silicone. The distal end of the drug insert was sealed with a cured solid Loctite4305 medical grade adhesive. The drug insert may be placed in the aperture of the lacrimal plug with the Loctite4305 adhesive not contacting the tissue or tear film. The drug insert may have an inner diameter of 0.32mm and a length of 0.95 mm. Three latanoprost concentrations in the final drug product were clinically tested: the drug core may comprise 3.5, 7, or 14 μ g of latanoprost, expressed as a weight percent concentration of 5, 10, and 20%, respectively. Assuming a total elution rate of about 100 ng/day, a drug core comprising 14 μ g of latanoprost is suitable for delivering the drug for about at least 100 days, e.g., 120 days. The total weight of the drug core including latanoprost may be-70 μ g. The weight of the drug insert including the polyimide sleeve may be about 100 μ g.

In many embodiments, the drug core may elute at an initially elevated therapeutic drug level, followed by a substantially constant elution of the therapeutic drug. In many cases, the amount of therapeutic drug released from the core per day may be lower than the level in drops and still provide benefit to the patient. The eluted elevated therapeutic drug level may produce a residual amount of the therapeutic drug and/or a residual effect of the therapeutic drug to provide relief to the patient. In embodiments where the level of treatment is about 80ng per day, the device may deliver about 100ng per day for the initial delivery period. An additional 20ng delivered per day may have a beneficial immediate effect. The initial elevated dose does not cause complications and/or adverse events to the patient since the amount of drug delivered can be precisely controlled.

Additionally, implants comprising two or more drugs released in a composition may be used, such as the structure disclosed in U.S. patent 4,281,654 (Shell). For example, in the case of glaucoma treatment, it may be desirable to use various prostaglandins, or prostaglandins with cholinergic agents or adrenergic antagonists (beta blockers) (such as) Or a prostaglandin and a carbonic anhydrase inhibitor.

In various embodiments, the implant may have at least one surface and upon implantation of an implant comprising at least one surface in contact with tear or tear film fluid, release therapeutic amounts of two therapeutic agents into the tear or tear film fluid of the eye over a period of at least one week. For example, the implant may be adapted to release therapeutic agents in therapeutic amounts over a period of about one month to twelve months. The release rate of each therapeutic agent may be the same or each therapeutic agent may have a different release rate.

In some embodiments, the implant includes a single drug core with two therapeutic agents mixed within a matrix. In other embodiments, the implant includes two drug cores, each with a separate therapeutic agent.

In particular embodiments, at least a portion of the implant may be bioerodible, and the therapeutic agent may be released while a portion of the implant erodes.

In some embodiments, the second therapeutic agent may include a counter-acting agent (counter-active agent) to avoid side effects of the first therapeutic agent. In one example, the second therapeutic agent may include at least one anti-glaucoma drug or miotic drug. The anti-glaucoma agent may include at least one of a sympathomimetic agent, a parasympathetic function-like agent, a beta blocker, a carbonic anhydrase inhibitor, or a prostaglandin analog. In another example, the first therapeutic agent may be a steroid and the second therapeutic agent may be an antibiotic, where the steroid impairs the immune response but the antibiotic provides protection against infection. In another example, the first therapeutic agent may be pilocarpine and the second therapeutic agent may be a non-steroidal anti-inflammatory drug (NSAID). Analgesics may be good companion (compliance) for treatment.

In some embodiments, the therapeutic agent may be released with a characteristic that follows the kinetic progression of the release of the therapeutic agent, and the progression is in the range of about zero to about 1. In particular embodiments, the range is from about zero to about 0.5, such as from about zero to about 0.25. The therapeutic agent may be released in a profile that corresponds to a kinetic progression of therapeutic agent release, and the progression is from about zero to about 0.5, with release lasting for at least about one month after structure insertion, e.g., the progression is within the range and release lasts for at least about 3 months after structure insertion.

Referring now to fig. 17, an implant, such as a lacrimal plug 1700, is shown, according to an embodiment of the present invention, including a silicone body 1710, a drug core 1720, and an indwelling structure 1730. Body 1710 includes a proximal channel 1714 sized to receive a drug core insert 1720. A filament 1734 may be embedded in the body 1710 and wrapped around the hydrogel rod 1732 to secure the hydrogel rod 1732 to the body 1710. Drug core inserts and methods of producing drug core inserts are described in U.S. patent applications 11/695,537 and 11/695,545. Although drug core inserts are shown, some embodiments may include drug reservoirs, semi-permeable membranes, drug coatings, and the like, as described in U.S. patent 6,196,993(Cohan) and U.S. patent application 10/899,416(Prescott), 10/899,417(Prescott), 10/762,421(Ashton), 10/762,439(Ashton), 11/571,147(Lazar), and 10/825,047 (Odrich). In some embodiments, the implant comprises a lacrimal plug without a drug on the implant, such as an implant similar to lacrimal plug 1700 without channel 1714 and drug core insert 1720.

Indwelling structure 1730 may include a hydrogel rod, a hydrogel coating, and protrusions. Hydrogel rod 1732 may be inserted through the punctum into the lumen of the lacrimal duct in a narrow profile configuration. After insertion into the cavity, the hydrogel rod, the hydrogel coating, or both may be hydrated to expand into a wide profile configuration.

Fig. l8A shows a cross-sectional view of a sustained release implant 1800 having two therapeutic agents for treating an eye in accordance with one embodiment of the present invention. Implant 1800 has a proximal end 1812 and a distal end 1814, releasing the therapeutic agent at the proximal end. The implant 1800 includes two concentric drug cores 1810, 1815. The first drug core 1810 is a cylindrical structure with a central opening that includes a first therapeutic drug, and the second drug core 1815 is a cylindrical structure that includes a second therapeutic drug. The second drug core 1815 is configured to fit within the central opening of the first drug core 1810, as shown. The first drug core 1810 includes a first matrix 1870 comprising first inclusions 1860 of a first therapeutic agent; the second drug core 1815 includes a second matrix 1875 comprising second inclusions 1865 of a second therapeutic agent. The first and second enclosures 1860, 1865 often include concentrated forms of the first and second therapeutic agents, such as therapeutic agents in liquid or solid form, and the therapeutic agents may dissolve over time in the first matrix 1870 of the first drug core 1810 and in the second matrix 1875 of the second drug core 1815. The first and second substrates 1870, 1875 may comprise a silicone substrate or the like, and the therapeutic drug mixture within the substrate may be heterogeneous. In many embodiments, the heterogeneous mixture includes a silicone matrix portion saturated with the therapeutic drug and an inclusion portion including therapeutic drug inclusions such that the heterogeneous mixture includes a heterogeneous mixture of phases. The first matrix may differ from the second matrix in terms of, for example, the area of exposed surface, surfactant, cross-linking, additives, and/or matrix materials, including formulation and/or solubility. In some embodiments, the first and second enclosures 1860, 1865 include droplets of a therapeutic drug oil, e.g., latanoprost oil. In some embodiments, the first and second enclosures 1860, 1865 may include particles of a therapeutic agent, such as solid bimatoprost particles. In many embodiments, the first substrate 1870 comprises a first inclusion 1860 and the second substrate 1875 comprises a second inclusion 1865. The first and second enclosures 1860, 1865 may include microparticles having a size of about 0.1 μm to about 100 μm, or 200 μm. The included inclusions are at least partially dissolved in a surrounding solid matrix (e.g., silicone) that includes the microparticles such that the first and second matrices 1870, 1875 are substantially saturated with the therapeutic drug upon release of the therapeutic drug from the core.

The first and second drug cores 1810, 1815 are surrounded by the sheath body 1820 except for the exposed surfaces where the therapeutic agent is released, in this case, at the proximal end 1812. The therapeutic agent is substantially impermeable to the sheath body 1820 such that the therapeutic agent is released from the exposed surfaces on the open ends of the first and second drug cores 1810, 1815 not covered by the sheath body 1820. In some embodiments, the implant may be incorporated into a different structure, such as a punctal plug.

Fig. 18B illustrates a side cross-sectional view of the sustained release implant of fig. 18A. The first drug core 1810 containing the first therapeutic drug is a cylindrical structure and is shown as having a circular cross-section with an open center. The second drug core 1815 containing the second therapeutic drug is a cylindrical structure and is shown as circular in cross-section and configured to fit within the first drug core 1810, as shown. The sheath body 1820 includes an annular portion disposed over the first drug core 310.

Fig. 19A shows a cross-sectional view of a sustained release implant 1900 having a therapeutic agent for treating an eye according to one embodiment of the invention. The implant 1900 has a distal end 1914 and a proximal end 1912 in which the therapeutic agent is released. The implant 1900 includes first and second drug cores 1910, 1915 positioned in a side-by-side configuration. The first drug core 1910 is a cylindrical structure including a first therapeutic agent and the second drug core 1915 is a cylindrical structure including a second therapeutic agent.

The first and second drug cores 1910 and 1915 are disposed adjacent to each other and may be the same length or different lengths, as shown. The first drug core 1910 includes a first matrix 1970 comprising first inclusions 1960 of a first therapeutic agent; second drug core 415 includes a second matrix 1975 that comprises a second inclusion 1965 of a second therapeutic agent. The first and second wraps 1960, 1965 often include a concentrated form of the first and second therapeutic agents, such as a liquid or solid form of the therapeutic agents, and the therapeutic agents may dissolve over time in the first matrix 1970 of the first drug core 1910 and in the second matrix 1975 of the second drug core 1915. The first and second matrices 1970, 1975 may comprise silicone matrices or the like, and the therapeutic drug mixture within the matrices may be heterogeneous. In many embodiments, the heterogeneous mixture includes a silicone matrix portion saturated with the therapeutic drug and an inclusion portion including therapeutic drug inclusions such that the heterogeneous mixture includes a heterogeneous mixture of phases. The first matrix may differ from the second matrix in terms of, for example, the area of exposed surface, surfactant, cross-linking, additives, and/or matrix materials, including formulation and/or solubility. In some embodiments, the first and second inclusions 1960, 1965 include droplets of a therapeutic drug oil, e.g., latanoprost oil. In some embodiments, the inclusion bodies may include particles of a therapeutic drug, such as solid bimatoprost particles. The first and second inclusions 1960, 1965 may include microparticles having a size of about 0.1 μm to about 100 μm, or 200 μm. The contained inclusions are at least partially dissolved in a surrounding solid matrix (e.g., silicone) that contains the microparticles such that the first and second matrices 1970, 1975 are substantially saturated with the therapeutic agent upon release of the therapeutic agent from the core.

The first and second drug cores 1910, 1915 are surrounded by the sheath body 1920 except for the exposed surfaces where the therapeutic drug is released, in this case, at the proximal end 1912. The first and second therapeutic agents are substantially impermeable to the sheath body 1920 such that the first and second therapeutic agents are released from exposed surfaces on the open ends of the first and second drug cores 1910, 1915 not covered by the sheath body 1920. In some embodiments, the implant may be incorporated into a different structure, such as a punctal plug.

Fig. 19B illustrates a side cross-sectional view of the sustained release implant of fig. 19A. The first drug core 1910 containing the first therapeutic drug is a cylindrical structure and is shown as having a circular cross-section. A second drug core 1915 containing a second therapeutic drug is also a cylindrical structure and is shown with a circular cross-section. The first and second drug cores 1910, 1915 may have different diameters or the same diameter, as shown. The sheath body 1920 includes an annular portion disposed about the first and second drug cores 1910, 1915.

Fig. 20A shows a cross-sectional view of a sustained release implant 2000 having a therapeutic agent for treating an eye, in accordance with an embodiment of the present invention. Implant 2000 has a proximal end 2012 and a distal end 2014. The implant 2000 includes two concentric drug cores 2010, 2015 having hollow centers to allow fluid to flow through the implant 2000. First drug core 2010 is a hollow cylindrical structure including a first therapeutic drug and second drug core 2015 is a hollow cylindrical structure including a second therapeutic drug. The second drug core 2015 is configured to fit in the central opening of the first drug core 2010, as shown. The first and second drug cores 2010, 2015 may have different lengths or lengths of different lengths as shown. The first drug core 2010 includes a first matrix 2070 comprising first inclusions 2060 of a first therapeutic drug; the second drug core 2015 includes a second matrix 2075 comprising second inclusions 2065 of a second therapeutic agent. The first and second enclosures 2060, 2065 often include a concentrated form of the first and second therapeutic drugs, such as a liquid or solid form of the therapeutic drugs, and the therapeutic drugs may dissolve over time in the first matrix 2070 of the first drug core 2010 and the second matrix 2075 of the second drug core 2015, respectively. The first and second matrices 2070, 2075 may comprise silicone matrices or the like, and the therapeutic drug mixture within the matrices may be heterogeneous. In many embodiments, the heterogeneous mixture includes a silicone matrix portion saturated with the therapeutic drug and an inclusion portion including therapeutic drug inclusions such that the heterogeneous mixture includes a heterogeneous mixture of phases. The first matrix may differ from the second matrix in terms of, for example, the area of exposed surface, surfactant, cross-linking, additives, and/or matrix materials, including formulation and/or solubility. In some embodiments, the first and second enclosures 2060, 2065 comprise droplets of a therapeutic drug oil, e.g., latanoprost oil. In some embodiments, the inclusion bodies may include particles of a therapeutic drug, such as solid bimatoprost particles. The first and second enclosures 2060, 2065 may comprise microparticles having a size of about 0.1 μm to about 100 μm, or 200 μm. The included inclusions are at least partially dissolved in a surrounding solid matrix (e.g., silicone) that includes the microparticles such that the first and second matrices 2070, 2075 are substantially saturated by the therapeutic drug upon release of the therapeutic drug from the core.

The first drug core 2010 is surrounded on its outer surface by a sheath body 2020, forming the first drug core 2010 with an open inner surface 2085 and exposed proximal and distal end faces. The first therapeutic agent in the first drug core 2010 is substantially impermeable to the sheath body 2020 such that the first therapeutic agent is released from the exposed surface of the drug core 2010. Second drug core 2015 is surrounded on its outer surface by first drug core 2010, having an open inner surface 2080 and exposed proximal and distal end faces. Second drug core 2015 is shorter than first drug core 2010 such that portions of inner surface 2085 are exposed. The first therapeutic agent is released from exposed surfaces of first drug core 2010 not covered by sheath body 2020 and second drug core 2015, and the second therapeutic agent is released from exposed surfaces of second drug core 2015 not covered by first drug core 2010. In some embodiments, the implant may be incorporated into a different structure, such as a punctal plug.

Fig. 20B shows a side cross-sectional view of the sustained release implant of fig. 20A with a concentric drug core. A first drug core 510 containing a first therapeutic drug is shown having a circular cross-section with a first open center portion. A second drug core 2015 having a second therapeutic drug is shown having a circular cross-section with a second open center and is configured to fit in the first open center portion of the first drug core 2010. While allowing flow through the center of the second drug core 2015 as shown. The sheath body 2020 includes an annular portion disposed over the first drug core 2010.

The drug core disclosed above includes first and second therapeutic agents and a material for providing sustained release of the first and second therapeutic agents. The first and second therapeutic agents migrate from the drug core to the target tissue (e.g., the ciliary body of the eye). The surface of the eye can be targeted by cyclosporin a (to control inflammation) and mucin-inducing agents for dry eye. Uveal membranes can be targeted by steroids, NSAIDs and CSAs for uveitis. The first and second therapeutic agents may optionally be only sparingly soluble in the matrix, such that the first and second therapeutic agents maintain a "zero order" release rate over the duration of release when dissolved in the matrix and used for release from the exposed surface of the drug core. The first and second therapeutic agents differ in the exposed surface of the drug core to the tear or tear film, and the rate of migration from the drug core to the tear or tear film is related to the concentration of the first and second therapeutic agents dissolved in the matrix. In some embodiments, the concentration of the first and second therapeutic agents dissolved in the drug core can be controlled to provide a desired release rate of the first and second therapeutic agents. In some embodiments, the desired release rate of the first therapeutic agent may be the same as the desired release rate of the second therapeutic agent. In some embodiments, the desired release rate of the first therapeutic agent may be different from the desired release rate of the second therapeutic agent. The therapeutic agent included in the drug core may include a liquid, solid gel, solid crystalline, amorphous solid, solid particulate, and/or dissolved form of the therapeutic agent. In some embodiments, the drug core comprises a silicone matrix comprising the first and second therapeutic agents.

The drug core may be produced from one or more biocompatible materials capable of providing sustained release of the therapeutic agent. Although the drug core is described above with respect to embodiments comprising a substantially non-biodegradable matrix having drug particles positioned therein in at least partially dissolved form, the drug core can comprise any structure that provides sustained release of the first and second therapeutic agents, such as a biodegradable matrix, a porous drug core, a liquid drug core, and a solid drug core. In some embodiments, the drug cores have the same structure, while in other embodiments, the drug cores have different structures. The structure may be adapted to release the first and second therapeutic agents in therapeutic amounts over a period of about one month to twelve months after insertion of the structure into the eye. In some embodiments, the release rates of the first and second therapeutic agents may be the same or similar. In other embodiments, the release rates of the first and second therapeutic agents may be different, with one therapeutic agent being released at a higher rate than the other therapeutic agent. The matrix comprising the first and second therapeutic agents may be formed from biodegradable or non-biodegradable polymers. Examples of biodegradable polymers may include poly (L-lactic acid) (PLLA), poly (L-glycolic acid) (PLGA), polyglycolide, poly L-lactide, poly D-lactide, poly (amino acids), polydioxanone (polydioxanone), polycaprolactone, polygluconate, polylactic acid-polyethylene oxide copolymers, modified celluloses, collagen, polyorthoesters, polyhydroxybutyrate, polyanhydrides, polyphosphoesters, poly (alpha-hydroxy acids), collagen matrices, and combinations thereof. The device of the invention may be fully or partially biodegradable or non-biodegradable. Examples of non-biodegradable materials are various commercially available biocompatible polymers including, but not limited to, silicones, polyethylene terephthalate, acrylates, polyethylenes, polyolefins (including very high molecular weight polyethylene, expanded polytetrafluoroethylene, polypropylene), polycarbonate urethanes, polyurethanes, polyamides, coated collagen. Examples of additional polymers may include cyclodextrins (cyclodextrins), chitins (chitans), hyaluronic acid, chondroitin sulfate (chronditioninsulfonate) and any cross-linked derivatives of these polymers. In some embodiments, the drug core may include a hydrogel polymer that is degradable or non-degradable. In some embodiments, therapeutic drugs may be included in drug eluting materials used as coatings, such as those available from SurmodicsofEden prairie, Minnesota, Angiotech pharmaceuticals of British Columbia, Canada, and the like.

The first and second therapeutic agents may include any substance that affects the eye, such as a drug. In some embodiments, the first and second therapeutic agents work together to treat the eye. In other embodiments, the first therapeutic agent may counteract possible side effects of the second therapeutic agent. An additional negative therapeutic agent (counteractive therapeutic agent) may be included in the core, which releases the therapeutic agent that treats the eye, as shown in fig. 2A; or separate drug cores may be provided for separately releasing additional counteractive therapeutic agents, as shown in figures 3A, 4A and 5A.

For example, one possible side effect of a medication for treating cycloplegia is pupil dilation, which may lead to photophobia. Thus, miotic therapeutic drugs are released into the eye to balance the dilation of the pupil caused by the cycloplegic. The cycloplegic treatment may include atropine, cyclopentolate, succinylcholine, homatropine, scopolamine, and tropicamide. Miotic therapeutics may include diethoxyphosphothiocholine, pilocarpine, physostigmine salicylate, isoflurophosphate, carbachol, methacholine, carbamoylmethacholine, epinephrine, dipivefrine, neostigmine, iodecoy, and demecimibride. Other suitable therapeutic agents include mydriatic agents such as amphetamine, ephedrine, cocaine, tropicamide, phenylephrine, cyclopentolate, hydroxyethylamine, and eucalyptol. In addition, anticholinergic drugs such as pirenzepine may be used. Examples of suitable therapeutic agents can be found in U.S. patent applications 20060188576 and 20030096831.

Another possible side effect of drugs for treatment of cycloplegia is glaucoma, which may be associated with dilation of the pupil. Thus, the second therapeutic agent is an anti-glaucoma drug that releases to balance the potential glaucoma-inducing side effects of the first therapeutic agent used to treat the eye. Suitable anti-glaucoma therapeutic agents include: sympathomimetics such as apraclonidine, brimonidine, clonidine, dipivefrin, and epinephrine; parasympathomimetic functional drugs such as aceclidine, acetylcholine, carbachol, phenyl decadiammine, diethoxyphosphorylthiocholine, isofluorophosphate, neostigmine, paraoxon, physostigmine, and pilocarpine; carbonic anhydrase inhibitors such as acetazolamide, brinzolamide, dichlorfenamide, dorzolamide, and methazolamide; beta blockers such as, for example, benfurolol, betaxolol, carteolol, levobunolol, metiprolol, and timolol; prostaglandin analogs such as bimatoprost, latanoprost, travoprost and unoprostone; and other drugs such as dapiprazole and guanethidine. In a preferred embodiment, atropine is released as a first therapeutic agent for the treatment of developmental myopia in children, bimatoprost and/or latanoprost is released as a second therapeutic agent for the treatment of glaucoma.

Other non-limiting examples of active agents or drugs suitable for use in the present invention include, by way of example only: topical prostaglandin derivatives such as latanoprost, travoprost and bimatoprost for the topical treatment of glaucoma. Suitable for treating corneal infections are ciprofloxacin, moxifloxacin, or gatifloxacin. Systemic medications for use in the present invention are those for hypertension such as atenolol, nifedipine, or hydrochlorothiazide. Drugs for any other chronic disease requiring long-term administration may be used. The active agent or drug may be an anti-infective drug. For example, fluoroquinolones, beta lactams, aminoglycosides or cephalosporins are used for bacteria. The antiviral agent is an antifungal agent. Anti-inflammatory applications use glucocorticosteroids, NSAIDs and other analgesics.

The treatment of allergic conjunctivitis and rhinitis is also an application of the present invention, for example the use of antihistamines and anti-allergic agents, such as olopatadine and cromolyn sodium, in or on implants.

This list of active agents is not exhaustive and there are many other drugs that can be used in the present invention. For example, treatment of dry eye by topical cyclosporin for administration in accordance with the invention is of particular interest where a therapeutic amount of cyclosporin lower than the daily dose of cyclosporin administered as drops per day can be delivered, e.g., the therapeutic amount may be the amount of cyclosporin administered as drops or from Allergan 5-10% of the total weight of the composition. Many other active agents may also be administered using the methods and devices of the present invention. The active agent may be a lubricantAnd emollients such as PVA, PVP, modified cellulose molecules such as carboxymethyl cellulose and hydroxypropyl methyl cellulose, and hyaluronic acid and mucin stimulants.

It is noted that some therapeutic agents may have more than one effect on the eye. For example, anti-glaucoma therapeutics may also cause pupil constriction. Thus, in some embodiments, the second therapeutic agent may counteract more than one side effect of the first therapeutic agent released to treat the eye.

Upon implantation of the above disclosed implants in or near the tissue of the eye, the first and second therapeutic agents are released at therapeutic levels to provide the desired therapeutic response. Preferably, the first and second therapeutic agents are released at a uniform rate, e.g., a rate that corresponds to zero order kinetics, although they may be released at a rate that corresponds to the kinetics of other reaction orders, e.g., first order kinetics. In many embodiments, the kinetic order of the response to release of the first and second therapeutic agents varies from zero order to one order. Thus, the release profile of the first and second therapeutic agents corresponds to a variety of kinetic orders that vary from zero order to one order. Desirably, the drug core is removed before the release rates of the first and second therapeutic agents change significantly to provide uniform delivery of the first and second therapeutic agents. Since a uniform delivery rate is desired, it may be desirable to remove and/or replace the drug core before the reaction kinetics are completely shifted to first order. In other embodiments, first order or higher release kinetics may be desirable in some or all treatments, so long as the first and second therapeutic drug release profiles remain within safe and effective ranges. In some embodiments, the drug core can release the first and second therapeutic agents at an effective rate for 1 week to 5 years, more particularly 3-24 months. As noted above, in some embodiments, it may be desirable for the drug core to have similar release rates for the first and second therapeutic agents. In other embodiments, it may be desirable for the drug core to have different release rates of the first and second therapeutic agents, depending on the therapeutic agent used.

The release rates of the first and second therapeutic agents may be related to the concentrations of the first and second therapeutic agents dissolved in the drug core. In many embodiments, the drug core includes additional non-therapeutic drug substances selected to provide a desired solubility of the first and second therapeutic agents in the drug core. The non-therapeutic drug substance of the drug core may include polymers and additives as described above. The polymer of the drug core may be selected to provide the desired solubility of the first and second therapeutic agents in the matrix. For example, the drug core may include a hydrogel that may promote the solubility of a hydrophilic therapeutic drug. In some embodiments, functional groups may be added to the polymer to modulate the release kinetics of one or both therapeutic agents. For example, functional groups can be attached to the silicone polymer. In some embodiments, different ions may produce different salts with different solubilities.

In some embodiments, a modulator is used to control the concentration of the first and second therapeutic agents by increasing or decreasing the solubility of the therapeutic agents in the drug core. Solubility can be controlled by providing the matrix with suitable molecules and/or substances that increase and/or decrease the solubility of the therapeutic drug in dissolved form. The solubility of the therapeutic agent in dissolved form can be related to the hydrophobic and/or hydrophilic properties of the matrix and the therapeutic agent. For example, surfactants, salts, hydrophilic polymers can be added to the matrix to modulate the release kinetics. Additionally, oils and hydrophobic molecules may be added to the matrix to modulate the release kinetics of the matrix.

Instead of or in addition to controlling the rate of migration based on the concentration of the first and second therapeutic agents dissolved in the matrix, the surface area of the drug core may be controlled to obtain a desired rate of drug migration from the core to the target site. For example, a larger exposed surface area of the drug core may increase the migration rate of the first and second therapeutic agents from the drug core to the target site, while a smaller exposed surface area of the drug core decreases the migration rate of the first and second therapeutic agents from the drug core to the target site. The area of the exposed surface of the drug core may be increased in a number of ways, such as by making the exposed surface distorted or porous, thereby increasing the available surface area of the drug core.

The sheath body of the above disclosed implants comprises suitable shapes and materials to control migration of the first and second therapeutic agents from the drug core. The sheath body houses the drug core and may be closely fitted to the core. The sheath body is made of a substantially impermeable material to the therapeutic agent such that the rate of migration of the therapeutic agent can be controlled to a large extent by the exposed surface area of the drug core not covered by the sheath body. Typically, the migration of the therapeutic agent through the sheath body is one tenth or less, often one hundredth or less, of the migration of the therapeutic agent through the exposed surface of the drug core. In other words, the migration of the therapeutic agent through the sheath body is at least one order of magnitude less than the migration of the therapeutic agent through the exposed surface of the drug core. Suitable jacket body materials include polyimide, polyethylene terephthalate (hereinafter "PET"). The wall thickness of the sheath body is about 0.00025 "to about 0.0015". The sheath extending across the drug core has an overall diameter of about 0.2mm to about 1.2 mm. The drug core may be formed by dip coating the drug core in a sheath material. Alternatively, the sheath body may be a tube and the drug core is introduced into the sheath as a liquid or slid into the sheath body tube.

The sheath body may be provided with additional features to facilitate clinical application of the implant. For example, the sheath may replaceably receive a drug core that is replaceable while the indwelling element and the sheath body remain implanted in the patient. The sheath body is often rigidly attached to an indwelling element, as described above, the drug core is replaceable while the indwelling element retains the sheath body. For example, the sheath body may have external protrusions that, when squeezed, exert a force on the sheath body and push the drug core out of the sheath body. Another drug core may then be positioned in the sheath body.

In another embodiment, a therapeutic implant includes an implantable body sized and shaped for insertion into a patient's body. The implantable body has a first reservoir and a second reservoir. The first container includes a first therapeutic agent and a first surface for releasing the first therapeutic agent. The second container includes a second therapeutic agent and a second surface for releasing the second therapeutic agent. The first and second therapeutic agents may be any of the therapeutic agents described herein. The first and second therapeutic agents may be released at therapeutic levels through the first and second surfaces of the first and second reservoirs over a sustained period of time when the implant is implanted for use. As disclosed herein, the release rate and/or the release time period of the first and second therapeutic agents may be the same or different. In other embodiments, the first and second containers are shaped and positioned within sustained release implants and therapeutic implants described herein.

Fig. 21 schematically illustrates one embodiment of a lacrimal insert in the shape of a lacrimal plug 2100 for use in a therapeutic implant configured as a sustained release implant for receiving at least one drug core comprising first and second therapeutic drugs. Punctal plug 2100 includes a rolled edge 2110 at a proximal end that rests on the exterior of punctum 11, 13 (see fig. 34), a bulb 2120 with a tapered portion 2125 that projects obturatively into lacrimal canals 10, 12 (see fig. 34) and terminates distally in a tip 2135, and a body portion 2130 that connects rolled edge 2110 and bulb 2120. The length of the punctal plug 2100 is approximately 2.0 mm. Bulb 2120 serves to prevent easy displacement of punctal plug 2100 from lacrimal canals 10, 12 and may be tapered to facilitate insertion into puncta 11, 13. The rolled edge 2110 is designed with a diameter to prevent the punctal plug 2100 from completely entering the lacrimal canals 10, 12 and is preferably smooth to minimize irritation of the eye. The body portion 2130 of the punctal plug 2100 is essentially a nonfunctional connection between the rolled edge 2110 and the portion of the bulb 2120. The binding 2110 includes a hole 2140 extending into the body portion 2130, and an implant 2145 is placed in the hole 2140. The size of the orifice 2140 is selected to hold the implant in place during treatment. In some embodiments, the sheath body of the implant may be omitted and the drug core may be inserted directly into the orifice 2140 of the lacrimal plug 2100. In some embodiments, the end 2135 is closed, in other embodiments, an opening 2150 at the distal end 2135 allows access to the orifice 2140, allowing fluid flow through the punctal plug. In some embodiments, an optional non-porous head 2115 is provided above the rolled edge 2110 so as to surround the orifice 2140. In accordance with one aspect of the present invention, the body 2110 and head 2115 are made of different materials, the body 2110 may be molded or otherwise formed of a flexible material that is impermeable to the therapeutic agent (such as silicone), and the head 2115 is made of a biocompatible, preferably soft and flexible, second material that is permeable to the agent. With the punctal plug 2100 in place, the therapeutic agent diffuses from the drug core into the tears of the lacrimal lake, where the therapeutic agent mixes with the tears and permeates the eye, as with eye drops, to exert the intended pharmacological effect. The size of the orifice 2140 is selected to hold the implant in place during treatment.

Fig. 22-25 illustrate different embodiments of a therapeutic implant having a structure such as a punctal plug 2100. Other structural descriptions suitable for use in the present invention are described in U.S. patent application publication 2006/0020253 entitled "Implantable device having control device within the field of medicine and methods of making the same", published under the name Prestot, 26.1.2006; and us patent 7,117,870 entitled "lacrimalin embedding in a living environment and method of manufacturing a living environment" published under the name presmott, 10.10.2006. The reservoir may include any therapeutic agent described herein for treating the eye, for example, an agent for treating an optical defect of the eye.

Fig. 22 schematically illustrates one embodiment of a therapeutic implant 2200 having a punctal plug 2100 and a sustained release implant comprising first and second therapeutic agents. In the illustrated embodiment, the sustained release implant is the sustained release implant 2200 discussed above having a drug core 2210 comprising first inclusions 2260 of a first therapeutic agent and second inclusions 2265 of a second therapeutic agent. This embodiment of the therapeutic implant 2200 additionally includes an optional head 2115 at the proximal end that is permeable to the first and second therapeutic agents. With the therapeutic implant 2200 in place, the first and second therapeutic agents diffuse from the proximal end of the drug core through the permeable head into the tears of the tear lake, where the first and second therapeutic agents mix with the tears and penetrate the eye as eye drops to exert the intended pharmacological effect. The size of the apertures 2240 is selected to maintain the sustained release implant in place during treatment. In the embodiment shown, the sheath body is also within the orifice 2140. In other embodiments, the sheath body 2220 may be omitted and the drug core 2210 may be inserted directly into the aperture 2140 of the lacrimal plug 2100.

Fig. 23 schematically illustrates one embodiment of a therapeutic implant 2300 having a lacrimal plug 2100 and a sustained release implant having first and second concentric drug cores of first and second therapeutic drugs. In the illustrated embodiment, the sustained release implant is a sustained release implant 2300 having an outer first drug core 2310 comprising first inclusions 2360 of a first therapeutic agent and an inner second drug core 2315 comprising second inclusions 2365 of a second therapeutic agent. With the therapeutic implant 2300 in place, the first and second therapeutic agents diffuse from the exposed end or proximal end of the drug core and into the tears of the lacrimal lake, where the first and second therapeutic agents mix with the tears and penetrate the eye as eye drops to exert the intended pharmacological effect. The size of the orifice 2140 is selected to hold the sustained release implant in place during treatment. In some embodiments, the sheath body 2320 of the implant 2300 may be omitted, and the first and second drug cores 2310, 2315 may be inserted directly into the orifice 2140 of the punctal plug 2100. Optionally, a permeable head 2115 for the first and second therapeutic agents may be used, wherein the first and second therapeutic agents diffuse from the first and second drug cores 2310, 2315 through the permeable head 2115.

Fig. 24 schematically illustrates one embodiment of a therapeutic implant 2400 having a punctal plug 2100 and a sustained release implant having first and second drug cores containing first and second therapeutic agents. In the illustrated embodiment, the sustained release implant is a sustained release implant 2400 having a first drug core 2410 next to a second drug core 2415, the drug core 2410 comprising first inclusions 2460 of a first therapeutic agent and the second drug core 2415 comprising second inclusions 2465 of a second therapeutic agent. With the therapeutic implant 2400 in place, the first and second therapeutic agents diffuse from the exposed end or proximal end of the drug core and into the tears of the lacrimal lake, where the first and second therapeutic agents mix with the tears and penetrate the eye as eye drops to exert the intended pharmacological effect. The size of the orifice 2140 is selected to hold the sustained release implant 2400 in place during treatment. In some embodiments, the sheath body 2420 of the implant 400 may be omitted and the first and second drug cores 2410, 2415 may be inserted directly into the orifice 2140 of the punctal plug 2100. Optionally, a permeable head 2115 for the first and second therapeutic agents may be used, wherein the first and second therapeutic agents diffuse from the first and second drug cores 2410, 2415 through the permeable head 2115.

Fig. 25 schematically illustrates one embodiment of a therapeutic implant 2500 having a lacrimal plug 2100 and a sustained release implant having first and second concentric drug cores in a flow-through configuration, each drug core containing a therapeutic drug. In the illustrated embodiment, the sustained release implant is a sustained release implant 2500 having an outer first drug core 2510 comprising a first wrap 2560 of a first therapeutic agent and an inner second drug core 2515 comprising a second wrap 2565 of a second therapeutic agent. In the embodiment shown, the lacrimal plug 2100 includes an opening 2150 in the tip 2135 at the distal end, allowing fluid to flow through the body of the lacrimal plug 2100 from the proximal end to the distal end and through the first and second drug cores 2510, 2515. With the therapeutic implant 2500 in place, the first and second therapeutic agents diffuse from the drug cores 2510, 2515 as fluid flows through the exposed ends and the exposed inner surfaces 2585, 2580. The size of the orifice 2140 of the punctal plug 2100 is selected to hold the implant in place during treatment, and the size of the opening 2150 allows for sufficient flow communication between the implant 2100 and the first and second drug cores 2510, 2515. In some embodiments, the sheath body of the implant may be omitted and the first and second drug cores 510, 2515 may be inserted directly into the orifice 2140 of the lacrimal plug 2100. Optionally, a head 2115 permeable to the first and second therapeutic agents may be used. Other flow-through structures suitable for the present invention are described in U.S. patent application 11/695,545 entitled "Nasolarix Drainage System Implants for drug therapy" filed on 2.4.2007.

Fig. 26A-26C illustrate a therapeutic implant 2600, 2600', 2600 "including a punctal plug and a structure releasing a first and second therapeutic agent, according to an embodiment of the invention. Structures suitable for use in the present invention are described in U.S. Pat. No. 3,949,750, entitled "Puncturelugand method for transforming a keystroke junction simulation," published in the name of Freeman at 13.4.1976. The head portion may include any two of the therapeutic agents described herein for treating the eye.

In the treatment of ophthalmic diseases where it is desirable to prevent or reduce the flow of lacrimal fluid and/or drugs away from the eye, punctal orifices in one or both of the upper and lower eyelids are blocked with a therapeutic implant, two corresponding embodiments are shown in fig. 26A and 26B. Referring now to the embodiment of fig. 26A, the therapeutic implant 2600 has a blunt tip or barb portion 2620 at the distal end, an intermediate neck or waist portion 2630 having a slightly smaller diameter than the tip, and a smooth discoid head portion 2610 at the proximal end having a relatively larger diameter. The therapeutic implant 2600 'of fig. 26B has generally similar dimensions as the first described embodiment, with a blunt tip or barb portion 2620', a cylindrical middle portion 2630 'of substantially the same dimensions, and a dome-shaped head portion 2610' of slightly smaller diameter than its counterpart of the embodiment of fig. 26A. If desired as an alternative to grasping with forceps, the head portions 2610, 2610 'of both embodiments may be provided with central bore openings 2640, 2640' adapted to receive the protruding tips of an insertion tool to provide a releasable grip on the therapeutic implant when the insertion is manipulated, as described below.

Fig. 26C shows a hollow therapeutic implant 2600 "having similar dimensions to the first described embodiment, with a blunt tip or barb portion 2620", an intermediate neck or waist portion 2630 "of slightly smaller diameter than the tip, a smooth discoid head portion 2610" of relatively larger diameter, and a central bore 2640 "through the plug. The central bore 2640 "allows fluid to flow from the proximal end to the distal end of the therapeutic implant 2600".

In some embodiments of the invention, both of the therapeutic agents described herein are incorporated into the punctal plugs described in U.S. patent application publication 2005/0197614. The gel may be used to form the therapeutic implant 2600, 2600', 2600 "and the gel may expand from a first diameter to a second diameter, wherein the second diameter is about 50% greater than the first diameter. The gel may be used to entrap the first and second therapeutic agents, for example within a microporous structure, wherein the agents are uniformly dispersed within the microporous structure, and the gel may slowly elute the first and second therapeutic agents into the patient. Various therapeutic agents have been described herein, and additional therapeutic agents are described in U.S. provisional application 60/550,132, entitled "punctplus, Materials, AndDevices," and may be combined with the gels and devices described herein.

In other embodiments of the invention, the therapeutic implant 2600, 2600', 2600 "is made entirely or only partially of a porous material (such as HEMA hydrophilic polymer) that is drug-impregnable, or may be otherwise made into capillaries or the like, for storing and slowly dispensing ophthalmic drugs to the eye as the drugs are leached by the lacrimal fluid. For example, the head portions 2610, 2610', 2610 "of each embodiment may be a drug-impregnable, porous material impregnated with a first and a second therapeutic agent.

Fig. 27 shows a therapeutic implant containing first and second therapeutic agents when applied to an eye. In the illustrated embodiment, therapeutic implant 2700 is designed for insertion into lower punctal orifice 13 of eye 2 and communication with the orifice along lacrimal duct 12. The therapeutic implant 2700 includes a rolled edge 2710 at a proximal end, a flared portion 2720 at a distal end, and a neck portion 2730. The beads 2710 are designed for positioning against the orifice 13. Examples of suitable therapeutic implants 2700 containing two therapeutic agents have been described above and include therapeutic implants 2200, 2300, 2400, 2500, 2600', and 2600 ". The therapeutic implant 2700 may be used to block fluid flow or may have a hollow portion that allows fluid flow. In the embodiment shown in fig. 27, therapeutic implant 2700 is shown in the shape of a hollow, suction tube for the passage of tears. Examples of these include therapeutic implants 2500 and 2600 ". Unlike the tear arresting therapeutic implants 2200, 2300, 2400, 2600, and 2600', the hollow therapeutic implants 2500 and 2600 ″ provide a significantly different method, regimen, and structure for drug administration. The hollow therapeutic implant is particularly useful where the active agent may be available on the interior surface or interior of the therapeutic implant and has a unique structure to administer the active therapeutic agent to the tear flow through the tear and thereby in a manner that is controllable by the flow of the tear, thereby allowing the tear to serve as a carrier for the therapeutic agent.

Fig. 27 additionally shows an implant 2700' containing first and second therapeutic agents that has been inserted into upper punctal orifice 11 and is substantially cylindrical in shape to block the flow of tears to lacrimal duct 10, with lower lacrimal plug 2700 passing tears to lacrimal duct 12. An example of a suitable implant 2700' containing two therapeutic agents may be any of the implants disclosed herein, or may be an occlusive plug of some inert biocompatible material.

Therapeutic implants 2700 and 2700' can be used individually or in any desired combination (as shown in fig. 27). For example, implant 2700' can be positioned in the lower lacrimal duct and therapeutic implant 2700 can be positioned in the upper lacrimal duct. Alternatively, two identical therapeutic implants 2700 or 2700' can be positioned in both lacrimal canals.

Fig. 28, 9A-29D, 30A and 30B illustrate different embodiments of drug delivery core elements for use in therapeutic implants that can be customized to the needs of an individual patient. The core element of the therapeutic implant is fan-shaped and can be combined into a cylindrical drug core with many different configurations of many different therapeutic drugs. This may allow for a therapeutic implant configuration that maximizes individual patient management. This approach allows tailoring of treatment for use of multiple therapeutic drugs for disease control. The method may also customize the dosage of the therapeutic drug based on the genetic condition and/or physiological condition of the patient.

Fig. 28 illustrates various core elements or drug cores that may be combined into, for example, a cylindrical drug core, in accordance with an embodiment of the present invention. The drug core need not be cylindrical, but a cylindrical drug core is preferred for ease of manufacture. Drug core 2810 is a blank core element containing no therapeutic drug, drug core 2820 contains therapeutic drug 2825 at a concentration of X, drug core 2830 contains therapeutic drug 2835 at a concentration of Y, and drug core 2840 contains therapeutic drug 2845 at a concentration of Z. The core and therapeutic agent may be any of the core and therapeutic agents disclosed herein. Although the drug core is shown as a fan shape (fan shape), the drug core is not limited to any particular shape. Because the drug cores 2810, 2820, 2830, and 2840, or any combination thereof, together form a right cylindrical shape (see, e.g., fig. 29A-D), in this case, each drug core is a regular prism shape with a particular cross-section, e.g., a sector-shaped cross-section. The drug core may have many different combinable shapes, such as square, rectangular, oval, saw tooth shaped portions, to name a few.

Each individual drug core comprises a matrix containing a therapeutic agent, which may be present as a solid solution or may be present as an inclusion body. The inclusions often include the therapeutic drug in a concentrated form, such as a crystalline form of the therapeutic drug, and the therapeutic drug may dissolve into the matrix of the drug core over time. A certain concentration of drug may be dissolved in a matrix that is in equilibrium with drug inclusions. The dissolved drug concentration may be a saturation concentration. The matrix may include a silicone matrix, a polyurethane matrix, or the like. In many embodiments, the heterogeneous mixture includes a silicone matrix portion saturated with the therapeutic drug and an inclusion portion including therapeutic drug inclusions such that the heterogeneous mixture includes a heterogeneous mixture of phases. The first matrix may differ from the second matrix in terms of, for example, the area of exposed surface, surfactant, cross-linking, additives, and/or matrix materials, including formulation and/or solubility. In some embodiments, the inclusion comprises droplets of a therapeutic drug oil, for example, latanoprost oil. In some embodiments, the inclusion bodies may include particles of a therapeutic drug, such as solid bimatoprost particles in crystalline form. In many embodiments, the matrix encapsulates the inclusions, and the inclusions may comprise microparticles having a size of about 0.1 μm to about 100 μm, or 200 μm. The encapsulated inclusions are dissolved in a surrounding solid matrix (e.g., silicone) that encapsulates the microparticles such that the matrix is substantially saturated with the therapeutic drug upon release of the therapeutic drug from the core.

Fig. 29A-29D illustrate different embodiments of a cylindrical drug core surrounded by a sheath body 2920 using the core element of fig. 28. The sheath body 2920 can be substantially impermeable to the therapeutic agent such that the therapeutic agent is often released from exposed surfaces on the ends of the cylindrical drug core not covered by the sheath body 2920. In some embodiments, the sheath body may be omitted and the cylindrical drug core placed directly in the implant, such as in the orifice of the lacrimal plug. Although only four cylindrical drug core embodiments are shown, any suitable drug core and therapeutic agent may be used.

Fig. 29A shows one embodiment of a cylindrical drug core 2900 using a combination of two core elements 2810 (blank core), one core element 2820 and one core element 2830. Cylindrical drug core 2900 is then capable of delivering therapeutic drug 2825 at a concentration of X and therapeutic drug 2835 at a concentration of Y.

Fig. 29A shows an embodiment of a cylindrical drug core 2905 using a combination of one core element 2810 (blank core), one core element 2820, one core element 2830, and one core element 2840. Cylindrical drug core 2905 is then capable of delivering therapeutic agent 2825 at a concentration of X, therapeutic agent 2935 at a concentration of Y, and therapeutic agent 2845 at a concentration of Z.

Fig. 29C shows one embodiment of a cylindrical drug core 2910 using a combination of two core elements 2810 (blank core) and two core elements 2840. The cylindrical drug core 2910 is then able to deliver two doses of therapeutic drug 2845 at a concentration Z.

Fig. 29D illustrates one embodiment of a cylindrical drug core 2915 using a combination of four core elements 2840. The cylindrical drug core 2915 is then able to deliver four concentrations of the therapeutic drug 2845.

Fig. 30A and 30B illustrate other embodiments of cylindrical drug cores resulting from combinations of differently shaped core elements. Fig. 30A shows a cylindrical drug core 3000 made of two core elements 3010, 3015 in a semi-circular shape surrounded by a sheath body 3020. Fig. 30B shows a cylindrical drug core 3030 made of three core members 3040, 3045 and 3050 surrounded by a sheath body 3020. Although embodiments may include a plurality of substantially equally sized core elements, as shown, other embodiments may include two or more differently sized core elements. For example, the semicircular core element 3010 may be combined with two 1/4 circular core elements 2830 and 2840. Various sizes and non-uniform shapes may also be combined with various geometries, with or without a sheath body material (or other material substantially impermeable to the therapeutic drug (s)) between adjacent drug core elements. For example, sheets of drug core material (including the matrix and the bound drug) may be formed separately and stacked or formed into multiple layers, and/or may be formed sequentially by polymerizing the matrix over a substrate or polymerizing under a drug core element. The multi-layered sheet of drug core elements may then be cut from the transverse layers to the desired length and/or width of the drug core. Ends and/or sides of the sheet may be exposed in the implanted device, the exposed ends or sides of each multi-layer drug core element having a surface area that depends on the thickness of the associated drug core layer or sheet.

Fig. 31 illustrates a cross-sectional view of a sustained release implant 3100 having a first drug core 3110 and a second drug core 3115 for treating an eye 2, the first drug core 3110 including a first therapeutic agent 3160 and the second drug core 3115 including a second therapeutic agent 3165, the first and second drug cores in a stacked configuration, according to an embodiment of the invention.

Fig. 31 shows a cross-sectional view of a sustained release implant 3100 having two therapeutic agents for treating an eye, in accordance with an embodiment of the invention. Implant 3100 has a proximal end 3112 and a distal end 3114, and releases therapeutic agents at the proximal end. Implant 3100 includes two drug cores 3110, 3115. The first drug core 3110 is a cylindrical structure including a first therapeutic drug, and the second drug core 3115 is a cylindrical structure including a second therapeutic drug. The first drug core 3110 and the second drug core 3115 are assembled in a stacked configuration, as shown, with the first drug core 3110 positioned adjacent the proximal end 3112. First drug core 3110 includes first matrix 3170 containing first inclusions 3160 of a first therapeutic agent and second drug core 3115 includes second matrix 3175 containing second inclusions 3165 of a second therapeutic agent. The first and second enclosures 3160, 3165 often include the first and second therapeutic agents in concentrated form, such as a liquid or solid form, and the therapeutic agents may dissolve over time in the first matrix 3170 of the first drug core 3110 and in the second matrix 3175 of the second drug core 3115. The first and second matrices 3170, 3175 may comprise silicone matrices or the like, and the therapeutic drug mixture within the matrices may be heterogeneous. In many embodiments, the heterogeneous mixture includes a silicone matrix portion saturated with the therapeutic drug and an inclusion portion including therapeutic drug inclusions such that the heterogeneous mixture includes a heterogeneous mixture of phases. The first matrix may differ from the second matrix in terms of, for example, the area of exposed surface, surfactant, cross-linking, additives, and/or matrix materials, including formulation and/or solubility. In some embodiments, the first and second enclosures 3160, 3165 include droplets of therapeutic drug oil, e.g., latanoprost oil. In some embodiments, the first and second enclosures 3160, 3165 may include particles of a therapeutic drug, such as solid bimatoprost particles. In many embodiments, first matrix 3170 comprises first inclusions 3160 and second matrix 3175 comprises second inclusions 3165. The first and second enclosures 3160, 3165 may include microparticles having a size of about 0.1 μm to about 100 μm, or 200 μm. The contained inclusions are at least partially dissolved in a surrounding solid matrix (e.g., silicone) that contains the microparticles such that first and second matrices 3170, 3175 are substantially saturated with the therapeutic drug upon release of the therapeutic drug from the core.

The first and second drug cores 3110, 3115 are surrounded by the sheath body 3120 except for exposed surfaces where therapeutic drugs are released, in this case, at the proximal end 3112. The therapeutic agent is substantially impermeable to the sheath body 3120 such that the therapeutic agent is released from exposed surfaces on the open ends of the first and second drug cores 3110, 3115 not covered by the sheath body 3120. In some embodiments, the sheath body is similar to the sheath body 3120 disclosed above, and an indwelling structure and an occlusive element can be connected to the sheath body, such as the indwelling element and the occlusive element discussed above. In other embodiments, the implant may be incorporated into a different structure, such as a punctal plug (see fig. 32).

Fig. 32 schematically illustrates one embodiment of a therapeutic implant 3200 having a punctal plug and a sustained release implant having first and second stacked drug cores of first and second therapeutic agents. In the illustrated embodiment, the sustained release implant is a sustained release implant 3100 having a proximal first drug core 3110 and a distal second drug core 3115, the first drug core 3110 having first inclusions 3160 of a first therapeutic agent and the second drug core 3115 having second inclusions 3165 of a second therapeutic agent. With the therapeutic implant 3200 in place, the first therapeutic agent diffuses from the proximal first agent core at the exposed or proximal end and into the tears of the lacrimal lake, where the first therapeutic agent mixes with the tears and permeates the eye, such as an eye drop, to exert a predetermined pharmacological effect. After that, the second therapeutic agent diffuses from the distal second agent core, through the first agent core to the exposed or proximal end and into the tears of the lacrimal lake, where the second therapeutic agent mixes with the tears and permeates the eye, as eye drops, to exert the intended pharmacological effect. The size of the orifice 2140 is selected to hold the sustained release implant 3100 in place during treatment. In some embodiments, the sheath body 3120 of the implant 3100 may be omitted, and the first and second drug cores 3110, 3115 may be inserted directly into the orifice 2140 of the punctal plug 2100. Optionally, a permeable head 2115 for the first and second therapeutic agents may be used, as shown in fig. 22, wherein the first and second therapeutic agents diffuse from the first and second drug cores 3110, 3115 through the permeable head 3115.

In other embodiments, referring to fig. 33, a multiple drug delivery therapeutic implant 3310 may be implanted in other parts of the body 3300, rather than just the punctum, for treating a body condition, as shown in fig. 33. The therapeutic implant 3310 is a sustained release implant having at least one drug core containing first and second therapeutic agents for delivering multiple agents to treat conditions or diseases other than the eye. The therapeutic implant 3310 may comprise a therapeutic implant, such as the therapeutic implant described above, having two or more therapeutic agents released from the exposed surface of the core. The therapeutic implant may be implanted in a known manner.

Upon implantation of the implant in the body, the first and second therapeutic agents are released at therapeutic levels to provide a desired therapeutic response. The first and second therapeutic agents are preferably released at therapeutic levels for a sustained period of time. In some embodiments, the drug core can release the first and second therapeutic agents at an effective rate for 1 week to 5 years, more particularly 3-24 months. In some embodiments, it may be desirable for the drug core to have similar release rates of the first and second therapeutic agents. In other embodiments, it may be desirable for the drug core to have different release rates of the first and second therapeutic agents, depending on the therapeutic agent used. In some embodiments, the therapeutic level is less than the administered dose or lower, or 5-10%, typically less than 10%, often 5% or less than the daily administered dose for an extended period of days. The administered dose may be an oral dose or may be an injectable dose.

In use, the therapeutic implant 3310 is implanted into the body 3300 where bodily fluids may contact the exposed surfaces of the drug core, releasing the first and second therapeutic agents. Depending on the implant location, any bodily fluids (such as blood) adjacent the therapeutic implant may contact the exposed surface, releasing the first and second therapeutic agents from the implant. Therapeutic implant locations may include body locations for local delivery to a joint (such as proximate a shoulder, knee, elbow) or wound location 3315 or wound location 3320, other locations for systemic drug delivery (such as the abdomen). The therapeutic implant 3310 may include one or more indwelling components known in the art to maintain the therapeutic implant 3310 in proximity to a body location, such as those listed above.

In one embodiment, the therapeutic implant may be used in oncology, where chemotherapy involves the use of cocktail therapy depending on the type of primary tumor. The use of local therapeutic implant drug delivery may allow the additional benefit of post-operative treatment of the tumor site and minimize collateral damage to the rest of the body. Examples are local lumpectomy for breast tumors or surgical treatment of prostate cancer, where therapeutic implants are implanted near the cancer site. In fact, by implanting a therapeutic implant near the tumor, any solid tumor is the target.

In another embodiment, the therapeutic implant may be used to deliver a variety of drugs for the treatment of HIV, sometimes referred to as cocktail therapy. In this case, the therapeutic implant treats the systemic disease. One example of a variety of drugs in therapeutic implants are protease inhibitors and nucleic acid targets.

Some treatments are prohibited due to other disease states. One example is diabetes, where patients with impaired circulation and wound healing often require surgery, including amputation. Steroids cannot be used systemically in these patients, but can be used topically. In such embodiments, the therapeutic implant is positioned at an appropriate location within the body after surgery for the local delivery of the steroid and another drug, such as an anti-inflammatory or anti-infective drug. In some embodiments, the steroid may be released at therapeutic levels for 8 weeks or longer and the anti-inflammatory agent may be released at therapeutic levels for 2-4 weeks.

In joints, non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat conditions such as osteoarthritis and rheumatoid arthritis. Local delivery of NSAIDs reduces the risks associated with systemic coxII inhibitors, such as gastrointestinal problems (occurring in the stomach or intestine), which may include gastric ulceration or gastrorrhagia, and potentially life threatening punctures (tears or holes) in the stomach and intestinal walls. In such embodiments, the therapeutic implant is positioned near the joint for local delivery of the NSAID and may include delivery of a nutritional supplement such as glucosamine, and possibly a positive physiological response in the local tissue.

In another embodiment, the therapeutic implant may be used for localized delivery of multiple drugs to a wound site, such as delivery of analgesics and anti-infective drugs.

Figures 34 and 35 illustrate the anatomical structure of an eye 2 suitable for treatment with an implant, in accordance with an embodiment of the present invention. The eye 2 comprises a cornea 4 and an iris 6. The sclera 8 surrounds the cornea 4 and iris 6 and is shown as white. The conjunctival layer 9 is substantially transparent and is located over the sclera 8. The lens 5 is located within the eye. The retina 7 is located near the back of the eye 2 and is generally light sensitive. The retina 7 includes a fovea 7F that provides high visual acuity and color vision. The cornea 4 and lens 5 refract light to form an image on the fovea 7F and retina 7. The optical power of the cornea 4 and lens 5 helps to form an image on the fovea 7F and retina 7. The relative positions of the cornea 4, lens 5 and fovea 7F are also important for image quality. For example, if the axial length of the eye 2 from the cornea 4 to the retina 7F is large, the eye 2 may be myopic. Furthermore, during accommodation, the lens 5 moves towards the cornea 4 in order to provide the eye with good near vision of the proximal object.

The anatomical tissue structure shown in fig. 34 also includes the lacrimal system, including upper lacrimal duct 10 and lower lacrimal duct 12, collectively referred to as the lacrimal duct, and nasolacrimal duct or lacrimal sac 14. Upper lacrimal duct 10 and lower lacrimal duct 12 extend from lacrimal sac 14 and terminate in upper punctum 11 and lower punctum 13, respectively, upper punctum 11 and lower punctum 13 also being referred to as punctal orifices. The punctal orifice is located at a slightly elevated position at the medial extremity of the eyelid margin, at the junction 15 of the ciliary and lacrimal parts near the medial canthus 17. The punctal orifice is a circular or slightly oval opening surrounded by a connecting ring of tissue. Each lacrimal duct extends from a punctal opening 11, 13 and includes a vertical position 10v, 12v of the respective lacrimal duct, followed by a horizontal swivel to engage other lacrimal duct portions thereof at an entrance of lacrimal sac 14. The lacrimal duct is tubular and is lined by a stratified squamous epithelium surrounded by elastic tissue to allow the lacrimal duct to expand. The upper and lower canaliculi may each include a ampulla 10a, 12a, or what is referred to as a small dilated portion, in the respective canaliculi.

Production of implants

Fig. 6A shows a method 600 of producing an implant according to an embodiment of the present invention. Sub-method 610 produces a punctal plug. The sub-method 650 produces a drug core insert, for example as described above. Sub-method 690 assembles the components into an integrated drug delivery system.

Fig. 6B shows a method 620 of producing a hydrogel rod for a punctal plug according to the method 600 of fig. 6A. In some embodiments, method 620 includes sub-methods or sub-steps of method 610. Step 622 combines 40 wt% of the hydrogel with an organic solvent. In some embodiments, the percentage of hydrogel includes about 5% to about 50% hydrogel, such as about 20% to about 40% hydrogel. Step 624 mixes the hydrogel with a solvent. In some embodiments, the hydrogel may be dissolved in an organic solvent. Step 626 injects the hydrogel into the silicone tube. In many embodiments, the silicone tube is permeable to organic solvents. The silicone tube includes a mold for forming the hydrogel. Step 628 cures the hydrogel. At least one of heat or pressure (in many embodiments, both heat and pressure) may be used to expel the solvent, for example, through a permeable mold, to cure the hydrogel. Step 629 cuts the cured hydrogel to a desired length. Curing can be optimized by empirical methods/validation studies using sufficient sample size, e.g., 10 samples of cured hydrogel, to determine material variability and/or process variability over time. Adjustable variables that can be optimized include time to cure, pressure, and temperature. Tolerance analysis can also be performed in connection with the method.

Fig. 6C shows a method 630 of molding the silicone stopper body 637 according to the method 600 of fig. 6A. Step 632 winds a filament comprising a solid material, such as a coil 632C, and heat sets the filament. Step 634 places the filament including heat-set coil 632C in a mold. Step 636 molds the stopper body 637 with the coil 632C embedded therein. The stopper body may include a sleeve, a tube, a retention structure, and/or at least one lumen, as described above. The filaments may include at least one of a heat activated substance, Nitinol, shape memory material, polymer, polypropylene, polyester, nylon, natural fiber, stainless steel, polymethylmethacrylate, or polyimide. In some embodiments, the filament may comprise an absorbable thermoplastic polymer, such as at least one of polylactic acid, polyglycolic acid (PGA), or polylactic-co-glycolic acid (PLGA). Heat-setting of the filaments can be optimized by appropriately controlling the time and/or temperature at which the filaments are heated based on empirical data from samples of heat-set filaments (e.g., 10 filaments). The molding of step 636 can be optimized in several ways, such as proper time and temperature, mold hard tooling (hardtooling), multi-cavity mold, mold equipment parameters. In some embodiments, the filaments used to remove the drug core insert as described above may be molded with the stopper body such that the filaments are embedded in the stopper body and positioned adjacent to the channel that receives the drug core insert.

Fig. 6D illustrates a method 640 of assembling a punctal plug member according to the method 600 of fig. 6A. Step 630 molds lacrimal plug body 637 with coil 632C. Step 620 molds the hydrogel rod. Step 642 inserts the hydrogel rod component into the passageway of the body component of the stopper. Step 644 extends the windings of coil 632C over the hydrogel rod. Step 648 dip-coating the hydrogel rod and the plug body. Step 646 may prepare a hydrogel coating solution 646 that includes, for example, a 5 wt% hydrogel solution. Needles 648N may be placed in the channels of the plug body to hold the body while the hydrogel rod and plug body are immersed in the solution.

Fig. 6E illustrates a method 650 of producing a drug core insert according to the method 600 of fig. 6A. Step 661 prepares an injector assembly for injecting the drug matrix into the polyimide tube. Step 662 prepares a polyimide tube for injection. Step 670 prepares a drug core matrix for injection into a tube. Step 670 injects the drug core matrix into the polyimide tube. Step 680 cures the matrix within the polyimide tube. Step 682 cuts the polyimide tube and cured matrix into lengths and applies the adhesive.

Step 661 can use a known commercially available syringe in the syringe assembly. The syringe assembly may include a syringe barrel and a cartridge assembly. The syringe barrel and cartridge assembly may include a barrel connected to a modified needle tip that is connected to a syringe. The syringe may be connected to a syringe pump or other mechanism for pressurizing the tubing. The syringe assembly may be used to inject the drug core mixture and/or material into a polyimide tube. In some embodiments, multiple syringes may be used, for example to produce a drug insert comprising two or more drug cores. In some embodiments, the syringe assembly may include a manifold having two or more injection ports, available for use with separate syringes, each syringe including a different drug core mixture.

Step 662 may prepare a polyimide tube for injection by connecting a 15cm length of polyimide tube to a luer. The luer may be connected to a syringe for injecting the drug core mixture and/or material. In some embodiments, the tubing connected to the syringe may comprise PMMA and/or PET. In many embodiments, the tube comprises a material that inhibits release of the therapeutic drug from the drug core through the tube, e.g., a material through which the therapeutic drug stream is substantially impermeable, such that the therapeutic drug stream is directed toward the exposed end of the drug core. In some embodiments, such as where the drug core insert includes two or more concentric drug cores, the tube may comprise concentric tubes, such as concentric polyimide tubes, the outer tube being designed to receive the outer drug core mixture and the inner tube being designed to receive the inner drug core mixture. Using an annular drug core as described above, concentric tubes may be used to form the annular drug core, and the inner tube may be removed after curing of the drug core matrix material.

In some embodiments, a filament for removal of a drug core insert may be embedded in the drug core. The filament may pass through a sheath (e.g., a tube) and the mixture injected into the tube. The matrix material is then cured, embedding the filaments in the matrix.

Step 670 may prepare a drug core mixture comprising a therapeutic drug and a matrix material (e.g., silicone). In some embodiments, the therapeutic agent may include at least one of latanoprost, bimatoprost, or travoprost. Embodiments may use silicones including polydimethylsiloxanes such as Med-4011, Med-6385, and Med-6380, all available from NuSiloflafLafayette, Calif. In some embodiments, two or more drug core mixtures are prepared, each for injecting a separate drug core, e.g., one of the two mixtures for the inner drug core and the other for the outer drug core.

In certain embodiments, step 670 may prepare a drug core mixture comprising silicone containing latanoprost oil inclusions. The therapeutic agent and drug core matrix material may be prepared prior to mixing the therapeutic agent with the drug core matrix material.

Preparation of the therapeutic drug:

latanoprost oil may be provided as a 1% solution in methyl acetate. An appropriate amount of 1% solution can be placed in the tray. The solution can be evaporated using a dry nitrogen flow until only latanoprost remains. The pan containing latanoprost oil was placed under vacuum for 30 minutes. In some embodiments, such as those cases where bimatoprost obtained as crystals is used as a therapeutic drug, evaporation and vacuum may not be used to prepare the therapeutic drug.

In some embodiments where a solid therapeutic agent (e.g., bimatoprost crystals) is used, the therapeutic agent may be ground and passed through a screen prior to mixing with the matrix material. In some embodiments, the sieve may comprise a 120 mesh sieve (125um) and/or a 170 mesh sieve (90 um). Work in connection with embodiments of the present invention indicates that a screen can remove a very small fraction of a therapeutic agent, and many embodiments involve therapeutic agent inclusions that are larger in size than an optional screen. In many embodiments, the release rate is independent of the size and/or particle size distribution of the inclusion, and the release rate may be independent of the particle size of the particles from about 0.1um to about 100 um. In some embodiments, the size and/or particle size distribution of the particles and/or inclusions can be characterized by at least one of: a sieve, light scattering measurement data of the core, optical microscopy of the core, scanning electron microscopy of the core or transmission electron microscopy of a cross section of the core. Sieves can generally be used to produce a desired particle size and/or to exclude undesirable particle sizes prior to mixing with the matrix. Exemplary screens include fine screens that pass only particles of a desired size or smaller, thereby limiting the therapeutic drug to finer drug particles. This can be used to produce a more homogeneous drug core and/or drug particle size that is easier to mix with the silicone matrix than oversized particles, although the particle size can remain significantly variable. Various sieves can be used. For example, a 120 mesh screen may be used such that the maximum particle size passed is about.0049 inches. A 170 mesh screen can pass particles of.0035 inches in diameter or less. A 70 mesh screen would allow passage of a.0083 inch diameter particle size. The screens may optionally be used in series.

Preparation of organic silicon:

silicones, such as NuSil6385, can be obtained from manufacturers in the form of sealed containers. An appropriate amount of silicone may be weighed based on the determined batch size.

The combination of the therapeutic drug and the organic silicon

A therapeutic drug (e.g., latanoprost) can be combined with the silicone based on a predetermined and/or measured percentage of the therapeutic drug in the drug core matrix. The percentage of latanoprost to silicone may be determined by the total weight of the drug matrix. Therapeutic agents such as latanoprost are incorporated into the silicone by weighing out the appropriate amounts of the components. The following formula can be used to determine the percentage of therapeutic agent in the drug core matrix.

Drug percentage = (drug weight)/(drug weight + silicone weight) X100

For a specific example of latanoprost in silicone, the percentage of latanoprost in silicone is:

(20mg of latanoprost)/(20 mg of latanoprost +80mg of silicone) X100= 20%.

The therapeutic drug (e.g., latanoprost) is combined and mixed with the silicone using known methods and devices for mixing silicones. In some embodiments, a therapeutic drug comprising latanoprost oil can form a microemulsion comprising inclusions that can scatter light and appear white.

In the case of using a therapeutic drug such as latanoprost (a physical state in which latanoprost is liquid at about room temperature (22 ℃) and thus is also liquid at human body temperature (37 ℃), the drug and the matrix material can be mixed by a technique in which droplets of liquid latanoprost that are substantially insoluble in the matrix material are highly dispersed in the matrix material. The mixing technique should provide a dispersion of droplets within the matrix material such that, upon solidification, the liquid therapeutic drug is present within the matrix of the solid silicone material as relatively small, relatively uniformly dispersed discrete droplets. For example, mixing may include sonication, i.e., using ultrasonic frequencies, such as generated by an ultrasonic probe. The probe can be contacted with a mixture of a matrix material and a liquid therapeutic drug to produce an intimate mixture of the two substantially immiscible materials. See, e.g., example 12 below.

Step 672 may inject a mixture of a therapeutic drug and silicone into the tube. A syringe (e.g., a 1ml syringe) may be attached to the syringe barrel and cartridge assembly. A drop of catalyst suitable for silicone (e.g., MED-6385 curative) can be placed in the syringe and the syringe then filled with uncured silicone and therapeutic drug, or silicone drug matrix. The mixture that is still liquid to flow or pump (i.e., the uncured silicone and drug mixture) can be cooled to a temperature below room temperature. For example, the mixture may be frozen to a temperature below 20 ℃. For example, the mixture may be frozen to 0 ℃ or frozen to-25 ℃. The drug/matrix mixture was injected into the polyimide tube until the tube was filled. The tube and associated device may also be frozen to maintain the sub-ambient temperature of the mixture throughout the filling or injection of the sheath with the mixture. In various embodiments, the polyimide tube or sheath is filled with the drug matrix mixture under pressure, for example using a high pressure pump. For example, a drug/matrix mixture (such as that obtained as a mixture of latanoprost and MED-6385 part a, to which different amounts of catalyst part B have been added) can be pumped into the tube at a pressure of at least about 40 psi. The tube may be filled at any suitable rate, but preferably at a rate of less than about 0.5 linear cm/sec. The inventors believe that relatively rapid filling of the tube at higher head pressures can reduce the degree of phase separation of the substantially immiscible latanoprost oil and silicone monomer material, such that upon polymerization ("curing") a final silicone polymerization product is provided in which the latanoprost droplets are finely dispersed in a solid matrix in which they are only slightly soluble.

Curing is carried out in the presence of a catalyst ("part B") of NuSilMED-6385 and can be carried out at a temperature of at least about 40 ℃, at a Relative Humidity (RH) of at least about 80%, or both. Curing may be initiated immediately after filling the tube and clamping the end of the filled tube in order to prevent the formation of voids and loss of precursor material from the tube end.

After curing (perhaps done at 40 ℃ and 80% RH for about 16-24 hours), the clamp can be removed from the end of the tube because the silicone is fully cured. The tube may then be cut to a suitable length for use as a drug insert, for example, a length of about 1 mm.

In the case of extrusion at temperatures below room temperature, small and more uniform drug inclusions can be obtained. For example, where the drug is latanoprost (liquid at room temperature), extrusion at-5 ℃ provides significantly smaller and more uniform droplets of inclusions. In the examples, cold extrusion resulted in drug cores comprising an organosilicon matrix containing latanoprost droplets with a mean diameter of 6 μm and a standard deviation of 2 μm in diameter. By comparison, extrusion at room temperature yielded drug cores comprising a silicone matrix containing Latanoprost droplets with a mean diameter of 19 μm and a standard deviation of the droplet diameters of 19 μm. Clearly, the cold extrusion technique provides smaller, more uniform inclusions than room temperature extrusion. This in turn results in a more uniform concentration of the drug in the core or in the insert comprising the core, which is desirable for medical applications because the uniformity of dosing is improved.

The open end of the polyimide tube can be closed until the silicone begins to cure. In some embodiments using two or more drug cores, two or more separate mixtures may each be injected separately from two or more syringes.

Step 680 cures a drug core matrix comprising the mixture silicone and therapeutic drug. The silicone is allowed to cure, for example, for 12 hours. The time and temperature of curing can be controlled and empirical data can be generated to determine the desired curing time and temperature. Work in connection with embodiments of the present invention indicates that the silicone material and drug loading of the core (e.g., the percentage of therapeutic drug in the core) can affect the optimal time and temperature for curing. In some embodiments, empirical data may be generated for the percentage of each silicone matrix material and each therapeutic drug to determine the optimal cure time for the injected mixture. In some embodiments where two or more drug cores are used in the drug core insert, the two or more mixtures may be cured together to cure the drug core of the insert.

Table 1 shows drug insert silicones and related curing properties that may be used according to embodiments of the present invention. The drug core insert matrix material may comprise a base polymer comprising dimethylsiloxane, such as MED-4011, MED6385, and MED6380, all available from nusilscompley. The base polymer may be cured with a curing system such as a platinum-vinyl hydride curing system and/or a tin-alkoxy curing system, both of which are available from NuSil. In many embodiments, the curing system may comprise a commercially known curing system for known materials, such as the known platinum vinyl hydride curing system used in the known MED-4011. In the particular embodiment shown in Table 1, 90 parts of MED-4011 can be combined with 10 parts of a crosslinking agent such that the crosslinking agent comprises 10% of the mixture. The mixture containing MED-6385 can include 2.5% crosslinker, while the mixture of MED-6380 can include 2.5% or 5% crosslinker.

TABLE 1 drug insert Silicone selection

Work in connection with embodiments of the present invention suggests that the curing system, as well as the type of silicone material, may affect the curing properties of the solid drug core insert, and may potentially affect the yield of therapeutic drug from the drug core matrix material. In particular embodiments in the case of high concentrations of latanoprost, e.g., more than 20% latanoprost, curing MED-4011 with a platinum vinyl hydride system may be inhibited, such that a solid drug core may not be formed. In particular embodiments, curing MED-6385 and/or MED630 with a tin alkoxy system may be slightly inhibited by high concentrations (e.g., 20%) of latanoprost. This slight cure inhibition can be compensated by increasing the time and/or temperature of the curing process. For example, embodiments of the present invention can prepare drug cores of 40% latanoprost and 60% MED-6385 with a stannoxy system using appropriate curing times and temperatures. Similar results can be obtained using MED-6380 systems, tin-alkoxy systems and appropriate curing times and/or temperatures. In many embodiments, the solid drug core is formed so as to form a solid structure, such as a solid cylinder, within the drug core corresponding to the dimensions of the tube. Despite the excellent results of tin alkoxy curing systems, work in connection with embodiments of the present invention suggests that there may be an upper limit, for example, at over 50% latanoprost, tin-alkoxy curing systems may not yield solid drug cores. In many embodiments, the therapeutic agent includes a prostaglandin analog, e.g., latanoprost in the drug solid drug core may constitute at least about 5% by weight of the drug core, such as about 5% to 50% by weight, and may be about 20% to about 40% by weight. In particular embodiments where the drug core comprises a medium to high therapeutic drug loading, the drug core may comprise from about 25% to about 50% therapeutic drug in the drug core, for example 50% latanoprost oil in the drug core and/or in the matrix material.

In some embodiments, the therapeutic agent may include functional groups that can at least potentially react with the curing system. In some embodiments, the therapeutic agent may include a prostaglandin analog, such as latanoprost, bimatoprost, or travoprost, each of which may include an unsaturated carbon-carbon double bond that may potentially react with the platinum vinyl hydride curing system. These unsaturated carbon-carbon double bonds may be similar to the vinyl groups in platinum-curing vinyl hydride systems and may potentially react with vinyl hydride curing systems through a hydrosilation reaction. Latanoprost includes an unsaturated carbon-carbon double bond in one side chain. Bimatoprost and travoprost each include two unsaturated carbon-carbon double bonds, one in each side chain. Work in connection with embodiments of the present invention indicates that the hydrosilation reaction of the unsaturated double bond in the prostaglandin analog with the platinum vinyl hydride curing system does not significantly reduce the amount of prostaglandin analog available for release from the drug core.

In some embodiments, the therapeutic agent may include a prostaglandin analog, such as latanoprost, bimatoprost, or travoprost, each of which may include a hydroxyl group that may potentially react with a stannoxy curing system. These hydroxyl groups can potentially react with alkoxy groups by alkoxy condensation reactions. Bimatoprost, latanoprost and travoprost each contain three hydroxyl groups per molecule that can potentially react by alkoxy condensation. Work in connection with embodiments of the present invention indicates that the condensation of hydroxyl groups in a prostaglandin analog with alkoxy groups of a stannoxy curing system does not significantly reduce the amount of prostaglandin analog available for release from the drug core. Work in connection with embodiments of the present invention indicates that only a negligible amount of therapeutic drug is consumed by solidification or otherwise unavailable because therapeutic drug extraction data for solid cores indicates that at least 95%, e.g., 97% or more, of the therapeutic drug can be extracted from the drug core.

In some embodiments, the silicone material may include an inert filler to add rigidity to the cured matrix. Work in connection with embodiments of the present invention suggests that filler materials may enhance the release rate of therapeutic agents. MED-4011 and MED-6385 materials are commercially available as filler-containing materials. The MED-4011 material can include an inert silica filler material to add rigidity to the cured silicone matrix. MED-4385 may include an inert diatomaceous earth filler to add rigidity to the cured silicone matrix.

The inert filler material may increase the drug concentration in the silicone of the component matrix because the filler material may not substantially adsorb the therapeutic drug, and the inert filler material may decrease the silicone fraction in the drug core matrix. In some embodiments, MED-4385 comprises about 25% diatomaceous earth filler and about 75% dimethicone. In a particular embodiment, the drug core may comprise 40% therapeutic drug and 60% material. The 60% material, for example MED-4385, corresponds to 45% dimethylsiloxane base polymer and 15% inert diatomaceous earth filler. If very little of the therapeutic agent is adsorbed into the inert filler material, 40% of the therapeutic agent is contained within 45% of the dimethicone base polymer such that the concentration of therapeutic agent in the base polymer is 47% or about 50%. Thus, the release rate of the therapeutic agent from the exposed surface of the silicone drug core insert may be slightly increased, as the concentration of the therapeutic agent in the silicone portion of the matrix material may be increased due to the presence of the filler. In some embodiments, the drug core may include a matrix material without filler such that the therapeutic drug (e.g., latanoprost oil) comprises about 50% of the solidified solid drug core, and may also include a concentration of about 50% in the matrix base polymer.

In many embodiments, the size and/or particle size distribution of the inclusions in the core may be characterized by at least one of: light scattering measurement data of the core, optical microscopy of the core, scanning electron microscopy of the core, or transmission electron microscopy of a cross-section of the core.

Step 680 cuts the polyimide tube containing the cured solid matrix mixture to a predetermined length and may apply an adhesive to one end of the cut length of the tube. In many embodiments, the matrix material is cured to form a solid drug core structure, such as a cylindrical rod corresponding to the shape of the tube, such that the exposed surface of the cut solid drug core substantially retains its shape when implanted in a patient. In some embodiments having two or more drug cores in the drug core insert, the two or more drug cores may be cut together, e.g., the tube and the cores of concentric drug cores may be cut together.

Cutting the drug insert to length:

the polyimide tube may be inserted into a fixture and cut into sections of a specified length. In some embodiments, the cut section of polyimide tubing may be placed in a vacuum for 30 minutes. The cut polyimide tube including the drug core insert may be inspected and weighed after vacuum and the weight recorded.

End-blocking of drug core insert:

an adhesive may be applied to one end of the drug core insert. The adhesive may be applied as a liquid and cured under UV light, for example, for five seconds. In particular embodiments, the adhesive may include Loctite4305UV adhesive. In many embodiments, the material applied to one end of the drug core insert comprises a material that is substantially impermeable to the therapeutic agent such that release of the therapeutic agent by passing through the covered end is inhibited. Such inhibition of release of the drug core through the covered ends may result in effective and/or efficient delivery of the drug through the exposed surface of the drug core on the opposite end, such that the drug is selectively released to the target tissue and/or bodily fluid, e.g., to the tear fluid or tear film. In some embodiments, the end-binding filaments may be as described above to facilitate removal of the drug core insert from the implant.

In some embodiments, the end may be closed by heat welding, clamping the closed tube end and covering the tube end with an end cap of a material that is substantially impermeable to the therapeutic agent so as to inhibit release of the therapeutic agent through the end cap. In embodiments where two or more drug cores are used in the drug core insert, the capped ends may cover both cores, e.g., an inner cylindrical core and an outer annular core.

In some embodiments, where the drug is allowed to pass through the drug core, the ends of the drug core may not be closed, or may be partially closed, for example using an end cap having openings to allow fluid flow through the channels in the core, with the outer periphery of the end cap covering the annular ends of the core.

In some embodiments, the exposed end opposite the closed end is shaped to increase the surface area of the exposed end, as described above. In some embodiments, a cone with a sharp tip (similar to a sharp pencil tip) may be inserted into the exposed surface to retract the exposed surface to have an inverted conical shape, which increases the surface area. In some embodiments, the exposed end may be hemmed to reduce surface area.

Fig. 6F shows a method 690 of final assembly according to the method 600 of fig. 6A. Step 692 inserts the drug core component into the channel of the lacrimal plug. Step 694 packages the lacrimal plug with the drug core insert in the passage. Step 696 sterilizes the packaged stopper and drug core insert. Step 698 publishes the product.

Step 692 inserts the drug core into an implant (e.g., a punctal plug). The drug core may be inspected prior to insertion and may be part of the insertion procedure. The inspection may include visual inspection to ensure that the sleeve including the cut tube is completely filled, there are no air holes or foreign matter in the silicone matrix, check that the silicone is flush with the polyimide tube and has the same length, check that the adhesive including cyanoacrylate completely covers one end of the tube, and check that the tube has the correct length. Drug inserts and implants including punctal plugs can be loaded into drug insertion tools and clamps. The drug insert may be loaded into the implant bore or channel using a plunger on the drug insertion tool. The drug insert insertion tool may be removed. The implant including the punctal plug can be inspected to verify that the drug core insert is fully located in the bore hole, that the drug core insert is below the surface of the chimb of the punctal plug, and that no visible damage has occurred to the implant/drug core assembly.

Step 694 packages a punctal plug comprising a drug core inserted in the passageway.

The punctal plugs can be packaged in known packages and methods, for example, using an inner pouch, an outer Mylar pouch, a pouch sealer, argon, and an inflation needle. In a particular embodiment, two complete drug delivery systems are placed in and sealed within an inner pouch, each comprising a lacrimal plug implant comprising a drug core insert. The sealed inner pouch is placed in the outer pouch. The outer pouch may extend about 1/4 beyond the pouch sealer element. A 25 gauge needle can be inserted into the pouch and under the seal under a stream of argon gas. The sealer element can be clamped and the package allowed to expand. The argon gas stream needle can be removed and the sealing operation repeated. The package can be inspected by gently pressing the argon filled pouch to check for leaks. If a leak is detected, the inner pouch is removed and repackaged in a new Mylar outer pouch.

Step 696 may sterilize the packaged stoppers and drug core inserts using known sterilization methods, such as using commercially available electron beams from Nutek corporation of Hayward, Calif.

Step 698 may release the product according to the final verification and release process.

It should be appreciated that the specific steps illustrated in fig. 6A-6E provide a particular method of producing a stopper containing a drug core insert according to some embodiments of the present invention. Other sequences of steps may also be performed, according to alternative embodiments. For example, alternative embodiments of the present invention may perform the above steps in a different order. Further, the individual steps illustrated in fig. 6A-6E may include multiple sub-steps that may be performed in different sequences as appropriate to the individual step, as desired. Further, additional steps may be added or steps may be deleted depending on the particular application. Those skilled in the art will recognize many variations, modifications, and alternatives.

Detailed description of the preferred embodiments

Example 1

Latanoprost drug core elution data

Drug cores as described above have been manufactured with different cross-sectional sizes (0.006 inches, 0.012 inches, and 0.025 inches) and different drug concentrations (5%, 10%, and 20%) in the silicone matrix. These drug cores can be produced as follows: using a syringe tube and cartridge assembly (syringetube and cartridge assembly), latanoprost was mixed with silicone, and the mixture was injected into a polyimide tube, cut to a desired length and sealed. The length of the drug core was about 0.80-0.95mm for a diameter of 0.012 inches (0.32mm), corresponding to a total latanoprost content of about 3.5 μ g, 7 μ g, and 14 μ g at 5%, 10%, and 20% concentrations, respectively, in the drug core.

Syringe and cartridge assembly 1. polyimide tubing of three different diameters of 0.006 inch, 0.0125 inch and 0.025 inch was obtained. 2. Polyimide tubes of different diameters were cut to-15 cm length. 3. The polyimide tube was inserted into the syringe adapter. 4. The polyimide tube adhesive was bonded in a luer adapter (Loctite, low viscosity UV cure). 5. Trimming the ends of the assembly. 6. The cartridge assembly was cleaned with distilled water, then methanol, and dried in an oven at 60 ℃.

Latanoprost is mixed with silicone. Preparing latanoprost. Latanoprost is provided as a 1% solution in methyl acetate. The appropriate amount of solution was placed in a dish and the solution was evaporated using a stream of nitrogen until latanoprost alone remained. The pan containing latanoprost oil was placed under vacuum for 30 minutes. Latanoprost was combined with silicone. Silicone Nusil6385 containing three different concentrations of latanoprost (5%, 10%, and 20%) was prepared and injected into tubes of different diameters (0.006 inch, 0.012 inch, and 0.025 inch) to give a 3X3 matrix. The percentage of latanoprost to silicone is determined by the total weight of the drug matrix. And (3) calculating: weight of latanoprost/(weight of latanoprost + weight of silicone) X100= drug percentage.

And (4) injecting a tube. 1. The cartridge and polyimide tube assembly were inserted into a 1ml syringe. 2. A drop of catalyst (MED-6385 curative) was added to the syringe. 3. Excess catalyst was pushed out of the polyimide tube with clean air. 4. The syringe was filled with a silicone drug matrix. 5. The tube is injected with the drug matrix until the tube is filled or the syringe plunger becomes difficult to push. 6. The distal end of the polyimide tube was closed and pressure was maintained until the silicone began to cure. 7. Cured at room temperature for 12 hours. 8. The mixture was placed under vacuum for 30 minutes. 9. The tubes were placed in a suitable size trim fixture (homemade, for holding different sized tubes) and the drug inserts were cut to length (0.80-0.95 mm).

And (6) checking. Elution study (in vitro). 1. 10 stoppers of the same size and concentration were placed in each centrifuge tube and 1.5ml of 7.4pH buffer solution was added thereto. 2. After an appropriate time the solvent was replaced with fresh 7.4pH buffer. 3. The eluate was subjected to HPLC, detected at 210nm using a PDA detector 2996, using a SunfireC18, 3mmx10mm column (Waters corporation, Milford, Mass.). Gradient elution was performed using a mixture of acetonitrile and water. Internal calibration was performed before and after each analysis, using home-made standards of precisely weighed latanoprost concentrations. 4. The amount of drug released from different sized tubes with different concentrations of latanoprost per device per day was calculated. 5. The elution rates at day 1 and day 14 were plotted against area and concentration.

Figures 7A and 7B show latanoprost elution data at day 1 and 14 for three core diameters of 0.006, 0.012, and 0.025 inches and three latanoprost concentrations of approximately 5%, 11%, and 18%. The rate of latanoprost elution in nanograms per day (ng/day) was plotted against the percent concentration. These data show that the elution rate is mildly dependent on concentration and strongly dependent on the area of the exposed surface over the two time periods. On day 1, the 0.006 inch, 0.012 inch and 0.025 inch diameter cores released about 200ng, 400ng and 1200ng of latanoprost, respectively, indicating that the amount of latanoprost released increased with increasing size of the exposed surface area of the drug core. For each tube diameter, the amount of latanoprost released was compared to the drug concentration in the drug core using a least squares regression curve. The slopes of the regression curves were 11.8, 7.4, and 23.4 for the 0.006, 0.012, and 0.025 inch drug cores, respectively. These values show that doubling the drug concentration of latanoprost in the core does not cause a doubling of the elution rate of latanoprost from the core, consistent with droplets of latanoprost suspended in the drug core matrix and the drug core matrix being substantially saturated with latanoprost dissolved therein, as described above.

On day 14, the 0.006 inch, 0.012 inch (0.32mm), and 0.025 inch diameter cores released about 25ng, 100ng, and 300ng of latanoprost, respectively, indicating that the amount of latanoprost released increased with increasing size of the exposed surface area of the drug core over an extended period of time, and that the amount of latanoprost released was mildly dependent on the therapeutic drug concentration in the core. For each tube diameter, the amount of latanoprost released was compared to the drug concentration in the drug core using a least squares regression curve. The slopes of the regression curves were 3.0, 4.3, and 2.2 for the 0.006, 0.012, and 0.025 inch drug cores, respectively. These values show that doubling the drug concentration of latanoprost in the core does not cause doubling of the elution rate of latanoprost from the core, for 0.012 and 0.025 inch cores, consistent with the droplets of latanoprost suspended in the drug core matrix and the drug core matrix being substantially saturated with latanoprost dissolved therein, as described above. However, for a 0.006 inch diameter core, there is an approximately first order relationship between the initial amount in the core and the amount of drug released at day 14, which may be caused by depletion of the latanoprost drug droplets in the core.

Fig. 7D and 7E show graphs showing the dependence of the elution rates at day 1 and day 14 for the three core diameters and the three concentrations in fig. 7A and 7B on the exposed surface area of the drug core, according to embodiments of the present invention. The elution rate of latanoprost in nanograms per day (ng/day) versus the diameter in mm determined by the diameter of the drug core²The exposed surface area of the drug core is plotted as units. These data indicate that at 1 day and 14 days, the elution rate depends mildly on the drug concentration in the core and strongly on the area of the exposed surface. The areas of the exposed surfaces of the 0.006 inch, 0.012 inch and 0.025 inch diameter cores were about 0.02, 0.07 and 0.32mm, respectively². On day 1, 0.02, 0.07 and 0.32mm²The core released about 200ng, 400ng and 1200ng of latanoprost, respectively, indicating that the amount of latanoprost released increased with increasing size of the exposed surface area of the drug core. For each concentration of therapeutic drug in the drug core, the release was compared using a least squares regression lineThe amount of latanoprost and the area of the exposed surface of the drug core. The slopes of the regression curves were 2837.8, 3286.1, and 3411.6 for 5.1%, 11.2%, and 17.9% drug cores, respectively, with an R2 coefficient of 0.9925, 0.9701, and 1, respectively. On day 14, 0.02, 0.07 and 0.32mm ²The core released about 25ng, 100ng and 300ng of latanoprost, respectively, indicating that the amount of latanoprost released increased with increasing size of the exposed surface area of the drug core. The slopes of the regression curves were 812.19, 1060.1, and 764.35 for 5.1%, 11.2%, and 17.9% drug cores, respectively, and the R2 coefficients were 0.9904, 0.9924, and 0.9663, respectively. These values indicate that the elution rate of latanoprost from the core increases linearly with the surface area of the drug core, consistent with the drug sheath being able to control the area of the exposed surface, as described above. The weak dependence of latanoprost elution on the concentration in the drug core is consistent with the droplets of latanoprost suspended in the drug core matrix and the drug core matrix with latanoprost dissolved therein being substantially saturated, as described above.

Figure 7C shows elution data showing latanoprost from 0.32mm diameter, 0.95mm long drug cores at concentrations of 5, 10, and 20%, and drug weights of 3.5, 7, and 14 μ g, respectively, according to embodiments of the present invention. The drug cores were produced as described above. The elution rate per day is plotted from 0-40 days in ng. A14. mu.g core showed a rate of approximately 100 ng/day for about 10-40 days. Cores of 7. mu.g showed comparable rates from 10 to 20 days. These data are consistent with droplets of latanoprost suspended in the drug core matrix and substantial saturation of the drug core matrix by latanoprost dissolved therein, as described above.

Table 2 shows the expected parameters for each drug concentration. As shown in figure 7C, in vitro results in a buffered saline elution system showed that the stopper initially eluted about 500ng latanoprost per day, rapidly dropping to about 100 ng/day within 7-14 days, depending on the initial concentration of drug.

TABLE 2 drug elution Properties

Total latanoprost content	14μg	7μg	3.5μg
				Rate of elution in vitro	See FIG. 7C	See FIG. 7C	See FIG. 7C
Duration of time	About 100 days	About 45 days	About 25 days

In many embodiments, the duration of the drug core may be determined based on maintaining-10% of the initial drug amount in the drug insert, e.g., a calculated time wherein the elution rate drops and remains substantially constant at about 100 ng/day.

Example 2

Cyclosporin drug core elution data

The drug core as described in example 1 was prepared with a cyclosporin concentration of 21.2%. Fig. 8A shows a graph showing elution of cyclosporin from the drug core into surfactant-free and surfactant-containing buffer solutions, according to an embodiment of the present invention. The buffer solution was prepared as described above. Surfactant containing solutions include 95% buffer and 5% surfactant, UP-1005UltraPurefluid from Dow Corning, Midland MI. Work in connection with embodiments of the present invention indicates that, in at least some instances, surfactants can be used to mimic in vitro elution from the eye in situ, as the eye can include a natural surfactant, such as surfactant protein D, in the tear film. The elution of cyclosporin into the surfactant is characterized by about 50-100ng per day from 30-60 days. Empirical data from tears from a patient population (e.g., 10 patients) can be measured and used to modify the in vitro model with the appropriate amount of surfactant. The drug core matrix may be modified based on human tear surfactant as determined in a modified in vitro model. The drug core may be modified in response to human tear film surfactants in a number of ways, such as increasing the area of exposed surface and/or additives to increase the amount of cyclosporin drug dissolved in the core, as described above, and if desired, to increase elution from the core to therapeutic levels.

Example 3

Bimatoprost bulk elution data

Bulk samples of 1% bimatoprost known to be 0.076cm (0.76mm) in diameter were prepared. The height of each sample was determined from the weight and the known sample diameter.

TABLE 3 bulk sample size

The calculated height is 0.33cm-0.42 cm. The exposed surface area on each end of each bulk sample was about 0.045cm²For 0.42 and 0.33cm samples, 0.019cm is provided³And 0.015cm³The volume of (a). Exposure of samples calculated from height and diameter of drug-free sheathThe area of the surface is about 0.1cm². Three formulations were evaluated: 1) organic silicon 4011, 1% bimatoprost, 0% surfactant; 2) silicone 4011, 1% bimatoprost, about 11% surfactant; and 3) organosilicon 4011, 1% bimatoprost, about 33% surfactant. The elution data measured for bulk samples of formulations 1, 2 and 3 were normalized to ng per device per day, (ng/device/day), assuming that the surface area of the bulk device was 0.1cm²And the surface area of the clinical device is 0.00078cm²(0.3mm diameter). Fig. 9A shows the normalized elution profile in ng per device per day for a bulk silicone sample containing 1% bimatoprost over a 100 day period, assuming an exposed surface diameter on the end of the device of 0.3mm, according to an embodiment of the present invention. The normalized elution profile was about 10 ng/day. The data show an approximately zero order release kinetics from about 10 days to about 90 days for each formulation. These data are consistent with the bimatoprost particles suspended in the drug core matrix and the drug core matrix being substantially saturated with bimatoprost dissolved therein, as described above. Similar formulations may use a drug core sheath and have a shaped core exposed surface exposed to tears to increase the area of the exposed surface and deliver the drug in therapeutic amounts over a delayed period of time, as described above.

In some embodiments, the core may comprise a 0.76mm diameter core with an exposed surface having a diameter of 0.76mm, corresponding to 0.0045cm²The area of the exposed surface of (a). The core may be covered with a sheath to define the exposed surface of the core, as described above. Based on the bulk sample data above, the normalized elution characteristics of this device was approximately 6 times (0.0045 cm) the elution characteristics of a device having a 0.3mm diameter exposed surface area²/0.00078cm²). Thus, a zero order elution profile with an elution rate of about 60 ng/day may be obtained over a period of about 90 days. If the area of the exposed surface is increased to about 0.0078cm²E.g., having many exposed surface shapes as described above, the zero order elution rate is about 100 ng/day over a period of about 90 days. The concentration can also be increased from 1%. Using latanoprost canTo obtain similar elution characteristics.

Example 4

Latanoprost elution data

Drug cores were produced as described above in example 1 using latanoprost and silicones 4011, 6385 and/or NaCl. Four formulations were produced as follows: A) silicone 4011, about 20% latanoprost, and about 20% NaCL; B) silicone 4011, about 20% latanoprost, and about 10% NaCl; C) silicone 4011, about 10% latanoprost, and about 10% NaCl; and D) silicone 6385, about 20% latanoprost.

Figure 10 shows a graph of elution of latanoprost from the core of four formulations of latanoprost according to an embodiment of the invention. The results show an initial rate of approximately 300ng per device per day, which drops to approximately 100ng per device per day by the third week (21 days). The result shown is a non-sterile drug core. Similar results have been obtained with sterile latanoprost drug cores. These data are consistent with droplets of latanoprost suspended in the drug core matrix and substantial saturation of the drug core matrix by latanoprost dissolved therein, as described above.

Example 5

Drug release as a function of cross-linking

Figure 11A shows an embodiment according to the present invention showing the effect of material and cross-linking on the elution of a drug core with 20% latanoprost. The drug cores were produced using the production methods in fig. 6E and table 1, as described above. The drug core comprises 4011 silicone, 6385 silicone with 2.5% crosslinker, 6380 with 2.5% crosslinker and 6380 with 5% crosslinker. The therapeutic drug in all samples included approximately 20% latanoprost. The 6380 material with 5% crosslinker provided the lowest elution rate at all time points. Since 6380 material containing 5% crosslinker elutes at a lower rate than 6385 material containing 2.5% crosslinker, it appears that increased crosslinker and concomitant crosslinking reduce the elution rate. The 6385 material containing 2.5% crosslinker provided the highest elution rates at days 1, 4, 7 and 14. 6380 material with 2.5% crosslinker had a slightly lower elution rate than 6385 material on days 1, 4, 7 and 14. Both 6385 and 6380 materials elute faster than 4011 materials that do not include a filler material. 4011. 6380 and 6385 materials include dimethylsiloxane as the base polymer. As noted above, the 6385 material comprises a diatomaceous earth filler and the 6380 material comprises a silica filler, suggesting that inert filler materials may increase the elution rate based on the elution rate discussed above.

Example 6

Effect of drug concentration on Latanoprost elution

Figure 11B shows a graph showing the effect of drug concentration on latanoprost elution, according to an embodiment of the present invention. The drug cores were produced using the production methods in fig. 6E and table 1, as described above. The drug core comprised 6385 materials containing 5%, 10%, 20%, 30% and 40% latanoprost, respectively. The amount of tin-alkoxy curing system was 2.5% of the total sample. The release of latanoprost was weakly dependent on latanoprost concentration at all time periods, with 40% of latanoprost eluting at the highest rate and 5% of latanoprost eluting at the lowest rate. The elution rate for all samples dropped below 500 ng/day by day 7, after which release at therapeutic levels continued.

Example 7

Effect of covering one end of a drug core insert

FIG. 11C illustrates the effect of covering one end of a drug core insert according to an embodiment of the present invention. The drug cores were produced using the production methods in fig. 6E and table 1, as described above. The drug core comprises 6385 material containing 20% latanoprost. The elution rate of the cut tubes as described above was measured with both ends of each cut tube open, referred to as open both ends. As described above, the elution rate of one end exposed and one end covered with UV cured Loctite, referred to as one open-ended cut tube, was measured. For comparison, the elution rate of the drug core insert with open ends is shown divided by 2, referred to as "open ends/2" at all time points, the value of the open ends/2 is very close to the data for one end open, indicating that covering one end of the drug core insert with a substantially impermeable adhesive to the therapeutic drug can inhibit the release of the therapeutic drug from the drug core, allowing efficient delivery of the drug through the exposed surface of the drug core on the open end of the tube.

Example 8

Elution of fluorescein and Effect of surfactant on fluorescein elution

FIG. 12 shows elution of fluorescein and the effect of a surfactant on fluorescein elution according to an embodiment of the invention. Elution data for fluorescein demonstrate the flexibility of the drug core described above and the manufacturing process for sustained release of many therapeutic agents including water-soluble and water-insoluble therapeutic agents as well as relatively low and high molecular weight therapeutic agents. Fluorescein has a molecular mass of 332.32g/mol, is soluble in water, and can be used as a model for the release of water-soluble therapeutic drugs from the eye. Work in connection with embodiments of the present invention indicates that molecular weight and aqueous solubility, respectively, can affect the release rate of a drug from a solid drug core matrix. For example, a lower molecular weight may enhance diffusion through the solid matrix material, i.e., through the silicone, so that low molecular weight compounds may be released more rapidly. In addition, aqueous solubility can also affect the release rate of the drug, and, in some cases, increased aqueous solubility of the drug can increase the release rate from the solid drug core matrix, for example, by transport from the solid matrix material to bodily fluids (such as tears). According to these embodiments, therapeutic agents having a higher molecular weight than fluorescein and lower water solubility than fluorescein, e.g., cyclosporine and prostaglandins as described above, may be released from the solid core at a lower rate. The surfactant may also affect the release rate of the therapeutic agent from the drug core into the surrounding body tissue and/or fluid (e.g., tear film fluid).

Each drug core tested included MED4011 silicone. In one embodiment, drug core formulation 1210 includes 9% surfactant and 0.09% fluorescein. An exponential fit 1212 of the elution rate of the drug core formulation 1210 is shown. In another embodiment, the drug core formulation 1220 comprises 16.5% surfactant and 0.17% fluorescein. An exponential fit 1222 of the elution rate of the drug core formulation 1220 is shown. In another embodiment, the drug core formulation 1230 includes 22.85% surfactant and 0.23% fluorescein. An exponential fit 1232 of the elution rate of the drug core formulation 1230 is shown. In embodiments that do not include a surfactant, drug core formulation 1240 includes 0% surfactant and 0.3% fluorescein. An exponential fit 1242 of the elution rate of the drug core formulation 1240 is shown.

A pharmaceutical core produced using a key formulation comprising: silicone Surfactant "190 Fluid" (dow corning); SurfactantMix: "190 Fluid" + fluorescein; silicone (Nusil): MED4011 part a, MED4011 part B; centrifuging the tube; 3mL syringe; a 20 gauge needle; 0.031 inch id Teflon tubing; and a buffer.

The key parameters include: preparing a mixture of 2.5g of a silicone surfactant and 0.025g of fluorescein; preparing a silicone composition comprising 3.5g part a and 0.37g part B (10:1 ratio) of NusilMED 4011; four (4) centrifuge tubes were prepared, each containing 0.5g of silicone and different surfactant mixture weights as follows: a.0.05g of surfactant mixture, 9% of surfactant and 0.09% of fluorescein; b.0.1g surfactant mixture, 16.5% surfactant, 0.17% fluorescein; c.0.15 surfactant mixture, 22.85% surfactant, 0.23% fluorescein; d.0.0015g fluorescein: 0% of surfactant, 0.3% of fluorescein; each of the four formulations was injected into a respective teflon tube using a syringe and needle; the injected tube was cured in an oven at 140 ℃ for 45 minutes; each tube was divided into three sections of 4mm length; each cut section was immersed in a centrifuge tube containing 0.3mL of buffer.

The data collection comprises the following steps: samples were collected at time points 24, 48, 72, 192 and 312 hours; performing UV spectroscopy analysis on each sample; each elution rate in μ g/mL/hr units was converted to μ g/cm using the dimensions of the teflon tube (4mm length, 0.031 inch inner diameter)²(ii)/hr; the elution rate data was plotted against time to compare the rate for each surfactant mixture formulation.

The analysis included fitting the trend line for each elution rate to an exponential curve, as shown in table 4.

TABLE 4 Trend line for each elution rate fitted as an exponential curve

Sample (I)	% surfactant	% fluorescein	R2	Trend line equation
					A	9.0	0.09	0.9497	636.66x-1.1161
B	16.5	0.17	0.8785	4289.6x-1.3706
					C	22.85	0.23	0.9554	1762.0x-1.0711
D	0	0.30	0.9478	1142.1x-1.2305

The trend line equation of table 4 indicates: the data fit well with the experimental curves, and the R2 values were 0.8785 to 0.9554. The trend line equation shows exponential coefficients from-1.0711 to-1.3706. The elution rate increases with increasing surfactant levels. Despite the relatively similar amount of fluorescein, the significant increase in elution rate between sample C and sample D demonstrates that the addition of surfactant to the silicone matrix significantly affects the elution rate of the water-soluble compound. The elution rate of sample a was comparable to that of sample D, although sample a contained only one-third the amount of fluorescein. This also demonstrates that the elution rate can be affected by the addition of surfactant to the silicone matrix.

Although the exponential coefficients of the trend line equations-1.0711 to-1.3706 fit with the first order release, the data includes an initial 48 hour period in which concentrated release of fluorescein from the core is observed. Such an initial irrigation period followed by a 2-3 day delivery of therapeutic agent at a high level followed by a sustained release at therapeutic levels for a period of time may be beneficial in some embodiments, for example, where elevated levels for a short period of time are tolerated and may result in accelerated effects on the eye. Work in connection with embodiments of the present invention suggests that after 48 hours, the elution data may be closer to zero order, for example in the range of about zero order to about one order. In some embodiments, the level of therapeutic drug released may decrease as the exposed surface area of the drug core decreases, for example as described above, so as to release the drug at therapeutic levels for an extended period of time.

Example 9

Effect of Disinfection on therapeutic drug elution

Work in connection with embodiments of the present invention suggests that radicals generated during sterilization can crosslink the drug core matrix material in order to inhibit the initial release rate of the therapeutic agent from the drug core matrix material. In particular embodiments where electron beam sterilization is used, such crosslinking may be localized to the surface and/or near the surface of the drug core matrix. In some embodiments, the surface of the drug core can be sterilized by electron beam penetration through a known Mylar bag. In some embodiments, other sterilization techniques to achieve sterilization may be used, such as gamma sterilization, and are not limited to the surface of the drug core and penetrate the drug core material completely and/or uniformly.

The drug core was synthesized and electron beam sterilized in Mylar packaging as described above. Figure 13A shows the elution of sterilized and non-sterilized drug cores. The sterile and non-sterile drug cores each included 6385 with 20% latanoprost synthesized as described above. The drug cores were electron beam sterilized and the elution rates were measured as described above. The sterilized and non-sterilized drug cores showed elution rates of about 450 and 1400 ng/day, respectively, on the first day. On days 4 and 7, the sterilized and non-sterilized drug cores showed similar elution rates of about 400 ng/day. On day 14, the sterilized and non-sterilized drug cores showed elution rates of 200 and about 150 ng/day, respectively. These data show that sterilization can reduce the initial or concentrated release of the therapeutic agent and that sterilization can be used to provide a more uniform rate of release of the therapeutic agent, e.g., in combination with the embodiments described above.

Example 10

Effect of salt on therapeutic drug elution

Work in connection with embodiments of the present invention suggests that known salts (e.g., sodium chloride) may affect the elution rate of the drug core.

Figure 14A shows the effect of salt on therapeutic drug elution. Drug cores comprising an organosilicon drug core matrix of 20% Bimatoprost (BT) and NuSil6385 were produced as described above. The drug core was produced with salt concentrations of 0%, 10% and 20%. At day 1, 20%, 10% and 0% of the drug cores showed elution rates of about 750 ng/day, 400 ng/day and about 100 ng/day, respectively. At all measured time periods up to two weeks, the 20% salt data showed the highest elution rate and the 0% salt data showed the lowest elution rate. These data indicate that, for example, many known salts (such as sodium chloride) can be added to the matrix to increase the level of therapeutic drug elution rate.

Example 11

Extraction of therapeutic drug from drug core to determine therapeutic drug yield

Drug core inserts comprising MED-6385 and 20% and 40% latanoprost were synthesized as described above. Each drug core was weighed and the weight of the solid drug core material was determined by correcting the weight of the drug tube and binder. The amount of therapeutic agent present in each sample is determined based on the weight of the drug core material and the percentage of therapeutic agent in the drug core, as described above. Therapeutic drug was extracted from drug cores using 1ml aliquots of methyl acetate. The concentration of the therapeutic agent in the solution of each sample was measured by reverse phase gradient HPLC using optical detection and peak integration at 210 nm. Measurements were performed on 6 drug cores containing 20% latanoprost and four drug cores containing 40% latanoprost. For the 20% sample, the mean extraction of latanoprost was 104.8%, with a standard deviation of about 10%. For 40% of samples, the mean extraction of latanoprost was 96.8%, with a standard deviation of about 13%.

Example 12

High pressure filling

A two-part silicone formulation (MED6385, nusil technologies) was used to prepare a composite resin containing latanoprost, which was used to fill a length of polyimide jacket. A sheath comprising polymerized silicone incorporates discrete latanoprost domains in the form of droplets having a maximum diameter of less than about 25 μm within a matrix. Several experiments were performed.

Part a of the MED6385 silicone formulation was mixed with 0.43 μ L of part B (tin catalyst) using a syringe to partially solidify the polymer in 30 minutes. Then, 37mg of this material was mixed with 0.14 μ L of additional catalyst and 13mg of latanoprost premix solution, and the mixture may be further mixed by sonication with an ultrasonic probe. The resulting mixture was transferred to a syringe needle attached to an HP7x syringe adapter that was connected to an EFD pump that was in turn connected to a compressed air system and the delivery pressure was set at 40 psi. The silicone-latanoprost mixture was then extruded down a length (10cm) of polyimide tubing (iwghighperformance controllers, Inc.). When the viscous mixture reached the bottom of the polyimide tubing, a clamp was applied at the junction of the bottom of the tubing and the top with the syringe adapter, then the pressure was released and the tubing section removed. The pipe sections with the clamps were placed in a humidity laboratory (ThunderScientific) and cured at 40 ℃ and 80% Relative Humidity (RH) for approximately 16-24 hours.

To process the filled polyimide tube containing the now solid matrix containing latanoprost into individual drug inserts, the filled precursor sheath was cut into 1mm sections using a jig and blade. One end of each 1mm segment was then sealed with Loctite4305UV quick cure adhesive and cured with a Loctite uv pen. Each segment is now ready for insertion with the sealed end inward into a punctal plug (Quintess) adapted to receive an insert.

Results

Scanning electron micrographs of the sheath containing the cured matrix (i.e., the filled precursor sheath) are shown in fig. 15A-D at the magnifications indicated. The inserts were cut into sections at low temperature. Fig. 15A and 15B show the insert core in which extrusion was performed at 40 ℃ (a) or 25 ℃ (B), respectively.

Example 13

During the injection process, the temperature of the mixture involved in filling the polyimide jacket and the temperature of the associated device were maintained at different temperatures. Of the temperatures, slightly higher temperatures (40 ℃) near room temperature (25 ℃) and temperatures below room temperature (such as 0 ℃, -5 ℃ and-25 ℃) were used. In this embodiment, a sub-ambient injection process is provided.

LatanoprostProduction of organosilicon mixtures

The silicone formulation (MED6385) is a two-part system. Part a contains silicone and crosslinker, while part B contains a tin catalyst to promote crosslinking. The two fractions were combined at a final ratio of 200:1 (fraction a: fraction B). The required amounts of latanoprost, MED6385 part a and part B were weighed onto glass slides and mixed using a small plastic spatula for approximately 2 minutes. The weight or volume of the components required to prepare 50mg of the mixture to be extruded is provided in the table below.

The proportions of the components

Extrusion into polyimide tubes

Preparation of syringe extrusion systems

A 15cm section was threaded through the plastic luer adapter and bonded in place using Loctite4304UV quick cure adhesive (fig. 2). A 1mL syringe (henkesassafwolfnorm) was modified by cutting the tip of the plunger flush. The pre-assembled tube/adapter part is inserted into the syringe barrel and threaded through the luer outlet and fitted in place.

Extrusion

After the silicone/latanoprost mixing was complete, the mixture was loaded into the barrel of a syringe extrusion system. The plunger was inserted and excess air was removed. The syringe is then ready to be loaded into a refrigerated extrusion apparatus. The apparatus is an all stainless steel belt jacketed tube in a tubular clean-welded heat exchanger and includes a gas purge cooled by the coil interior inside the coolant side of the heat exchanger. The operating temperature set point for the cooling system should be-10 ℃. The temperature inside the heat exchanger over the usable length of polyimide tube should be +/-2.5 ℃ of the average value. The steady state temperature of the cooling system was verified before the injector and tubing were inserted.

After setting, the EFD was started and the silicone latanoprost mixture was extruded along the length of the polyimide tube. After the mixture reaches the bottom of the tube, it can be visually inspected. The injector including the tubing was quickly removed from the cooling system. The syringe was removed by cutting the tube with a razor blade and then clamping the tube at both ends.

Curing

The pipe sections with the clamps were placed in a humidity laboratory (ThunderScientific) and cured at 40 ℃ and 80% Relative Humidity (RH) for approximately 16-24 hours.

Results

Scanning electron micrographs of the sheath containing the cured matrix (i.e., the filled precursor sheath) are shown in fig. 15A-D at the magnifications indicated. The inserts were cut into sections at low temperature. FIGS. 15C and 15D show the results of extrusion at 0 ℃ and-25 ℃, respectively. They are compared to FIGS. 15A and 15B, which are conducted at ambient temperature (25 ℃) or higher (40 ℃).

The measurement data of the mean inclusion diameter, and its standard deviation, are shown below:

cold extrusion (-5 ℃): 0.006 + -0.002 mm (n =40 inclusion)

Room temperature (22 ℃): 0.019 + -0.019 mm (n =40 inclusion)

The measured data for the average latanoprost content (μ g) per 1mm segment (core) from the filled precursor tube split (blade) are shown below:

cold extrusion (-5 ℃): 20.9 ± 0.5 (mean ± SD) RSD =2.4

Room temperature (22 ℃): 20.2 ± 1.9 (mean ± SD) RSD =9.4

Further embodiments

Although the foregoing relates primarily to treatment of the eye, embodiments of the drug delivery structures described herein may also be applied to treatment of a variety of tissues to treat a variety of different disease states. In some embodiments, these structures can be used to systemically elute and/or (more often) locally elute therapeutic agents to treat cancer. In embodiments for chemotherapy, the matrix may be configured to release a therapeutic cocktail, depending on the primary tumor type. The use of local delivery is particularly advantageous for treating post-operative tumor sites and can help minimize side effects and collateral damage to healthy tissues of the body. In some embodiments, a local lumpectomy of a breast tumor and/or a surgical treatment of prostate cancer may be treated. In many embodiments, the tumor is targeted by positioning the stroma within and/or near the target tumor. In some embodiments, the implant may include a radioactive agent for treatment of tumors in combination with a therapeutic agent.

Additional alternative embodiments may facilitate elution of therapeutic agents into the ear, mouth, urethra, skin, knee joint (or other joint), etc. of a patient. Conditions of the joints that may be treated include arthritis and other joint diseases, and therapeutic agents that may be used may include, for example, at least one cox ii inhibitor, NSAID, and the like. Such localized administration of NSAIDs and cox i inhibitors may reduce the risks associated with systemic use of these compounds. In some embodiments, the matrix may include a nutritional supplement such as glucosamine to achieve a positive physiological response in the local tissue of the joint and/or tissue near the joint. Implants for eluting therapeutic agents into or near intervertebral joints may be particularly advantageous. Similar (or other) analgesics, antibiotics, antimicrobials, etc. may also be included in the implant to elute one or more therapeutic agents into the localized wound. The implant (optionally, an implant having a structure derived from the punctal implant described above) can allow elution of one or more therapeutic agents into the nasal cavity. Variations or differences between such nasal implants and the punctal implants described above may include providing a pathway for controlled release of drug-containing tear fluid through a tubular lumen (canilicularlumen). Alternative nasal tissue structures may vary significantly in overall form, optionally including any of a variety of known nasal drug release shapes, but optionally taking advantage of one or more aspects of the drug core or other drug release structures described above for prolonged release of one or more suitable therapeutic drugs.

Further alternative embodiments may be useful in cosmetic applications. For example, these applications include the administration of prostaglandins to enhance eyelash growth.

Although exemplary embodiments have been described in some detail as examples and to facilitate a clear understanding, those skilled in the art will recognize that many variations, modifications, and changes may be employed. For example, multiple delivery mechanisms may be used, and each device embodiment may be adapted to include features or materials of another device embodiment, and additional multiple features or materials may be utilized in a single device. Accordingly, the scope of the invention is limited only by the claims.

Claims (30)

1. A drug insert for an implant body comprising a punctal plug adapted to be disposed within a punctum of a patient, wherein the drug insert comprises:

a drug core comprising a cured mixture comprising latanoprost and an organosilicon matrix, wherein the latanoprost is uniformly and homogeneously dispersed in the mixture as inclusions having a mean diameter of 6 μm with a standard deviation of diameter of 2 μm; and

a substantially latanoprost impermeable sheath body partially covering the cured mixture to provide at least one exposed surface.

2. The drug insert of claim 1 further comprising a seal on one end of the drug insert, wherein the second end is an exposed surface.

3. The drug insert of claim 2 wherein one end is sealed with a UV-curable adhesive, by clamping, by heat welding, or with an end cap.

4. The drug insert of claim 2 wherein one end is sealed with cyanoacrylate or epoxy.

5. The drug insert of claim 1 wherein the insert comprises at least 5% by weight latanoprost.

6. The drug insert of claim 1 wherein the insert comprises from 5% to 50% by weight of latanoprost.

7. The drug insert of claim 1 wherein the insert comprises 20% to 40% by weight of latanoprost.

8. The drug insert of claim 1 wherein the sheath body comprises at least one of polyimide, PMMA, PET, stainless steel, or titanium.

9. The drug insert of claim 1 wherein the drug core is 0.80-0.95mm in length.

10. The drug insert of claim 1 wherein the cross-sectional size of the drug core is 0.006 inches.

11. The drug insert of claim 1 wherein the drug core has a cross-sectional dimension of 0.012 inches.

12. The drug insert of claim 1 wherein the drug core has a cross-sectional size of 0.025 inches.

13. The drug insert of claim 1 wherein 14 μ g of the drug core exhibits an elution rate of about 100 ng/day over 10-40 days, wherein the latanoprost is from a 0.32mm diameter, 0.95mm long drug core at a concentration of 20% and a drug weight of 14 μ g.

14. The drug insert of claim 1 wherein 7 μ g of the drug core exhibits an elution rate of about 100 ng/day from 10-20 days, wherein the latanoprost is from a 0.32mm diameter, 0.95mm long drug core at a concentration of 10% and a drug weight of 7 μ g.

15. A method of producing a drug insert for an implant body comprising a punctal plug adapted to be disposed within a punctum of a patient,

the method comprises the following steps

Injecting a mixture comprising latanoprost and a silicone matrix into a precursor sheath body at an extrusion temperature of less than 20 ℃ such that the precursor sheath body is substantially filled, the latanoprost being substantially impermeable to the precursor sheath body,

curing the mixture in the precursor sheath body is carried out in the presence of a catalyst of NuSilMED-6385 and can be carried out at a temperature of at least 40 ℃, at a Relative Humidity (RH) of at least 80%, or both, to provide a cured, filled precursor sheath body comprising a prodrug core; and

the cured, filled precursor sheath body was segmented to form a plurality of drug inserts with drug cores having a mean diameter of 6 μm and a standard deviation of 2 μm in diameter.

16. The method of claim 15, wherein the amount of latanoprost in a volumetric portion of the solidified mixture differs by no more than 10% from the amount of latanoprost in any other equal volumetric portion of the solidified mixture.

17. The method of claim 15, wherein the amount of latanoprost in each of the plurality of drug inserts varies by no more than 10% therebetween.

18. The method of claim 15, wherein said segmenting the cured filled precursor sheath body comprises cutting the cured filled precursor sheath body with a blade or with a laser.

19. The method of claim 15, wherein the injecting comprises injecting at a pressure of at least 40 psi.

20. The method of claim 15, wherein the mixture is injected such that the precursor sheath body is filled at a rate of less than 0.5 cm/sec.

21. The method of claim 15, further comprising each drug insert being sealed at one end thereof, the second end providing an exposed surface.

22. The method of claim 21, wherein each drug insert is sealed at one end thereof with a UV-curable adhesive, by clamping, by heat welding, or with an end cap.

23. The method of claim 21, wherein each drug insert is sealed at one end thereof with a cyanoacrylate or epoxy.

24. The method of claim 22 or 23, further comprising irradiating the drug insert with UV light with a UV-curable adhesive.

25. The method of claim 22 or 23, further comprising inserting each drug insert into the channel of the lacrimal plug after sealing one end thereof.

26. The method of claim 15, wherein the insert comprises at least 5% by weight latanoprost.

27. The method of claim 15, wherein the insert comprises from 5% to 50% by weight latanoprost.

28. The method of claim 15, wherein the insert comprises 20% to 40% by weight latanoprost.

29. The method of claim 15, wherein the precursor sheath body comprises at least one of polyimide, PMMA, PET, stainless steel, or titanium.

30. A method of producing a punctal plug, the method comprising:

injecting a mixture comprising latanoprost and a silicone matrix into a precursor sheath body at an extrusion temperature of less than 20 ℃ such that the precursor sheath body is substantially filled, the latanoprost being substantially impermeable to the precursor sheath body,

curing the mixture in the precursor sheath body is carried out in the presence of a catalyst of NuSilMED-6385 and can be carried out at a temperature of at least 40 ℃, at a relative humidity of at least 80%, or both, to provide a cured, filled precursor sheath body comprising a prodrug core; and

Segmenting the cured filled precursor sheath body to form a plurality of drug inserts;

sealing each drug insert at one end of the drug insert; and

each drug insert was inserted into the channel of a punctal plug adapted to receive the insert therein, wherein the drug core had a mean diameter of 6 μm and a standard deviation of the diameter of 2 μm.