HK1162151B - Sustained released delivery of one or more agents - Google Patents

Description

Sustained release delivery of one or more pharmaceutical agents

Cross Reference to Related Applications

The present application claims priority benefits of U.S. patent application serial No. 61/146,860 filed on 23/1/2009, 61/152,909 filed on 16/2/2009, 61/228,894 filed on 27/7/2009, and 61/277,000 filed on 18/9/2009, all of which are specifically incorporated herein by reference in their entirety.

Technical Field

This patent document relates generally to ophthalmic devices, and in particular to ocular implants. More particularly, but not by way of limitation, this patent document relates to lacrimal implant (lacrimal implant) delivery systems (e.g., punctal plugs (punctal plugs) containing drug cores), methods of making such implant delivery systems, and methods of treating diseases or disorders, including ocular diseases or disorders, at least in part using such implant delivery systems.

Background

In the field of drug delivery (e.g., ophthalmic drug delivery), patients and physicians face a variety of challenges. In particular, the repetitive nature of the treatment (multiple injections, multiple eye drop daily regimens), the associated costs, and the lack of patient compliance can significantly impact the efficacy of the available treatments, resulting in reduced vision, and often blindness.

Patient compliance may be unstable when administered (e.g., instilled as eye drops), and in some cases, patients may not follow a prescribed treatment regimen. The lack of compliance may include: no drops are dropped, ineffective techniques (drops less than required), excess drops are used (resulting in systemic side effects), and over-prescribed drops are used or treatment regimens requiring multiple types of drops are not followed. Many drugs may require patients to drip them up to 4 times per day.

For example, glaucoma is a collection of conditions characterized by progressive visual field loss due to optic nerve damage. It is one of the leading causes of blindness in the united states, affecting 1-2% of individuals aged 60 and older. While there are many risk factors associated with the development of glaucoma (e.g., age, race, myopia, family history, and injury), elevated intraocular pressure (also known as ocular hypertension) is one risk factor that is successfully managed and associated with the reduction of glaucomatous optic neuropathy. Public health figure (figure) estimates that 250 million americans exhibit ocular hypertension.

To treat glaucoma and ocular hypertension, drugs may be applied to the eye. Traditional drug delivery methods are by applying topical drops to the surface of the eye. Topical eye drops, while effective, are less effective. For example, when eye drops are dropped into the eye, the eye drops often overfill the conjunctival sac (i.e., the pocket between the eyeball and the associated eyelid), causing a large portion of the eye drops to be lost due to overflow of the eyelid margin and overflow onto the cheek. In addition, a large portion of the eye drops remaining on the surface of the eye can be washed away into and through the lacrimal canaliculus, thereby diluting the concentration of the drug before the eye drops can treat the eye. Furthermore, in some cases, the topically applied agent has the highest ocular effect within about two hours, after which the agent should be administered again to maintain the therapeutic benefit.

For the difficulty of compound eye treatment, subjects often do not use their eye drops according to the prescription. The rate of non-compliance of 25% and greater users of drops has been previously reported. The poor compliance may be due to, for example, forgetfulness or the initial stinging or burning sensation caused by eye drops and experienced by the subject. It is difficult for a person to drip eye drops into their own eyes, in part because of the normal reflex of protecting the eyes. Thus, one or more droplets may miss the eye. Elderly subjects may have additional drip problems due to arthritis, instability and impaired vision. It also has difficulties for pediatric and psychiatric populations.

One promising approach to ocular drug delivery is the placement of implants that release drugs into the tissues within or near the eye.

Illustrative aspects and embodiments of the invention

The inventors have identified different promising techniques for delivering one or more drugs (also referred to as "therapeutic agents" or "pharmaceutical agents") to the eye, including, for example, one or more anti-glaucoma agents (anti-glaucomas). These techniques include the following methods: using a lacrimal implant delivery system, a drug (including, for example, one or more anti-glaucoma agents) is delivered from the punctum for sustained release over an extended period of time onto the surface of the eye, and thus to ocular tissue. In various embodiments, the drug is an anti-glaucoma therapeutic agent, such as a prostaglandin (e.g., latanoprost). The drug (e.g., latanoprost or other prostaglandins) may be released at one or more therapeutic levels. The medicament comprises a pharmaceutical substance, compound or mixture thereof, which is suitable and medically indicated for treating a condition (malcondition) in a patient. Specific examples of types or classes of agents for use in the present invention include: glaucoma drugs, muscarinic agents, beta blockers, alpha agonists, carbonic anhydrase inhibitors or prostaglandins or prostanoid analogs; anti-inflammatory agents; an anti-infective agent; a dry eye drug; or any combination thereof. More specifically, one example of a glaucoma drug is a prostaglandin or a prostaglandin analog. An example of a muscarinic agent 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 (softsteroid), or non-steroidal anti-inflammatory drugs (NSAID) such as ibuprofen. An example of an analgesic includes salicylic acid and acetaminophen. The antibiotic (antibacterial agent) may be a beta-lactam antibiotic, a macrocyclic antibiotic such as erythromycin, fluoroquinolone, and the like. The antiviral 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, demulcent (delmulcent), or sodium hyaluronate.

In one aspect, the invention provides a method of delivering an anti-glaucoma agent, such as latanoprost or other prostaglandins, to an eye having an associated tear fluid, the method comprising placing a topical formulation (topical formulation) comprising the anti-glaucoma agent into the punctum of the eye. In one embodiment, the topical formulation is in the form of a drug core, optionally disposed in a lacrimal implant body configured to be at least partially inserted into a punctum or lacrimal duct (canaliculus) of an eye. The core may comprise a matrix and latanoprost or other anti-glaucoma agent inclusions (inclusions) within the matrix. A portion of the core is exposed to tear fluid so as to release latanoprost or other anti-glaucoma agent into the tear fluid. Latanoprost or other anti-glaucoma agents may be dissolved or dispersed in the matrix and release latanoprost at one or more therapeutic levels over a sustained period of time via the exposed core portion. In another aspect, the invention provides a method of delivering an anti-glaucoma agent (e.g., latanoprost) to an eye having an associated tear fluid, the method comprising placing a topical formulation consisting essentially of the anti-glaucoma agent and a polymer into a punctum of the eye. In one embodiment, the topical formulation is impregnated (impregnated) within a pre-formed lacrimal implant, or made in the form of a lacrimal implant composed of a mixture of an anti-glaucoma agent (e.g., latanoprost) and a polymer.

The latanoprost or other anti-glaucoma agent may be released via an exposed core portion or impregnated body (impregnated body) at one or more therapeutic levels for about 90 days. The latanoprost or other anti-glaucoma agent may comprise an oil. Latanoprost or other anti-glaucoma agents may be encapsulated in a matrix, and the matrix may comprise a non-bioabsorbable polymer.

In various embodiments, the present invention provides a drug core comprising an anti-glaucoma agent and a polymeric matrix (polymeric core) for placement into or into a drug insert (drug insert) or an implant body, the drug insert or implant body adapted for placement in or near the eye of a subject, wherein the anti-glaucoma agent is homogeneously dispersed throughout the matrix in an amount of about 42 micrograms, about 44 micrograms, about 65 micrograms, or about 81 micrograms, or the anti-glaucoma agent forms a solid or liquid inclusion within the matrix at least partially in an amount of about 42 micrograms, about 44 micrograms, about 65 micrograms, or about 81 micrograms; wherein the amount of anti-glaucoma agent in one volume portion (volumetric portion) of the drug insert or implant body is similar to the amount of anti-glaucoma agent in any other same volume portion of the drug insert or implant body. For example, the amount of the anti-glaucoma agent in one volume portion of the drug insert or implant body may differ by no more than about 30% from the amount of the anti-glaucoma agent in any other same volume portion of the drug insert or implant body. For example, the amount of the anti-glaucoma agent in one volume portion of the drug insert or implant body may differ by no more than about 20% from the amount of the anti-glaucoma agent in any other same volume portion of the drug insert or implant body. For example, the amount of the anti-glaucoma agent in one volume portion of the drug insert or implant body may differ by no more than about 10% from the amount of the anti-glaucoma agent in any other same volume portion of the drug insert or implant body. For example, the amount of anti-glaucoma agent in one volume portion of the drug insert or implant body may differ by no more than about 5% from the amount of anti-glaucoma agent in any other same volume portion of the drug insert or implant body. For example, the amount of anti-glaucoma agent in one volume portion of the drug insert or implant body is the same as the amount of anti-glaucoma agent in any other same volume portion of the drug insert or implant body. In various embodiments, the drug insert or implant body can be adapted to release and/or for providing sustained release of an agent to the eye, surrounding tissue, systemically (or any combination thereof).

The invention also provides a method of reducing intraocular pressure by inserting a lacrimal implant delivery system into at least one punctum of a subject, wherein the implant body is at least partially impregnated with an anti-glaucoma agent (e.g., latanoprost), or comprises a sustained release core comprising at least the anti-glaucoma agent, and wherein the implant continuously releases the anti-glaucoma agent for at least about 90 days. In one embodiment, the method treats elevated glaucoma-associated intraocular pressure by inserting an implant body comprising an anti-glaucoma agent at least partially into a punctum of a subject to achieve sustained release of the agent to the subject resulting in a reduction of at least 6mm Hg in the intraocular pressure of the eye concerned.

In some embodiments, the lacrimal implant delivery system releases the anti-glaucoma agent (e.g., latanoprost) during a continuous period of time of at least about 7 days, at least about 28 days, at least about 52 days, at least about 88 days, or at least about 90 days after insertion of the implant body. In some embodiments, the lacrimal implant delivery system releases about 25 nanograms (ng) per day to about 250ng per day of latanoprost. For other anti-glaucoma agents, equivalent therapeutic amounts may be employed, based on therapeutic equivalence to these amounts of latanoprost. Likewise, for other agents, alternative therapeutically effective amounts of the drug may be employed. Therapeutic equivalence can be determined by Reference to the "Physician's Desk Reference". In some embodiments, the topical formulation of the lacrimal implant delivery system comprising the anti-glaucoma agent is administered to one or both eyes of the subject less than 10 times, less than 5 times, or less than 3 times over the continuous period of time (e.g., over a period of one year). In alternative embodiments, the continuous period of time can be more than 1 year or less than 1 year, for example, when the topical formulation of the lacrimal implant delivery system comprises an alternative drug.

In certain embodiments, the present invention provides methods of reducing intraocular pressure by inserting a lacrimal implant delivery system into at least one punctum of a subject having an intraocular pressure (IOP) of about 32mmHg, about 31mmHg, about 30mmHg, about 29mmHg, about 28mmHg, about 27mmHg, about 26mmHg, about 25mmHg, about 24mmHg, about 23mmHg, about 22mmHg, about 21mmHg, about 20mmHg, about 19mmHg, about 18mmHg, about 17mmHg, about 16mmHg, about 15mmHg, about 14mmHg, about 13mmHg, about 12mmHg, about 11mmHg, or about 10 mmHg. In one embodiment, the present invention provides a method of treating ocular hypertension. In one embodiment, the invention provides a method of treating primary open angle glaucoma. In other embodiments, the invention provides methods of treating angle-closure glaucoma. In other embodiments, the present invention provides methods of treating low tension glaucoma. In other embodiments, the invention provides methods of treating secondary glaucoma.

In certain embodiments, the reduction in intraocular pressure is maintained for a continuous period of time of up to about 7 days, up to about 14 days, up to about 21 days, up to about 28 days, up to about 52 days, up to about 88 days, or up to about 105 days. In one embodiment, the reduction in intraocular pressure is maintained for a continuous period of time of at least about 90 days. Another embodiment provides a treatment course of about 90 days.

The invention described herein also provides a method of reducing intraocular pressure by inserting a sustained release lacrimal implant delivery system into at least one punctum of a subject, wherein the intraocular pressure of an associated eye is reduced by at least about 25%.

In some embodiments, the present invention provides methods of treating a subject with ocular hypertension by administering a topical formulation consisting of an anti-glaucoma agent (e.g., latanoprost) that elutes from a drug core or other lacrimal implant delivery system configured to be at least partially inserted into at least one punctum of the subject, wherein the formulation is capable of reducing intraocular pressure for at least 90 days. In one embodiment, the drug core is configured to be inserted into a lacrimal implant. In other embodiments, the lacrimal implant is a punctum plug.

In one embodiment, the methods of the invention result in at least a 10% reduction in intraocular pressure within 1 day after insertion into the lacrimal implant delivery system, or at least a 20% reduction in intraocular pressure within 7 days after insertion into the lacrimal implant delivery system. In some embodiments, the reduction in intraocular pressure is maintained for at least 75 days. In other embodiments, the reduction in intraocular pressure is maintained for at least 90 days. In other embodiments, the reduction in intraocular pressure is maintained for at least 120 days. In other embodiments, there is about a 20% reduction, about a 25% reduction, about a 30% reduction, about a 35% reduction, about a 40% reduction, about a 45% reduction, or about a 50% or greater reduction in intraocular pressure about 90 days or less after insertion into the lacrimal implant delivery system.

The invention described herein also provides methods of reducing or treating intraocular pressure in an eye of a subject by administering to the eye an effective amount of latanoprost or other anti-glaucoma agent administered from a lacrimal implant delivery system. The invention described herein also provides a method of reducing or treating intraocular pressure in an eye of a subject by administering to the eye an effective amount of latanoprost or other anti-glaucoma agent and an effective amount of a penetration enhancer (also referred to as an absorption enhancer), wherein at least latanoprost or other anti-glaucoma agent is administered from a lacrimal implant delivery system. In some embodiments, the lacrimal implant delivery system is inserted into at least one punctum of a subject. In some embodiments, the lacrimal implant delivery system includes an implant body and an anti-glaucoma (e.g., latanoprost) insert. In certain embodiments, the anti-glaucoma agent is administered from the lacrimal implant delivery system for at least about 90 days. In some embodiments, the lacrimal implant delivery system comprises at least about 42 microclatanoprost, such as about 42 micrograms to about 44 microclatanoprost. In some embodiments, the lacrimal implant delivery system comprises about 44 micrograms of latanoprost. In other embodiments, the lacrimal implant delivery system (such as a system comprising 2 lacrimal implants) comprises at least about 65 micrograms of latanoprost. In other embodiments, the lacrimal implant delivery system comprises about 81 micrograms of latanoprost. In other embodiments, the lacrimal implant delivery system (such as a system comprising 2 lacrimal implants) comprises at least about 88 micrograms of latanoprost. For other anti-glaucoma agents, equivalent therapeutic amounts may be employed, based on therapeutic equivalence to these amounts of latanoprost. Therapeutic equivalence can be determined by Reference to the "Physician's Desk Reference".

In certain embodiments, the intraocular pressure is associated with glaucoma or ocular hypertension. In one embodiment, the lacrimal implant delivery system is inserted into at least one punctum of a subject in a single insertion procedure.

In some embodiments, a penetration enhancer (e.g., benzalkonium chloride) is administered at least once as an eye drop adjuvant composition. In some embodiments, the penetration enhancer is administered from a lacrimal implant delivery system, such as from a drug core inserted within the body of the implant. In some embodiments, the intraocular pressure prior to administration is greater than or equal to about 22 mmHg. The penetration enhancer may increase the penetration of the anti-glaucoma agent (e.g., latanoprost) into the eye, and thus may reduce the amount of the anti-glaucoma agent needed to effectively treat a subject over a given period of time.

The invention described herein also provides methods of reducing or treating intraocular pressure (including glaucoma-associated intraocular pressure) in an eye of a subject by administering to the eye an effective amount of latanoprost or other anti-glaucoma agent and an effective amount of an artificial tear fluid, wherein at least latanoprost or other anti-glaucoma agent is administered from a lacrimal implant delivery system. In some embodiments, the lacrimal implant delivery system comprises an implant body and an anti-glaucoma (e.g., latanoprost) insert and an artificial tear, the latter of which is delivered to the ocular surface via topical drops or other delivery forms (such as ointments, suspensions, etc.). In some embodiments, the use of artificial tears is used as a means of increasing the basal tear level in a subject, which can aid in the dispersion of the anti-glaucoma agent dispensed from the lacrimal implant delivery system, and thus act as a vehicle for the drug. In some embodiments, the artificial tears used in the present invention include a penetration enhancer. In other embodiments, the artificial tears used in the present invention do not include a penetration enhancer. Examples of artificial tears useful in the present invention include, but are not limited to: formulations including eye drops, ointments, sprays, gels, and the like, including, for example, Hypotears ^TM、Refresh^TMTear, Visine^TMTear fluid, Bion^TMTears, and the like.

In some embodiments, the lacrimal implant delivery system includes an implant body including first and second portions, the implant body extending from a proximal end of the first portion to a distal end of the second portion; the proximal end of the first portion defines a longitudinal proximal axis and the distal end of the second portion defines a longitudinal distal axis; the implant body is configured such that, when implanted in a lacrimal canaliculus, there is an angled intersection (angular interaction) between the proximal and distal axes for biasing at least a portion of the implant body against at least a portion of the lacrimal canaliculus at or more distal to a canalicular curvature; and wherein the second portion of the implant body comprises a longitudinal length having a measurement (magnitude) that is less than 4 times the longitudinal length of the first portion of the implant body.

In other embodiments, the lacrimal implant delivery system includes an implant body extending non-linearly from a proximal portion positionable within a vertical segment (section) of the lacrimal canaliculus to a distal portion positionable within a horizontal segment of the lacrimal canaliculus and having a middle portion therebetween; the intermediate portion extending partially in a first direction toward the proximal portion and partially in a second direction toward the distal portion such that when implanted in the lacrimal canaliculus, the implant body is directionally biased laterally against at least a portion of the lacrimal canaliculus at or distal to the curvature of the lacrimal canaliculus; and wherein the implant body inhibits fluid ingress and egress to the lacrimal canaliculus.

Also contemplated herein are methods of treating elevated glaucoma-associated intraocular pressure in a subject by inserting a lacrimal implant delivery system into at least one punctum of the subject, wherein the lacrimal implant delivery system comprises an implant body and a drug insert comprising an anti-glaucoma agent (e.g., latanoprost) and a penetration enhancer (e.g., benzalkonium chloride). In some embodiments, the lacrimal implant delivery system provides for the sustained release of latanoprost or other anti-glaucoma agent and benzalkonium chloride or other penetration enhancing agents to a subject. In various embodiments, the lacrimal implant delivery system continuously releases latanoprost or other anti-glaucoma agent and benzalkonium chloride or other penetration enhancer for at least about 90 days, and in some embodiments, the lacrimal implant delivery system is inserted only once during the time period.

In some embodiments, the intraocular pressure prior to administration is greater than or equal to 22 mmHg. In some embodiments, the lacrimal implant delivery system comprises about 42 to about 44 microclatanoprost. In certain embodiments, the lacrimal implant delivery system comprises about 44 micrograms of latanoprost. In other embodiments, the lacrimal implant delivery system comprises about 65 micrograms of latanoprost to about 88 micrograms of latanoprost. In some embodiments, the lacrimal implant delivery system comprises about 65 micrograms of latanoprost. In certain embodiments, the lacrimal implant delivery system comprises about 81 micrograms of latanoprost. For other anti-glaucoma agents, equivalent therapeutic amounts may be employed, based on therapeutic equivalence to these amounts of latanoprost. Therapeutic equivalence can be determined by Reference to the "Physician's Desk Reference". The lacrimal implant delivery system may be inserted bilaterally into the inferior punctum of both eyes, bilaterally into the superior punctum of both eyes, or a combination thereof.

Also contemplated are topical formulations comprising an anti-glaucoma agent (e.g., latanoprost), benzalkonium chloride or other penetration enhancing agent, and a pharmaceutically acceptable vehicle, wherein the formulation is capable of reducing intraocular pressure for at least about 90 days in a single administration, and wherein the topical formulation is provided by a sustained release matrix. In some embodiments, the sustained release matrix comprises about 42 or about 44 microclatanoprost. In some embodiments, the sustained release matrix comprises about 44 micrograms of latanoprost. In other embodiments, the sustained release matrix comprises from about 65 micrograms to about 88 micrograms of latanoprost. In certain embodiments, the sustained release matrix comprises about 81 micrograms of latanoprost. The latanoprost can be released to the eye continuously for at least 90 days. In some embodiments, the intraocular pressure prior to administration is greater than or equal to 22 mmHg. In some embodiments, the sustained release matrix is inserted into a lacrimal implant delivery system.

Also contemplated herein are methods of treating elevated intraocular pressure by inserting a lacrimal implant delivery system into at least one punctum of a subject, wherein the lacrimal implant delivery system comprises from about 65 micrograms to about 88 micrograms of latanoprost. In some embodiments, the lacrimal implant delivery system remains inserted in at least one punctum of the subject for at least about 90 days. In some embodiments, the lacrimal implant delivery system comprises an implant body and a latanoprost insert. In some embodiments, the elevated intraocular pressure is associated with glaucoma or ocular hypertension. In some embodiments, the lacrimal implant delivery system is inserted into at least one punctum of a subject in a single or two insertion procedure. In some embodiments, the intraocular pressure prior to insertion of the lacrimal implant is greater than or equal to 22 mmHg.

The lacrimal implant delivery system may be inserted bilaterally into the inferior punctum of the eye, bilaterally into the superior punctum of the eye, or a combination thereof. Other lacrimal implants that do not contain any anti-glaucoma agents may optionally be inserted into other puncta.

Other embodiments include administering to the subject an effective amount of a penetration enhancer (e.g., benzalkonium chloride). Benzalkonium chloride or other penetration enhancers may be administered as an eye drop adjunctive composition. Benzalkonium chloride or other penetration enhancers may also be administered from the lacrimal implant delivery system. In some embodiments, the benzalkonium chloride or other penetration enhancer is administered as an eye drop adjunctive composition and from the lacrimal implant delivery system.

Other embodiments include administering to the subject an effective amount of an artificial tear in combination with the use of a lacrimal implant delivery system comprising an implant body and an anti-glaucoma agent (e.g., latanoprost). The artificial tear may be administered as an eye drop composition. In some embodiments, the use of artificial tears is used as a means of increasing the basal tear level of a subject, which can aid in the dispersion of the anti-glaucoma agent dispensed from the lacrimal implant delivery system. In some embodiments, the artificial tear is administered as one or more drops one or more times per day. In other embodiments, one or more artificial tears may be administered to a subject in one or more eyes 2 or more times, or 3 or more times, or 4 or more times per day. In some embodiments, the artificial tear comprises eye drops, and the eye drops are administered by dropping two drops per day in the morning and evening into one or more eyes. In other embodiments, such as on individual indicia of commercial artificial tear products Indicated, administration of artificial tears, such as Hypotears^TM、Refresh^TMTear, Visine^TMTear fluid, Bion^TMTear fluid, Advanced Eye Relief^TM、Clarymist^TM、Oasis^TMTear, Soothe^TM、Similasan^TM、Genteal^TMGel, Refresh^TMLiquid gel, Systane^TMLubricating eye drops, Systane^TMFree liquid gel, Lacri-Lube^TM、Refresh pM^TM、Tears Naturale^TM、Tears Again^TM、Dwelle^TM、Lacrisert^TMAnd the like.

Also contemplated herein are methods of treating elevated intraocular pressure in an eye of a subject by inserting at least one anti-glaucoma agent lacrimal implant delivery system into at least one punctum of the eye, wherein, for example, the total amount of latanoprost contained in the at least one lacrimal implant delivery system comprises from about 65 micrograms to about 88 micrograms of latanoprost. In certain embodiments, the lacrimal implant delivery system comprises about 42 micrograms, about 44 micrograms, about 65 micrograms, or about 81 micrograms of latanoprost. In some embodiments, the latanoprost is present in a single latanoprost lacrimal implant delivery system. In some embodiments, the single latanoprost lacrimal implant delivery system is inserted into a lower punctum of an eye. In some embodiments, the method comprises inserting a lacrimal implant that does not contain an anti-glaucoma agent into an upper punctum of the eye.

Latanoprost can be present in 2 latanoprost lacrimal implant delivery systems, one of which is inserted into the superior punctum of the eye and another of which is inserted into the inferior punctum of the eye. For example, a latanoprost lacrimal implant delivery system inserted into an upper punctum of an eye comprises about 21 micrograms of latanoprost, and a latanoprost lacrimal implant delivery system inserted into a lower punctum of an eye comprises about 44 micrograms of latanoprost. For other anti-glaucoma agents, equivalent therapeutic amounts should be used, based on therapeutic equivalence to these amounts of latanoprost. Therapeutic equivalence can be determined by reference to the "Physician's desk reference".

In some embodiments, the method further comprises administering to the subject an effective amount of a penetration enhancer (e.g., benzalkonium chloride). Benzalkonium chloride or other penetration enhancers may be administered as an eye drop adjunctive composition. Benzalkonium chloride or other penetration enhancers may also be administered from the lacrimal implant delivery system. In some embodiments, the benzalkonium chloride or other penetration enhancer is administered as an eye drop adjunctive composition and from the lacrimal implant delivery system.

In some embodiments, the lacrimal implant delivery system includes an implant body including first and second portions, the implant body extending from a proximal end of the first portion to a distal end of the second portion; the proximal end of the first portion defines a longitudinal proximal axis and the distal end of the second portion defines a longitudinal distal axis; the implant body is configured such that, when implanted in a lacrimal canaliculus, there is an angled intersection between the proximal and distal axes for biasing at least a portion of the implant body against at least a portion of the lacrimal canaliculus at or distal to a curvature of the lacrimal canaliculus; and wherein the second portion of the implant body comprises a longitudinal length having a measure of less than 4 times a longitudinal length of the first portion of the implant body.

The methods of the invention described herein also provide implants that are at least partially impregnated with an anti-glaucoma agent or have a sustained release core comprising a non-biodegradable polymer. In some embodiments, the sustained release core comprises silicone. In some embodiments, the sustained release core comprises a penetration enhancer (e.g., benzalkonium chloride).

The implant can be inserted into either the superior or inferior punctum, or the implant can be inserted into both the superior and inferior punctum. The implant may be inserted into one punctum of one eye, or the implant may be inserted into each punctum of both eyes. In some embodiments, implants with different amounts of anti-glaucoma agents are inserted into different puncta. For example, in one embodiment, a 44 microclatanoprost implant is inserted into the lower punctum of both eyes, and a 21 microclatanoprost implant is inserted into the upper punctum of both eyes. In another embodiment, an implant that provides one anti-glaucoma agent is inserted into the lower punctum of both eyes, and an implant that provides another anti-glaucoma agent is inserted into the upper punctum of both eyes. In other embodiments, the implant providing the anti-glaucoma agent is inserted bilaterally into the upper or lower punctum and the implant without the anti-glaucoma agent is inserted bilaterally into the other punctum to plug or occlude the other punctum.

The implant may contain at least 0.5 micrograms, 3 micrograms, at least 10 micrograms, at least 20 micrograms, at least 30 micrograms, at least 40 micrograms, at least 50 micrograms, at least 60 micrograms, at least 70 micrograms, or at least 80 micrograms of latanoprost. In some embodiments, the implant contains from about 40 micrograms to about 50 micrograms of latanoprost. The implant may contain about 40 micrograms, about 41 micrograms, about 42 micrograms, about 43 micrograms, about 44 micrograms, about 45 micrograms, about 46 micrograms, about 47 micrograms, about 48 micrograms, about 49 micrograms, or about 50 micrograms of latanoprost. In one embodiment, the implant contains about 3.5 micrograms, about 14 micrograms, about 21 micrograms, about 42 micrograms, about 44 micrograms, about 65 micrograms, or about 81 micrograms of latanoprost. For other anti-glaucoma agents, equivalent therapeutic amounts may be employed, based on therapeutic equivalence to these amounts of latanoprost. Therapeutic equivalence can be determined by Reference to the "Physician's Desk Reference".

In some embodiments, a topical formulation consisting essentially of an anti-glaucoma agent (e.g., latanoprost) and a pharmaceutically acceptable vehicle is provided, wherein the formulation is eluted from a solid drug core or other implant body configured to be at least partially inserted into at least one punctum of a subject, wherein the formulation is capable of lowering intraocular pressure for at least 90 days. In some embodiments, the topical formulation comprises a penetration enhancer (e.g., benzalkonium chloride).

The present invention further provides methods of reducing or reducing the incidence of adverse effects resulting from the topical administration of anti-glaucoma agents, such as prostaglandins, including but not limited to latanoprost, travoprost, and bimatoprost, and as another example timolol, for treating ocular diseases, comprising delivering the anti-glaucoma agents from implants, including but not limited to the implants disclosed herein, to the eye. In one embodiment, such implants may be partially or completely impregnated with the anti-glaucoma agent. In another embodiment, such an implant may comprise a sustained release core containing the anti-glaucoma agent and optionally a penetration enhancer. In another embodiment, such an implant may comprise a sustained release core containing the anti-glaucoma agent and optionally a penetration enhancer, and the implant may be used in combination with one or more artificial tears. In another embodiment, the adverse effects include, but are not limited to, eye purity (eye purities), eye burn, eye congestion, and punctate keratitis.

Also contemplated herein are kits for treating an ocular disease comprising a lacrimal implant (e.g., a punctum plug) described herein and instructions for use. In some embodiments, the lacrimal implants are individually packaged for a single use. In some embodiments, the kit has: a first container containing the lacrimal implant delivery system, a second container containingAnd instructions for use. In other embodiments, the kit has: a first container comprising the lacrimal implant delivery system, a second container comprising an artificial tear. The artificial tears may contain benzalkonium chloride (AT-BAK) or other penetration enhancers and instructions for use. In some embodiments, the kit has: a first container comprising the lacrimal implant delivery system comprising an anti-glaucoma agent and a penetration enhancer, a second container comprising an artificial tear fluid, and instructions for use. In some embodiments, the artificial tearThe liquid does not contain a penetration enhancer. In some embodiments, using the kit, glaucoma, ocular hypertension, pre-and post-operative eye conditions, dry eye, eye infection, post-operative inflammation or pain, allergy, or inner ear disorders, such as dizziness or migraine, can be treated.

Also contemplated herein are compositions for a drug core suitable for placement in an implant in vivo for providing controlled release of a therapeutic agent to tissue in the vicinity of the implant. In various embodiments, the implant is an ocular implant for placement within a punctum of a patient to deliver a therapeutic agent, such as a prostanoid, to the eye. The core comprises one or more excipients that, in some embodiments, modulate the release rate of the agent to body tissue, or increase the residence time of the agent in adjacent tissue, or provide enhanced tissue penetration, such as corneal penetration in the eye. In other embodiments, the one or more excipients may also allow for higher drug loading in the core composition while maintaining the desirable properties of substantially homogeneous distribution of the inclusion of the pharmaceutical agent in the polymer matrix forming the core.

In various embodiments, the present invention provides an implant configured for placement within or near a body cavity, tissue, tube, or fluid, the implant comprising a core comprising: (a) a matrix comprising a polymer; (b) a therapeutic agent dissolved or dispersed within the matrix; and (c) an excipient dissolved or dispersed within the matrix, the excipient configured for any one of the following purposes: (1) modulating the release rate of the therapeutic agent into the body cavity, tissue, tube or fluid compared to the equivalent (compatible) release rate in the absence of the excipient; or (2) increasing the loading of the therapeutic agent substantially uniformly dissolved or dispersed within the matrix as compared to an equivalent loading of the therapeutic agent substantially uniformly dissolved or dispersed in the absence of the excipient; or (3) increased retention of the agent at or near the site of release in vivo, or increased penetration of the agent into adjacent body tissue, or both, as compared to retention or penetration from a comparable implant in the absence of the excipient, or both; or any combination thereof. In various embodiments, the amount of therapeutic agent in one volumetric portion of the matrix is similar to the amount of therapeutic agent in any other same volumetric portion of the matrix. In other embodiments, the implant body is adapted to receive a core therein for placement within a body cavity, tissue, tube, or fluid.

In various embodiments, the therapeutic agent is substantially uniformly and homogeneously dissolved in the matrix, or the agent is at least partially formed into solid or liquid inclusions having an average diameter of less than about 50 microns, the inclusions being substantially uniformly dispersed in the matrix on a sub-millimeter scale.

In various embodiments, the excipient may be a phospholipid, a polyol, a polyethylene glycol, or any combination thereof.

In various embodiments, the present invention provides a method of making an ocular implant, wherein the matrix polymer is a cross-linked silicone, the therapeutic agent is latanoprost, and the excipient comprises a phospholipid, a polyol, or a polyethylene glycol, or any combination thereof, the method comprising: silicone part a, latanoprost and excipients are combined with stirring, then silicone part B and crosslinker are added with stirring, then the mixture is extruded under pressure (e.g., at low temperature) into a tube containing an impermeable material, then the mixture is cured in the tube, and the cured, filled tube is cut into segments, each segment being a core for an implant.

Drawings

This patent document contains at least one drawing executed in color. Copies of this patent document in the form of this patent or patent application publication with color drawing(s) will be provided by the U.S. patent and trademark office upon request and payment of the necessary fee. In the drawings, like reference numerals may be used to describe similar components throughout the several views. The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments discussed herein.

Fig. 1 illustrates one embodiment of a release profile (profile) curve for a lacrimal implant comprising 44 micrograms of anti-glaucoma agent and a lacrimal implant comprising 21 micrograms of anti-glaucoma agent under accelerated dissolution conditions over a period of about 50 hours.

Fig. 2A illustrates an embodiment of an isometric view of a lacrimal implant configured to be at least partially retained within a punctum and lacrimal anatomy.

Fig. 2B illustrates one embodiment of a cross-sectional view of the lacrimal implant taken along a line parallel to a longitudinal axis of the lacrimal implant, such as along line 2B-2B of fig. 2A.

Fig. 2C illustrates one embodiment of a cross-sectional view of another lacrimal implant taken along a line parallel to a longitudinal axis of the implant.

Fig. 3A illustrates an embodiment of an isometric view of a lacrimal implant configured to be at least partially retained within a punctum and lacrimal anatomy.

Fig. 3B illustrates an embodiment of a cross-sectional view of the lacrimal implant taken along a line parallel to a longitudinal axis of the implant, such as along line 3B-3B of fig. 3A, and expansion of the anatomical structure receiving the implant.

Fig. 4A illustrates an embodiment of an isometric view of a lacrimal implant configured to be at least partially retained within a punctum and lacrimal anatomy.

Fig. 4B illustrates one embodiment of a cross-sectional view of the lacrimal implant taken along a line parallel to a longitudinal axis of the implant, such as along line 4B-4B of fig. 4A.

Fig. 5 illustrates one embodiment of a cross-sectional view of a lacrimal implant configured to be at least partially retained within a punctum and lacrimal anatomy.

Figure 6 illustrates an example graph of anti-glaucoma agent content per 0.95mm cross section of a drug-filled precursor sheath (precursor sheath) prepared by cold extrusion.

Figure 7 illustrates one embodiment method of producing a drug core comprising about 44 micrograms of anti-glaucoma agent.

Fig. 8A-8C illustrate an example of a release profile of a lacrimal implant comprising 44 micrograms of anti-glaucoma agent under in vitro dissolution conditions over a period of about 63 days.

Fig. 9 illustrates the release characteristics of an ocular implant of the present invention incorporating the excipients glycerol, PEG400, EPG, DMPC and DMPE.

Fig. 10 illustrates the release profile of an ocular implant of the present invention incorporating the excipients DMPC and EPG as compared to the release rate of an implant without the excipients.

Fig. 11 illustrates the release profile of an ocular implant of the invention incorporating excipients DPPE and long chain PC (PSPC, DPPC, DSPC), both of which exhibit reduced elution rates, and short chain PC (dmpc) and PG (EPG, POPG, DMPG), both of which exhibit increased elution rates.

Fig. 12 illustrates the release profile of an ocular implant of the present invention incorporating the excipients DOTAP, DODAP and C16 positively charged lipids.

Figure 13 illustrates a cross section of a filled and cured polyimide sheath containing a composition of the invention containing the therapeutic agent latanoprost (in the presence of the excipient DMPC or EPG) in a silicone matrix. The matrix is homogeneous on visual inspection (macropicailly) and has no isolated large Latanoprost inclusion.

Fig. 14 illustrates a cross-section of a sheath filled with a control composition that is the same as the composition of fig. 13 except for the absence of excipients. The extrusion showed a clear separation between the polymer matrix and latanoprost within the polyimide sheath. Also exhibiting observable changes. The upper one shows smaller latanoprost inclusion. The next one shows a large clear cross section of latanoprost.

Detailed Description

Defining:

the terms "a" or "an," as used herein, are used to include one or more than one, as is conventional in patent documents, regardless of any other circumstance or usage of "at least one" or "one or more.

The term "or" as used herein is intended to be non-exclusive or, alternatively, such that "a or B" includes "a is but B is not," "B is but a is not," and "a and B," unless otherwise indicated.

The term "about" as used herein is used to refer to an amount that is about, near, nearly, or about equal to the amount recited. The term "adverse event" as used herein refers to any undesirable clinical event experienced by a subject undergoing a therapeutic treatment (including a drug and/or medical device) in a clinical trial or clinical practice. Adverse events include changes in the condition or laboratory outcome of the subject that have or may have a deleterious effect on the health or well-being of the subject. For example, adverse events include, but are not limited to: device failure identified prior to placement, device malposition, device failure after placement, persistent inflammation, endophthalmitis, corneal complications (corneal edema, opacification or graft decompensation), chronic pain, iridochromic changes, conjunctival congestion, eyelash growth (increased length, thickness, pigmentation and number of eyelashes), eyelid skin darkening, intraocular inflammation (iritis/uveitis), macular edema including cystoid macular edema, blurred vision, burns and stings, foreign body sensation, itching, punctate epithelial keratopathy (punctate epithelial keratopathy), dry eye, hyperdacryosis, ocular pain, eyelid scabbing, eyelid discomfort/pain, eyelid edema, eyelid erythema, photophobia, VA descent, conjunctivitis, diplopia, expulsion from the eye (cause), retinal arterial embolism, retinal detachment, vitreal hematoma caused by diabetic retinopathy, retinal hemorrhage, retinal vascular disease, retinal hemorrhage, retinal, Upper respiratory infection/cold/flu, chest pain/angina, muscle/joint/back pain and rash/allergic skin reactions, eye itching, increased lacrimation, eye congestion and punctate keratitis.

The phrase "consisting essentially of.

The term "continuous" or "continuously" as used herein means uninterrupted or uninterrupted. For example, a continuously administered active agent is administered over time without interruption.

The term "eye" as used herein refers to any and all anatomical tissues and structures associated with the eye. The eye is a spherical structure comprising a wall with 3 layers: the outer sclera, the middle choroid layer, and the inner retina. The sclera includes a hard, fibrous coating that protects the inner layer. Most of it is white except for the front transmissive region, which is the cornea, which allows light to enter the eye. The choroid layer is located on the inner side of the sclera, contains many blood vessels, and is modulated into a hyperpigmented iris in the anterior portion of the eye. The lenticular lens is located behind and immediately adjacent to the pupil. The chamber is behind the lens and is filled with a vitreous humor, i.e., a gel-like substance. The anterior chamber and the posterior chamber are located between the cornea and the iris, respectively, and are filled with aqueous humor. Behind the eye is the retina that perceives the light. The cornea is a light-transmitting tissue that transmits an image to the back of the eye. It comprises vascular tissue supplied with nutrients and oxygen by immersion in tears and aqueous humor, and from blood vessels connecting the junction between the cornea and sclera. The cornea includes a passageway for the drug to permeate into the eye. Other anatomical structures associated with the eye include the lacrimal drainage system, which includes the secretory system, the distribution system, and the drainage system. The secretory system contains secretions that are stimulated by blinking and temperature changes due to tear evaporation and reflex, and secretions with efferent parasympathetic nerves supply and secrete tears in response to physical or emotional stimuli. The dispensing system includes the eyelids and a tear meniscus (tear meniscus) around the eyelid margin of the open eye that distributes tear fluid over the surface of the eye by blinking, thereby reducing the formation of dry zones.

The term "implant" or "lacrimal implant" as used herein refers to a structure that may be configured to contain or be impregnated with a drug core or drug matrix, such as those disclosed in this patent document and in WO07/115,261 (which is incorporated herein by reference in its entirety). When the structure is implanted or inserted into a target site along the subject's tear pathway, the lacrimal implant is capable of releasing an amount of a therapeutically active agent (such as latanoprost or other anti-glaucoma agent) into the tear fluid over a sustained release period of time. The terms "implant," "plug," and "lacrimal implant" are used herein to refer to similar structures. Likewise, the terms "implant body" and "plug body" are used herein to refer to similar structures. The lacrimal implants described herein may be inserted into a punctum of a subject and into an associated lacrimal duct. The lacrimal implant may also be a drug core or drug matrix itself configured to be inserted into the punctum without being disposed in a carrier (e.g., a punctal plug obturator), e.g., having a polymeric component and an anti-glaucoma agent component (e.g., latanoprost), without additional structure encasing the polymeric component and the agent component. In some embodiments, the lacrimal implant further comprises one or more penetration enhancers, for example, benzalkonium chloride.

As used herein, "effacement loss" (LoE) is defined as an increase in IOP to baseline (post-clearance) IOP in either or both eyes while continuously wearing (wear) a latanoprost punctal plug delivery system (L-PPDS) from day 0. Subjects were followed for at least 4 weeks, then subjects could end the study due to LoE, and LoE was confirmed in 2 consecutive follow-ups.

As used herein, a "pharmaceutically acceptable vehicle" is any physiological vehicle known to one of ordinary skill in the art that can be used to formulate a pharmaceutical composition. Suitable vehicles include: a polymer matrix, sterile distilled or purified water, isotonic solutions such as isotonic sodium chloride or boric acid solution, Phosphate Buffered Saline (PBS), propylene glycol and butylene glycol. Other suitable vehicle components include phenylmercuric nitrate, sodium sulfate, sodium sulfite, sodium phosphate, and monosodium phosphate. Other examples of other suitable vehicle ingredients include alcohols, fats and oils, polymers, surfactants, fatty acids, silicone oils, humectants, moisturizers, viscosity modifiers, emulsifiers, and stabilizers. The composition may also contain adjuvants, i.e., antimicrobials such as chlorobutanol, parabens or organic mercury compounds; pH adjusters such as sodium hydroxide, hydrochloric acid or sulfuric acid; and a tackifier such as methylcellulose. The final composition should be sterile, substantially free of foreign matter, and have a pH that achieves optimal drug stability.

The term "punctum" as used herein refers to the orifice at the end of the lacrimal canaliculus as seen on the margin of the eyelid at the lateral end of the lacrimal lake. The function of the punctum (the complex number of puncta) is to absorb tears produced by the lacrimal gland. In order of the drainage flow, the drainage portion of the lacrimal drainage system includes the punctum, canaliculus, lacrimal sac, and lacrimal duct. From the lacrimal duct, tears and other flowable materials drain into the passages of the nasal system. The lacrimal canaliculus includes an upper (superior) lacrimal canaliculus and a lower (inferior) lacrimal canaliculus that terminate in an upper punctum and a lower punctum, respectively. The upper and lower puncta bulge slightly at the junction of the ciliary and lacrimal duct portions near the conjunctival sac at the inner extremity of the eyelid margin. The upper and lower puncta are generally circular or slightly oval openings surrounded by a ring of connective tissue. Each punctum communicates (lead intro) with the vertical portion of their respective canaliculus and then turns more horizontally at the canalicular curvature to connect to each other at the entrance to the lacrimal sac. The canaliculi are generally tubular and lined internally with stratified squamous epithelium surrounded by elastic tissue, which allows them to be dilated.

The term "subject" refers to an animal, e.g., a mammal, including, but not limited to, a primate (e.g., human), a cow, a sheep, a goat, a horse, a dog, a cat, a rabbit, a rat, a mouse, and the like. In many embodiments, the subject is a human.

An "anti-glaucoma agent" may include a drug, and may be any of the following or their equivalents, derivatives or analogs, including: adrenergic agonists, adrenergic antagonists (beta-blockers), carbonic anhydrase inhibitors (CAIs, both systemic and local), parasympathomimetics, prostaglandins, and hypotensive lipids, and combinations thereof. Other agents or drugs useful in the present invention include antimicrobial agents (e.g., antibiotics, antiviral agents, antiparasitic agents (antiparasitic), antifungal agents, etc.), corticosteroids or other anti-inflammatory agents (e.g., NSAIDs), decongestants (e.g., vasoconstrictors), agents that prevent or reduce allergic reactions (e.g., antihistamines, cytokine inhibitors, leukotriene inhibitors, IgE inhibitors, immunomodulators), mast cell stabilizers, cycloplegic agents, and the like. Examples of conditions that may be treated with the agent include, but are not limited to, glaucoma, pre-and post-operative treatment, ocular hypertension, dry eye, and allergies.

As used herein, "penetration enhancer" refers to an agent or other substance that temporarily increases the ocular permeability characteristics (e.g., the permeability of the cornea of the eye) of a subject. Certain characteristics of the ocular penetration enhancers may include one or more of the following: immediate and unidirectional effects; the duration of the effect that can be expected; after removal, the ocular tissues restore their normal barrier properties; little or no systemic or toxic effects; little or no irritation or damage to the surface of the eye membrane; or physical compatibility with a wide range of anti-glaucoma agents and pharmaceutical excipients. Exemplary ocular penetration enhancers include, but are not limited to: calcium chelators (e.g., EDTA), surfactants (e.g., nonionic surfactants including polyoxyethylene-9-lauryl ether, tween 80 or span 60; or cholic acids and salts including deoxycholate, taurocholate or taurodeoxycholate), preservatives (e.g., benzalkonium chloride or cetylpyridinium chloride), glycosides (e.g., digitonin or saponin), fatty acids (e.g., capric acid, oleic acid or short fatty acids), azone, chitosan, tamarind seed polysaccharide, polycarbophil or derivatives thereof (e.g., polycarbophil or polycarbophil-cysteine conjugate), cytochalasin, or cyclodextrins. Other penetration enhancers for use in the present invention include, but are not limited to, those described in the following references (the entire contents of which are incorporated herein by reference): touitou, Elka, Barry, Brian w.enhancement in Drug delivery.taylor & FrancisGroup; 2007: 527-548.

The term "local" refers to any surface of a body tissue or organ. Topical formulations are those that are applied to a body surface (e.g., the eye) to treat the surface or organ. Topical formulations include liquid drops (such as eye drops), creams, lotions, sprays, emulsions and gels. Topical formulations, as used herein, also include formulations that can release an agent (e.g., an anti-glaucoma agent) into the tear fluid resulting in topical administration to the eye.

The term "treatment" or "management" of a disease as used herein includes: (1) preventing a disease, i.e., causing clinical symptoms of a disease not to develop in a subject who may be exposed to the disease or susceptible to the disease but has not experienced or exhibited symptoms of the disease; (2) inhibiting a disease, i.e., arresting or reducing the development of a disease or its clinical symptoms; or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

As used herein, an "effective amount" in the context of a therapeutic agent or a "therapeutically effective amount" of a therapeutic agent refers to the amount of such agent: which wholly or partially alleviates symptoms associated with the disorder or condition, or halts or slows further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disorder or condition. Specifically, an "effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount is also an amount wherein the therapeutically beneficial effect is superior to any toxic or detrimental effect of the compounds of the present invention. When the term "effective amount" is used in the context of a functional material (such as an effective amount of a dispersant), it is meant that the amount of functional material used is effective to achieve the desired result.

A "matrix" is a substance comprising a polymer in which a therapeutic agent is dispersed, the combination of substances, together with the excipient of the present invention, constituting the core of the implant, which serves as a reservoir for the agent from which it is released into the surrounding of the implant over a period of time.

The term "polymer" as used herein refers to a macromolecule containing one or more repeating units, as is well known in the art. "copolymer" refers to a polymer comprising at least two types of repeating units. The copolymer may be a block copolymer in which segments containing a plurality of the same type of repeating unit are combined with segments containing a plurality of the 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 body tissue or body fluids.

Within the meaning herein, "loading" of a therapeutic agent within an implant matrix refers to the concentration of the agent relative to the matrix within the implant, not including the weight of any sheath (if present).

The term "excipient" as used herein refers to a substance, other than a therapeutic agent, disposed within a matrix that does not itself exert the biological effects of the therapeutic agent. For example, if the therapeutic agent is a prostanoid having a physiological effect on the body tissue surrounding the implant, the second prostanoid having a physiological effect is not an excipient within the meaning herein. Excipients may include pharmaceutical agents that modulate (e.g., increase) the rate of release from the implant into body tissue. Excipients may include substances that alter (e.g., increase) the residence time (time of residence) of the therapeutic agent in the target tissue surrounding the location of the implant in the living body. Excipients may also include substances that can alter the nature of uptake of the therapeutic agent into the surrounding tissue, such as increasing penetration of the agent into the cornea in the presence of the excipient as compared to penetration in the absence of the excipient (penetration enhancer). Excipients may also include substances that can alter the physical properties of the implant itself, for example, by altering (e.g., increasing) the amount of therapeutic agent that can be present in the implant while maintaining the desired homogeneity of dispersion of the inclusion of the agent within the matrix as compared to the amount of agent that can be present in the matrix in the desired substantially dispersed manner in the absence of the excipient. Some examples of excipients within the meaning herein include, but are not limited to, lipids (such as phospholipids), polyols (such as glycerol) and polyethylene glycols of different molecular weights and benzalkonium chloride.

The term "wherein the amount of therapeutic agent in one volume portion of the matrix is similar to the amount of therapeutic agent in any other same volume portion of the matrix" refers to the uniformity of distribution of the agent in the matrix, whether the agent is homogeneously dissolved, or whether it forms separate inclusions, is a solid or a liquid in the matrix polymer, or both. In various embodiments, the therapeutic agent is contained in the matrix such that the amount of therapeutic agent in one volumetric portion of the core is similar to the amount of therapeutic agent in any other same volumetric portion of the core. For example, the amount of therapeutic agent in one volume portion of the core may differ by no more than about 30% from the amount of therapeutic agent in any other same volume portion of the core. For example, the amount of therapeutic agent in one volume portion of the core may differ by no more than about 20% from the amount of therapeutic agent in any other same volume portion of the core. For example, the amount of therapeutic agent in one volume portion of the core may differ by no more than about 10% from the amount of therapeutic agent in any other same volume portion of the core. For example, the amount of therapeutic agent in one volume portion of the core may differ by no more than about 5% from the amount of therapeutic agent in any other same volume portion of the core. Additionally, the concentration of the therapeutic agent in one volume portion of the core may be the same as any other same volume portion of the core, including in certain embodiments, embodiments wherein the agent is present as a homogeneous, homogeneous dispersion, and in embodiments wherein the agent is present in the matrix as a solid or liquid inclusion.

In some embodiments, the pharmaceutical agent may be dissolved in the matrix when the chemical identity (chemical identities) of the pharmaceutical agent and the matrix and the concentration of the pharmaceutical agent in the matrix allow for dissolution to be achieved. For example, certain lipophilic steroid derivatives may be dissolved in silicone at high concentrations, as is known in the art. In this case, the agent is said to be "dissolved" in the polymer, or "homogeneously and homogeneously dispersed" in the matrix, or "dispersed at the molecular level" in the polymer, just as the compound can be dissolved in a solvent, forming a "solid solution" of the agent in the polymeric material of the matrix.

In other embodiments, the agent is not completely dissolved in the matrix, but is present as a domain or "inclusion" of the agent within the polymer matrix. The inclusions may be liquid or solid at about room temperature or at about human body temperature. After the matrix precursor has been cured to form a matrix, the inclusions are non-uniformly distributed in the now solid or near solid matrix, thereby preventing, at least to some extent, recombination with one another (such as by droplet packing). This form is referred to as a "heterogeneous" distribution of the agent in the matrix. When inclusions of pharmaceutical agents are present, it is believed that a specific proportion of the pharmaceutical agent may also be dissolved in the matrix. However, dissolution is not necessary for the practice and function of the present invention. Furthermore, the heterogeneous distribution of the pharmaceutical agent to the matrix can be controlled at a macroscopic level, as discussed in connection with the definitions of the terms "concentration" and "similar" given below.

As the term is used herein, "concentration" of a therapeutic agent refers to the concentration of the agent within the macroscopic volume of the matrix-agent core, which is controlled to have a degree of reproducibility between different samples of the core. The concentration of the agent in the macroscopic volume of the core may vary, but only within limits, compared to the concentration in any other same macroscopic volume of the core. The term does not refer to concentrations at the molecular level (where discrete and/or irregular domains or inclusions of the agent in concentrated form may be present), but rather refers to the agent being at greater than at least about 0.1mm³Core volume (e.g., a core cube sample with about 100 micrometers (μm) on one side, or about 1mm²Cross sectional area of0.1mm thick core sheet).

The term "similar" as in a "similar" concentration of a therapeutic agent refers to an amount (e.g., concentration of an agent, e.g., in micrograms (μ g)/mm) within a defined boundary³In units) vary only to a certain extent between different measurements. The degree of variation is controlled or adjusted to provide uniformity of the core material, making most cores or inserts medically suitable because the dose of agent they can provide to the tissue is within certain limits between different samples. For example, "similar" concentrations between 2 equal volumes of core material or between 2 inserts made from filled precursor sheaths may differ by no more than about 30%, or may differ by no more than about 20%, or may differ by no more than about 10%, or may differ by no more than about 5%. The term "similar" also includes solid solutions and homogeneous, homogeneous dispersions as defined herein.

In various embodiments, the core contains a therapeutic agent dispersed in a matrix, the latter being in the form of solid or liquid inclusions, referred to herein as "inclusions. The inclusions may be of different sizes, and different size distributions of the various inclusions are possible, as defined herein. When referring to inclusions having a 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 majority of all inclusions have the recited dimensions. When referring to the average size or "average diameter" of inclusions within a population of inclusions, such as "average diameter of about 50 μm", it is meant the numerical average of the largest dimension of all inclusions. By "an average diameter of less than about 50 μm" is meant that the average is approximately less than the stated value. When referring to the distribution of inclusion diameters within a population of inclusions as "standard deviation," it is meant that the distribution of inclusion diameters is normal or near normal, and that the standard deviation is a measure of the permutation of values, as is well known in the art. A small standard deviation from the mean diameter represents a tight distribution of inclusion diameters, which is a feature of various embodiments of the present invention. The relative uniformity of the inclusion size distribution and the relative uniformity of the amount of medicament dispersed in the core per unit volume within the insert are features of different embodiments according to the present invention.

The size distribution of inclusion diameters may be monodisperse and may be closely monodisperse. By "monodisperse" herein is meant that the size distribution of the diameters of the plurality of inclusions is relatively tightly clustered around the mean diameter of the inclusions, even if the distribution is not a normal distribution. For example, the distribution may have a fairly sharp upper inclusion size limit greater than the average diameter, but may be attenuated in an inclusion distribution less than the average diameter (trail off). Nevertheless, the size distribution may be tightly packed, or monodisperse.

"organosilicon" refers to a polymer comprising the elements silicon, oxygen, carbon, and hydrogen, as is well known in the art. Carbon and hydrogen together form an organic group that can replace the silicon-oxygen backbone of the polymer, and that can be interspersed within the domains of the silicon-oxygen backbone, or both. The organic group may be an alkyl group (such as methyl), an aryl group (such as phenyl), or any combination thereof.

"crosslinking agent" is an agent that increases the degree of crosslinking between individual polymer chains in the formation of the polymer that makes up the matrix. For example, the cross-linking agent of the silicone polymer may be a tetraalkyl orthosilicate, such as tetraethyl orthosilicate (tetraethyl orthosilicate).

"polyurethane" refers to a variety of polymers or copolymers containing repeating units covalently bonded by urethane (i.e., urethane linkages-N-C (O) -O-in which the N and O atoms are attached to an organic radical). The organic radicals may be aliphatic, aromatic or mixed; other functional groups may be contained. Each radical (radial) is linked to the other radicals, except for the radicals at the ends of the molecular chain, by 2 (or more) urethane groups. The polyurethane polymer contains only groups of urethane-type linking repeat units. Polyurethane copolymers, such as polyurethane-silicone copolymers or polyurethane-carbonate copolymers, contain urethane and other types of groups linking repeat units, i.e., silicone and carbonate type groups, respectively.

"Release characteristics" or "release rate characteristics" refers to the release rate, i.e., the amount of agent that moves from an implant of the present invention into body tissue or fluid (e.g., eye or tear fluid) as a function of time. The release profile, in turn, may determine the concentration of the agent in the eye and surrounding tissue over the time period that the plug releases the agent. The excipient of the present invention can alter the release profile, such as increasing the release rate of the pharmaceutical agent in the presence of the excipient, or otherwise decreasing the release rate, as compared to the release rate observed in the absence of the excipient from a comparable implant.

Elevated intraocular pressure:

ocular Hypertension (OH) and Primary Open Angle Glaucoma (POAG) are caused by the accumulation of aqueous humor in the anterior chamber, primarily due to the inability of the eye to properly drain or excessive production of aqueous humor. The ciliary body, located at the root of the iris, continuously produces aqueous humor. Aqueous humor flows into the anterior chamber and is then drained through the angle between the cornea and the iris, through the trabecular meshwork and into the channels in the sclera. In a normal eye, the amount of aqueous humor produced is equal to the amount drained. However, in this functionally impaired eye, intraocular pressure (IOP) is elevated. Elevated IOP represents an important risk factor for glaucomatous visual field loss. The results of several studies suggest that early intervention aimed at lowering intraocular pressure slows the development of optic nerve damage and visual field loss leading to vision loss and blindness.

Latanoprost:

one anti-glaucoma agent for use in the methods described herein is latanoprost. The latanoprost is prostaglandin F_2αAnd the like. Its chemical name is isopropyl- (Z) -7[ (1R, 2R, 3R, 5S)3, 5-dihydroxy-2- [ (3R) -3-hydroxy-5-phenylpentyl group]Cyclopentyl group]-5-heptenoic acid ester. Its molecular formula is C₂₆H₄₀O₅Its chemical structure is:

latanoprost is a colorless to pale yellow oil that is very soluble in acetonitrile and readily soluble in acetone, ethanol, ethyl acetate, isopropanol, methanol, and octanol. It is practically insoluble in water.

Latanoprost is thought to lower intraocular pressure (IOP) by increasing aqueous humor outflow. Studies in animals and humans have shown that the main mechanism of action is to increase uveoscleral outflow of aqueous humor from the eye. Latanoprost is absorbed through the cornea, where the isopropyl ester prodrug is hydrolyzed to the acid form, becoming biologically active. Studies in humans have shown that peak concentrations in aqueous humor are reached approximately 2 hours after topical administration.

Latanoprost ophthalmic solutions are commercially available products suitable for lowering elevated IOP in subjects with open angle glaucoma or ocular hypertension. Commercially available productsThe amount of latanoprost in (a) is about 1.5 micrograms/droplet. As noted above, eye drops, while effective, are less effective and require multiple administrations or treatment regimens to maintain the therapeutic benefit. Low subject compliance can compromise (compound) these effects.

Fig. 1 illustrates the mean in vitro release profiles over a period of about 50 hours for 3 example lacrimal implants each having a drug core comprising 44 micrograms of latanoprost and 3 example lacrimal implants each having a drug core comprising 21 micrograms of latanoprost under accelerated dissolution conditions. Using 50% isopropanol, in part, provides accelerated dissolution conditions. The characteristic curves demonstrate that the lacrimal implant with a drug core comprising 44 microclatanoprost elutes the anti-glaucoma agent more rapidly than the lacrimal implant with a drug core comprising 21 microclatanoprost.

Using a High Performance Liquid Chromatography (HPLC) method, the release profile of fig. 1 was obtained. The lachrymal implant containing latanoprost was placed in a vial containing a 1: 1 mixture of 1ml of isopropanol and phosphate buffered saline pH 7.4 solution, and the vial was placed in a vibrating water bath at 60 ℃ and 100 cycles/min. Subsequently, at 2, 8, 24 and 48 hours, 50 microliter samples of this solution were taken and injected into a reverse phase HPLC system, using uv detection at 210nm to measure the amount of latanoprost released from the lacrimal implant.

Figures 8A-8C illustrate in vitro release profiles over a period of about 63 days for lacrimal implants having a drug core comprising 44 microclatanoprost under in vitro dissolution conditions. More specifically, fig. 8A illustrates the mean elution data (in ng) for 3 example lacrimal implants each having a drug core comprising 44 micrograms of latanoprost. Using a High Performance Liquid Chromatography (HPLC) method, the release profiles of fig. 8A-8C were obtained. The lachrymal implant containing latanoprost was placed in a vial containing 1mL of phosphate buffered saline, pH 7.4 solution (PBS), and the vial was placed in a stainless steel sinker (sinker) in a vibrating water bath at 37 ℃ and 100 cycles/min. At 24 hour sampling intervals (and multiples thereof), the lachrymal implant containing latanoprost was removed and placed in another vial with 1ml of PBS in a vibrating water bath set at 37 ℃ and 100 cycles/min. Subsequently, a liquid sample was collected and spiked (Spike) with an internal standard, injected into a reverse phase HPLC system, and the amount of latanoprost released from the lacrimal implant was measured using uv detection at 210 nm.

Initially, lacrimal implants were demonstrated to have a burst elution of latanoprost of more than 1500 ng; however, this initial burst of elution shifted between days 2 and 20 to a relatively constant elution of about 350 and 450ng at or near day 21. Figures 8B-8C illustrate that the increase in latanoprost eluted from the drug core (in percent and ng, respectively) over time, particularly after about 5 days, is substantially linear. Advantageously, these linear trends can be useful in determining or predicting the effective release duration for a given lacrimal implant (e.g., punctal plug).

The lacrimal implants used to generate the characteristic curves shown in fig. 8A-8C each include a drug core having a diameter of about 0.0165 inches. As noted below, the release level of latanoprost or other anti-glaucoma agent can be altered by altering the exposed surface area (e.g., diameter surface area) of the core.

Influence the release rate of latanoprost or other anti-glaucoma agents:

work in connection with embodiments of the present invention indicates that molecular weight and solubility in water can each affect the release rate of an anti-glaucoma agent (such as latanoprost or other prostaglandins) from a solid drug core matrix. For example, a lower molecular weight may increase diffusion through the solid matrix material (e.g., through silicone) so that low molecular weight compounds may be released more rapidly. In addition, solubility in water may also affect the release rate of the anti-glaucoma agent, and in some cases, increased water solubility of the agent may increase the release rate from the solid core matrix, for example, by transport from the solid matrix material to body fluids (e.g., tears). According to these embodiments, anti-glaucoma agents (e.g., cyclosporine and prostaglandins) having a higher molecular weight and lower aqueous solubility than fluorescein may be released from the solid core at a lower rate. The surfactant may also affect the rate of release of the anti-glaucoma agent from the drug core to the surrounding body tissues and/or fluids (e.g., tear film fluids).

Work in connection with embodiments of the present invention indicates that radicals (radials) generated during sterilization can crosslink the drug core matrix material, thereby inhibiting the initial release rate of the anti-glaucoma agent from the drug core matrix material. In particular embodiments where electron beam (e-beam) sterilization is used, the crosslinking may be limited at and/or near the surface of the drug core matrix. In some embodiments, a known Mylar bag (Mylar bag) can be penetrated with an electron beam to sterilize the surface of the drug core. In some embodiments, other sterilization techniques to effect sterilization, such as gamma sterilization, may be used and are not limited to the surface of the core, penetrating the core material completely and/or uniformly.

Work in connection with embodiments of the present invention has shown that known salts (e.g., sodium chloride) can affect the rate of elution from the core.

Work in connection with the present invention suggests that surfactants naturally present in the tear film (e.g., surfactant D and phospholipids) can affect the transport of anti-glaucoma agents dissolved in the solid matrix from the core to the tear film. The (adapt) core may be modified in response to a surfactant in the tear film to provide sustained delivery of the anti-glaucoma agent into the tear film at a therapeutic level. For example, empirical data can be generated from a population of patients (e.g., 10 patients whose tears are collected and analyzed for surfactant content). The elution profile of a sparingly water-soluble drug (e.g., cyclosporine) in collected tears can also be measured and compared to elution profiles in buffers and surfactants to develop an in vitro model of tear surfactants. An in vitro surfactant-containing solution based on this empirical data can be used to adjust the drug core in response to the surfactant of the tear film.

In some embodiments, the silicone or other solid core material may include an inert filler to increase the rigidity of the cured matrix. Work in connection with embodiments of the present invention has shown that a filler material can increase the release rate of a therapeutic agent. MED-4011 and MED-6385 materials are commercially available with filler materials. The MED-4011 material can comprise an inert silica filler material to increase the rigidity of the cured silicone matrix. MED-4385 may contain an inert diatomaceous earth filler material to increase the rigidity of the cured silicone matrix.

Work in connection with embodiments of the present invention indicates that by reducing the exposed surface area of the core, the release level of the anti-glaucoma agent can be reduced, thereby allowing the agent to be selectively released at one or more therapeutic levels for a sustained period of time.

Adverse events in clinical trials and clinical practice:

based onProduct information, the most commonly reported adverse ocular events associated with latanoprost in clinical trials are blurred vision, burns and stings, conjunctival congestion, foreign body sensation, itching, increased iris pigmentation, and punctal keratopathy. These events occurred in 5% to 15% of subjects. Less than 1% of subjects require discontinuation of treatment due to intolerance of conjunctival congestion. Dry eye, hyperdacryosis, ocular pain, eyelid scabbing, eyelid discomfort/pain, eyelid edema, eyelid erythema, and photophobia are reported in 1% to 4% of subjects. Conjunctivitis, diplopia and eye drainage were reported in < 1% of subjects. Very few reports have been made of vitreous hemorrhage due to retinal arterial embolism, retinal detachment and diabetic retinopathy.

The most common systemic adverse events in clinical trials are upper respiratory tract infections/colds/flu, with an incidence of about 4%. The incidence of chest pain/angina, muscle/joint/back pain and rash/allergic skin reactions, respectively, is 1% to 2%.

In clinical practice, the following adverse events have been observed in association with latanoprost: asthma and asthma exacerbations; corneal edema and erosion; dyspnea; eyelash and vellus changes (increased length, thickness, pigmentation and number); darkening of eyelid skin; herpetic keratitis; intraocular inflammation (iritis/uveitis); keratitis; macular edema, including cystoid macular edema; inverting the eyelashes, sometimes resulting in eye irritation; dizziness, headache and toxic epidermal necroschesis.

Subject non-compliance:

many studies have been published that show high noncompliance in subjects treated with eye drops for various eye disorders. One study showed that only 64% of subjects were on eye drops as directed (Winfield et al, 1990). Another study showed that 41% of subjects treated for glaucoma with eye drops missed 6 or more administrations over a 30 day period (Norell and Granstrom 1980).

The invention described herein provides methods of treating diseases and disorders (e.g., glaucoma) that avoid at least some of the non-compliance problems associated with eye drop administration. In some embodiments, the methods of the invention significantly reduce subject noncompliance by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% as compared to eye drop administration. In some embodiments, the total subject non-compliance of the methods described herein is about 5%, about 10%, about 15%, about 20%, or about 25%. Subject noncompliance can occur if the lacrimal implant delivery system of the present invention is intentionally removed by a subject, or if the subject does not want to reinsert the implant delivery system after such an implant is inadvertently detached from the punctum of the subject.

Benzalkonium chloride:

benzalkonium chloride (also known as BAK, alkyldimethylbenzyl ammonium chloride and ADBAC) is a mixture of alkylbenzyldimethylammonium chlorides of different even-numbered alkyl chain lengths. Benzalkonium chloride is a nitrogen-containing cationic surfactant belonging to the quaternary ammonium group. It has 3 broad categories of uses: as biocides (biochides), cationic surfactants and phase transfer agents in the chemical industry.

Benzalkonium chloride is readily soluble in ethanol and acetone. Although the dissolution in water is slower, aqueous solutions, for example, are easier to handle. The solution was neutral to slightly alkaline, with a color from clear to light yellow. Upon shaking, the solution foams up a lot, with a bitter taste and a weak almond-like smell (which is detectable only in concentrated solutions).

Benzalkonium chloride solutions are fast acting biocides with a reasonably long duration of action. They are active against bacteria and some viruses, fungi and protozoa. Bacterial spores are considered to be resistant. Depending on their concentration, the solutions are bacteriostatic or bactericidal. Gram-positive bacteria are generally more sensitive than gram-negative bacteria. pH does not significantly affect activity, but at higher temperatures and prolonged exposure times, activity increases dramatically.Is a commercially available artificial tear product containing benzalkonium chloride. Product safety information says that transient stinging and/or burns and local irritation may occur.

It has been reported that 59% of glaucoma subjects have signs and symptoms of ocular surface disease, and with various additional eye drops containing BAK, the chance of having such signs or symptoms is increased 2-fold (Leung et al 2008). Through in vitro studies, BAK has been found to increase corneal penetration. In addition to BAK, it is believed that one or more penetration enhancers, such as at least one of the following, may facilitate successful delivery of one or more anti-glaucoma agents across the complex tandem defense mechanisms of the eye (which make it difficult to achieve effective agent concentrations in a target region of the eye): calcium chelators (e.g., EDTA), surfactants (e.g., nonionic surfactants including polyoxyethylene-9-lauryl ether, tween 80 or span 60; or cholic acids and salts including sodium deoxycholate, sodium taurocholate or sodium taurodeoxycholate), preservatives (e.g., cetylpyridinium chloride), glycosides (e.g., digitonin or saponin), fatty acids (e.g., capric acid, oleic acid or short fatty acids), azone, chitosan, tamarind seed polysaccharide, polycarbophil or derivatives thereof (e.g., polycarbophil or polycarbophil-cysteine conjugate), cytochalins, or cyclodextrins.

Artificial tears:

in humans, under normal conditions, tear volume in the posterior fornix of the conjunctiva has been reported to be about 7-9 microliters, with a turnover rate of 0.5-2.2 microliters/min. It is estimated that the posterior fornix of the conjunctiva may contain a maximum volume of about 30 microliters. Commercial eye drops typically deliver 25.1 to 56.4 microliters; the average single drop volume was 35 microliters. The bolus of fluid can be used as a vehicle for the active ingredient in topical administration and provides eye drop fluid coverage of the ocular surface with sufficient access to the cornea. In some embodiments of the invention, e.g., those in which the subject has a suboptimal basal tear volume, excess fluid from one or more artificial tears used in conjunction with the lacrimal implant of the present invention may be used as a means of increasing the basal tear of the subject in order to assist in the dispersion and sufficient proximity of the anti-glaucoma agent to reach the cornea from the lacrimal implant. In some embodiments of the invention, the artificial tears used in the present invention comprise an eye lubricant formulation. In some embodiments, the ocular lubricant comprises a gel, a liquid gel, an ointment, a softener, a spray, and eye drops. In some embodiments, the artificial tears used in the present invention include a penetration enhancer. In other embodiments, the artificial tears used in the present invention do not include a penetration enhancer. Examples of artificial tears useful in the present invention can include, but are not limited to, lubricious formulations such as HypoTears ^TM、Refresh^TMTear, Visine^TMTear fluid, Bion^TMTear fluid, advanced eye Relief^TM、Clarymist^TM、Oasis^TMTear, Soothe^TM、Similasan^TM、Genteal^TMGel, Refresh^TMLiquid gel, Systane^TMLubricating eye drops, Systane^TMFree liquid gel, Lacri-Lube^TM、Refresh pM^TM、Tears Naturale^TM、TearsAgain^TM、Dwelle^TM、Lacrisert^TMAnd the like.

The treatment method comprises the following steps:

the invention described herein provides methods of treating glaucoma, elevated intraocular pressure, or glaucoma-associated elevated intraocular pressure with anti-glaucoma agents. In many embodiments, methods of treating an eye with an anti-glaucoma agent (e.g., latanoprost) are provided. In some embodiments, the anti-glaucoma agent is released to the eye for a sustained period of time. In one embodiment, the sustained period of time is about 90 days. In some embodiments, the method includes inserting a lacrimal implant having a body and a drug core through the punctum such that the drug core remains adjacent to the punctum. In some embodiments, the method comprises inserting a lacrimal implant through the punctum, the lacrimal implant having a body impregnated with an anti-glaucoma agent. The exposed surface of the core or impregnated body located near the proximal end of the implant contacts tear fluid or tear film fluid, and latanoprost or other anti-glaucoma agent migrates from the exposed surface to the eye over a sustained period of time while the core and body remain at least partially within the punctum. In many embodiments, methods of treating an eye with an anti-glaucoma agent (e.g., latanoprost) are provided that include inserting an implant with an optional retention structure in the lacrimal canaliculus through the punctum, and anchoring the implant body to the wall of the canaliculus through the retention structure. The implant releases an effective amount of the anti-glaucoma agent from the drug core or other agent donor into the tear fluid or tear film fluid of the eye. In some embodiments, the core can be removed from the retention structure while the retention structure remains anchored within the lumen. A replacement core may then be attached to the retention structure while the retention structure remains anchored. At least one exposed surface of the replacement core releases an anti-glaucoma agent (e.g., latanoprost) at therapeutic levels over a sustained period of time.

The replacement core may be attached to the retention structure approximately every 90 days for a period of about 180 days, about 270 days, about 360 days, about 450 days, about 540 days, about 630 days, about 720 days, about 810 days, or about 900 days to be continuously released to the eye. In some embodiments, replacement implants may be inserted into the punctum approximately every 90 days, allowing drug to be released to the eye for an extended period of time, including up to about 180 days, about 270 days, about 360 days, about 450 days, about 540 days, about 630 days, about 720 days, about 810 days, or about 900 days.

In other embodiments, methods of treating an eye with latanoprost or other anti-glaucoma agents are provided, the methods comprising inserting a drug core or other implant body at least partially into at least one punctum of the eye. The core may be combined with the implant body structure alone, or not. The drug core or drug-impregnated implant body provides sustained release delivery of latanoprost at therapeutic levels. In some embodiments, the sustained release delivery of latanoprost or other anti-glaucoma agent is for up to 90 days.

In many embodiments, methods of treating an eye with an anti-glaucoma agent (e.g., latanoprost) are provided that include inserting a distal end of an implant body into at least one punctum of the eye. In some embodiments, the retention structure of the implant can expand, thereby inhibiting expulsion of the implant. Expansion of the retention structure may assist in sealing tear flow through the punctum. In some embodiments, the implant body is configured such that, when implanted, there is at least a 45 degree angular intersection between a first axis defined by the proximal end of the implant and a second axis defined by the distal end of the implant body to inhibit expulsion of the implant body. Latanoprost or other anti-glaucoma agents are delivered proximally from the implant body to adjacent the tear fluid of the eye. Distal to the proximal end, delivery of latanoprost or other anti-glaucoma agents is inhibited.

The methods of the invention provide for the sustained release of latanoprost or other anti-glaucoma agents. In some embodiments, latanoprost is released from the implant for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, or at least 16 weeks. In one embodiment, latanoprost is released for at least 12 weeks. In another embodiment, the method of treatment according to the invention described above further comprises delivering an eye drop solution of latanoprost (e.g.,) The adjuvant therapy of (1).

The amount of anti-glaucoma agent (e.g., latanoprost) associated with the implant can vary depending on the desired therapeutic benefit and the time over which the device is expected to deliver therapy. Since the devices of the present invention exist in a variety of shapes, sizes and delivery mechanisms, the amount of drug incorporated into the device will depend on the particular disease or condition to be treated as well as the dosage and duration of time for which it is desired to achieve a therapeutic effect. Typically, the amount of latanoprost is at least that amount which is effective to achieve the desired physiological or pharmacological local or systemic effect upon release from the device.

Embodiments of the implants of the present invention may be configured to deliver latanoprost or other anti-glaucoma agents at a daily rate substantially lower than therapeutically effective drop treatment modalities, thereby providing a large treatment range with a wide margin of safety. For example, many embodiments treat the eye with a therapeutic level of no more than 5% or 10% of the daily drop dose for an extended period of time. In particular embodiments, the amount may be less than 5% of the recommended amount of a drop administered. As a result, during the initial bolus or washout period of about 1-3 days, the implant can elute latanoprost or other anti-glaucoma agent at a rate that is substantially higher than the sustained release level and well below the daily drop dose. For example, with an average sustained release level of 100 ng/day and an initial release rate of 1000 to 1500 ng/day, the amount of drug initially released is less than 2500ng of drug, which may be present in drops delivering the drug to the eye. Using sustained release levels substantially below the daily dosage of one or more drops allows the device to release a therapeutically beneficial amount of drug to achieve the desired therapeutic benefit within a wide safety margin while avoiding under or over dosing of the drug at the target site or area.

For comparison purposes, assuming a 35 microliter drop volume, drops (e.g., those used in the art) are usedDrops) of the sameQuasi-therapeutic delivery of about 1.5 micrograms of latanoprost. In contrast, the implants of the present invention deliver significantly less drug than the conventional drop administration described above. Although the sustained release amount of latanoprost released per day may vary, a sustained release of about 100 ng/day using the implant of the present invention corresponds to about 6% latanoprost administered with a single drop of 0.005% or more solution.

Methods of inserting and removing implants are known to those skilled in the art. For example, Tools for inserting and retrieving/extracting implants are described in U.S. patent application No. 60/970,840 (filed on 7.9.2007 under the heading insert and Extraction Tools for general implants), the disclosure of which is incorporated herein in its entirety. Typically, the size of the lacrimal implant to be used may be determined for placement by using an appropriate magnification, or if provided, a sizing tool. The subject's punctum can be dilated, if necessary, to fit the lacrimal implant. If necessary, a drop of lubricant may be applied to facilitate placement of the implant into the punctum. The implant can be inserted into the upper or lower punctum of the eye using a suitable placement tool. After placement, the cap of the implant may be visible. This process may be repeated for the other eye of the subject. To remove the implant, small ophthalmic or medical forceps may be used to securely grasp the portion of the tube of the implant below the cap. The implant can be removed gently using a gentle distraction motion.

Implant:

in various embodiments, latanoprost or other anti-glaucoma agents are administered via a core that may or may not be associated with the implant body structure alone for a sustained period of time. In certain embodiments, lacrimal implants for use in the methods described herein are provided. The lacrimal implant may be configured to release an amount of latanoprost or other anti-glaucoma agent into the tear fluid daily for a period of days, weeks, or months when implanted at a target site along a tear channel of a subject. The lacrimal implant may be one of a number of different designs that release latanoprost or other anti-glaucoma agents over a sustained period of time.

The disclosures of the following patent documents, which describe example implant embodiments for use in the methods of the present invention and methods of making those implants, are incorporated herein by reference in their entirety: U.S. application Ser. No. 60/871,864 (filed on 26.12.2006, entitled Nasolarix Drainage System for Drug Therapy); U.S. application Ser. No. 11/695,537 (filed on 2.4.2007 under the heading Drug Delivery Methods, Structures, and composites for Nasolicral System); U.S. application Ser. No. 60/787,775 (filed 3/31/2006 under the heading Nasolarix Drainage systems Implants for Drug Therapy); U.S. application Ser. No. 11/695,545 (filed on 2.4.2007, titled Nasolarix Drainage System for drug therapy); U.S. application Ser. No. 60/970,696 (filed on 7/9/2007 under the heading Expandable Nasolarix Drainage System Implants); U.S. application Ser. No. 60/974,367 (filed on 21/9/2007 under the heading Expandable Nasolarian Drainage System Implants); U.S. application Ser. No. 60/970,699 (filed on 7/9/2007, entitled manufacturing of Drug Cores for Sustainated releases of therapeutic Agents); U.S. application Ser. No. 60/970,709 (filed on 7/9/2007 under the heading Nasolarix Drainage System for Drug Delivery); U.S. application Ser. No. 60/970,720 (filed on 7/9/2007 under the heading Manual of Expandable Nasolanacrimal Drainage systems Implants); U.S. application Ser. No. 60/970,755 (filed on 7/9/2007 under the heading Prostaglandin analogs for Implant Devices and Methods); U.S. application Ser. No. 60/970,820 (filed on 7/9/2007 under the heading Multiple Drug Delivery Systems and Combinations of drugs with Punctal Implants); U.S. application Ser. No. 61/049,347 (filed on 30.4.2008, entitled Lacrial Implants and Related Methods); U.S. application Ser. No. 61/049,360 (filed on 30.4.2008, entitled Lacamidal Implants and related Methods); U.S. application Ser. No. 61/209,630 (filed 3/9/2009 under the heading Lacamid Implants and Related Methods); unknown U.S. application serial No., docket No. 2755.023PV9 (filed herewith under the title Lacrimal Implants and related Method); U.S. application Ser. No. 61/036,816 (filed 3/14/2008, entitled Lacrial Implants and Related Methods); U.S. application Ser. No. 61/049,337 (filed on 30.4.2008, entitled Lacrial Implants and RelatedMethods); U.S. application serial No. 61/049,329 (filed on 30/4/2008, entitled Composite Laccrimal Insert); U.S. application serial No. 61/049,317 (filed on 30.4.2008, entitled Drug-Releasing Polyurethane latex Insert); U.S. application serial No. 61/050,901 (filed 5/6/2008, entitled larlimit immPLANTdetection); U.S. application Ser. No. 12/231,989 (filed on 5.9.2008, entitled Lacrial Implants and Related Methods); U.S. application Ser. No. 61/134,271 (filed on 8.7.2008, entitled Lacrial image BodyInclusing Comforming Agent); U.S. application Ser. No. 12/231,986 (filed on 5.9.2008, titled Drug Cores for Sustanated Release of therapeutics); U.S. application serial No. 10/825,047 (filed 4/15/2004 under the heading drug delivery via punch Plug); international published application WO 2006/014434; international application Ser. No. PCT/US2007/065789 (filed 3/31.2006, published as WO2007/115259, titled Nasolarix Drainage System for drug therapy); international application Ser. No. PCT/US2008/010487 (filed 5.9.2008, titled Drug Cores for Sustainated Release of Therapeutic Agents); international application Ser. No. PCT/US2008/010479 (filed on 8.9.2008, titled Laclimaly Implants and Related Methods); U.S. application Ser. No. 61/139,456 (filed on 19.12.2008, entitled Substance rendering efforts publications and methods).

Typically, the lacrimal implant includes an implant body. In some embodiments, the implant body has a distal portion and a proximal portion. The distal portion of the body is insertable at least partially through the punctum into a lacrimal canaliculus lumen of the subject. The implant body may be at least impregnated with latanoprost, or otherwise contain latanoprost or latanoprost + a corneal penetration enhancer (e.g., benzalkonium chloride), for example in a matrix core inserted within the implant body. Exposure of the matrix core or impregnated body to tear fluid results in effective release of latanoprost into the tear fluid for a sustained period of time. The implant may include a sheath (sheath) disposed over at least a portion of the core to inhibit release of latanoprost from portions thereof. The implant body may have an outer surface configured to engage (engage) the cavity wall tissue to inhibit expulsion when disposed therein.

In many embodiments, an integral feedback (intubator) or other protrusion is attached around the sheath near the proximal end of the core. In one embodiment, the feedback or other projection includes one or more wings (wing) sized to remain outside of the punctum, thereby leaving the proximal end of the core in the vicinity of the punctum. In other embodiments, the feedback or other projection comprises a complete or partial (e.g., trim) loop (collar) attached around the sheath near the proximal end of the core. The loop is sized to remain outside the punctum, thereby leaving the proximal end of the core in the vicinity of the punctum.

In some embodiments, the implant comprises a single core, lacking additional structure surrounding the core. In some embodiments, the core comprises a matrix of latanoprost or other anti-glaucoma agent including a pharmaceutically acceptable vehicle, such as a non-bioabsorbable polymer, such as silicone in a heterogeneous mixture containing latanoprost. The heterogeneous mixture in the core may comprise a silicone matrix saturated with latanoprost or the inclusion of latanoprost. The contents of the core are a concentrated form of latanoprost and a silicone matrix surrounds the contents of the core. In particular embodiments, the latanoprost inclusions encased in the silicone matrix comprise a heterogeneous mixture of inclusions encased in the silicone matrix. The core inclusion may contain latanoprost oil.

It is also within the scope of the present invention to adjust or modify the implant device to deliver a high release rate, a low release rate, a bolus release (bolus release), a burst release (burst release), or a combination thereof. The bolus of drug can be released by forming an erodible polymeric cap that dissolves immediately in the tear fluid or tear film. As the polymer cap contacts the tear fluid or tear film, the solubility properties of the polymer erode the cap and latanoprost is all released at once. Burst release of latanoprost can be achieved using polymers that also erode in the tear fluid or tear film based on polymer solubility. In this embodiment, the drug and polymer may be layered along the length of the device, with the drug being released immediately as the outer polymer layer dissolves. By changing the solubility of the erodable polymer layer, the drug layer is released rapidly or slowly, and a high or low release rate of the drug can be achieved. Other methods of releasing latanoprost or other anti-glaucoma agents may be achieved by porous membranes, soluble gels (such as those in typical ophthalmic solutions), microparticle encapsulation or nanoparticle encapsulation of drugs.

A sheath body:

the sheath may be of a suitable shape and material to control migration of latanoprost or other anti-glaucoma agents from the drug core. In some embodiments, the sheath body houses the core and may be suitably tightened against the core. The sheath may be formed of a material that is substantially impermeable to latanoprost or other anti-glaucoma agents, such that the rate of migration of the agent is largely controlled by the exposed surface area of the core that is not covered by the sheath. In many embodiments, the migration of latanoprost or other anti-glaucoma agent through the sheath body may be about 1/10 or less, often 1/100 or less, of the migration of latanoprost or other anti-glaucoma agent through the exposed surface of the drug core. In other words, migration of latanoprost or other anti-glaucoma agent through the sheath is at least about 1 order of magnitude lower than migration of latanoprost or other anti-glaucoma agent through the exposed surface of the core. Suitable sheath materials include polyimide, polyethylene terephthalate (hereinafter "PET"). The sheath body has a thickness of about 0.00025 "to about 0.0015" as defined from a sheath surface adjacent the core to an opposite sheath surface distal from the core. The overall diameter of the sheath extending across the core is in the range of about 0.2 mm to about 1.2 mm. The core may be formed by dip coating the core in a sheath material. Alternatively or in combination, the sheath body may comprise a tube and a drug core introduced into the sheath, for example as a liquid or solid that can be slid, injected or extruded into the sheath tube. The sheath body may also be dip coated around the core, for example around a pre-formed core.

The sheath may be provided with additional features to facilitate clinical use of the implant. For example, the sheath may receive a replaceable cartridge while the implant body, retention structure, and sheath body remain implanted in the subject. The sheath is often securely attached to the retaining structure as described above and the core is replaceable while the retaining structure is retained in the sheath. In particular embodiments, the sheath may be provided with external protrusions which, when squeezed, apply a force to the sheath and eject the drug core from the sheath. Another core can then be placed into the sheath. In many embodiments, the sheath or retention structure can have a distinctive feature, such as a distinctive color, to indicate placement so that placement of the sheath or retention structure in the lacrimal duct or other bodily tissue structure can be readily observed by the subject. The retention element or sheath can include at least one marker to indicate a placement depth in the lacrimal duct, based on which the retention element or sheath can be placed to a desired depth in the lacrimal duct.

And (3) reserving a structure:

in many embodiments, a retention structure is employed to retain the implant in the punctum or lacrimal duct. The retention structure is attached to or integral with the implant body. The retention structure comprises a suitable material sized and shaped so that the implant can be easily placed in a desired tissue location, such as the punctum or lacrimal duct. In some embodiments, the core may be at least partially attached to the retention structure via a sheath. In some embodiments, the retention structure comprises a hydrogel configured to expand when the retention structure is placed into the punctum. The retaining structure may comprise a connecting member having a surface facing the shaft. In some embodiments, the swelling of the hydrogel may press against the surface facing the shaft to retain the hydrogel as it hydrates. In some embodiments, the attachment means may comprise at least one of: a projection, flange, frame, or opening through a portion of the retaining structure. In some embodiments, the retention structure includes an implant body portion sized and shaped to substantially match the anatomy of the punctum and lacrimal duct.

The retention structure may be sized to fit at least partially within the lacrimal canaliculus lumen. The retention structure may be expandable between a small profile configuration (profile configuration) suitable for insertion and a large profile configuration that anchors the retention structure within the lumen, and the retention structure may be attached near the distal end of the core. In particular embodiments, the retention structure slides along the core near the proximal end as the retention structure expands from the small-profile configuration to the large-profile configuration. The length of the retention structure along the core may be shorter in the large profile configuration than in the small profile configuration.

In some embodiments, the retention structure is elastically expandable. The small profile may have a cross-section of no more than about 0.2mm and the large profile may have a cross-section of no more than about 2.0 mm. The retention structure may comprise a tubular body having arms separated by slots. The retention structure may be at least partially disposed on the core.

In some embodiments, the retention structure is mechanically deployable and generally expands to a desired cross-sectional shape, e.g., the retention structure comprises a superelastic shape memory alloy such as Nitinol^TM. Other than Nitinol may be used^TMOther materials than elastic metals or polymers, plastically deformable metals or polymers, shape memory polymers, etc., to provide the desired expansion. In some embodiments, polymers and coated fibers available from Biogeneral, inc. Many metals such as stainless steel and stainless steel may be used Shape memory alloy and provide the desired expansion. This expansion capability allows the implant to fit into hollow tissue structures of different sizes, such as from 0.3mm to 1.2mm canaliculus (canaliculus) (i.e., one size is generally applicable). Although a single retention structure may be adapted to fit canaliculi having diameters from 0.3mm to 1.2mm, a plurality of alternative retention structures may be adapted to fit this range, if desired, e.g., a first retention structure to fit canaliculi having diameters from 0.3 to about 0.9mm, and a second retention structure to fit canaliculi having diameters from about 0.9 to 1.2 mm. The retention structure has a length compatible with the anatomical structure to which it is to be attached, for example, a length of about 3mm for the retention structure to be placed near the punctum of the lacrimal duct. The length may suitably provide sufficient retention for different anatomical structures, for example 1mm to 15mm in length (as required).

Although the implant body may be connected to one end of the retention structure as described above, in many embodiments, the other end of the retention structure is not connected to the implant body, such that the retention structure may slide over the implant body including the sheath and the core while the retention structure expands. This ability to slide at one end is desirable because as the width of the retention structure expands, the length of the retention structure may contract to assume the desired cross-sectional width. It should be noted, however, that many embodiments may employ a sheath that does not slide relative to the core.

In many embodiments, the retention structure may be removed from the tissue. A projection, such as a hook, loop or loop, may extend from a portion of the implant body to facilitate removal of the retention structure.

In some embodiments, the sheath and retention structure may comprise 2 portions.

Occlusion element (occlusion element):

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

Medicine core:

the core may be inserted into the body of the implant or may be used as the implant itself without any other structural components. The core comprises one or more active agents (in some embodiments, one or more anti-glaucoma agents, e.g., latanoprost) and a material to provide sustained release of the agent. Optionally, the core may additionally comprise a penetration enhancer (e.g., benzalkonium chloride). In some embodiments, the core comprises a sustained release formulation consisting of, or consisting essentially of, latanoprost and silicone as a carrier. Latanoprost or other anti-glaucoma agents or other agents migrate from the drug core to the target tissue (e.g., ciliary muscle of the eye). The drug core may optionally comprise latanoprost or other anti-glaucoma agents or other agents in a matrix, wherein the latanoprost or other agents are dispersed or dissolved within the matrix. Latanoprost or other anti-glaucoma agents or other agents may be only sparingly soluble in the matrix, such that a small amount is dissolved in the matrix and can be released from the surface of the core. As latanoprost or other anti-glaucoma agent or other agent diffuses from the exposed surface of the core to the tear fluid or tear film, the rate of migration from the core to the tear fluid or tear film can be correlated to the concentration of latanoprost or other agent dissolved in the matrix. Additionally or in combination, the rate of migration of latanoprost or other anti-glaucoma agents or other agents from the drug core to the tear fluid or tear film can be correlated to the nature of the matrix in which the latanoprost or other agents are dissolved.

In some embodiments, the sheath body contains the core and may be suitably secured against the core. Suitable sheath materials include polyimide and polyethylene terephthalate (hereinafter "PET"). The sheath body may comprise a tube and the drug core is introduced into the sheath, for example as a liquid or solid that can be slid, injected or squeezed into the sheath tube.

In particular embodiments, the rate of migration from the drug core to the tear fluid or tear film may be based on the silicone formulation. In some embodiments, the concentration of an agent, such as an anti-glaucoma agent (e.g., latanoprost), dissolved in the drug core can be controlled to provide a desired rate of release of the agent. The medicament contained in the core may comprise a liquid (e.g. oil), a solid gel, a solid crystalline, a solid amorphous, a solid particulate or a dissolved form. In some embodiments, the core may comprise liquid or solid inclusions, such as droplets of liquid latanoprost dispersed in a silicone matrix.

Table 1 shows drug insert (insert) silicones and related curing properties that may be used in accordance with embodiments of the present invention. The drug core insert matrix material may comprise a base polymer, including dimethylsiloxanes, such as MED-4011, MED 6385, and MED 6380, each of which is commercially available from NuSil. The base polymer may be cured with a curing system, such as a platinum-vinyl hydride curing system or a tin-alkoxy curing system, both of which are commercially available from NuSil. In many embodiments, the curing system may comprise known curing systems that are commercially available for known materials, such as the known platinum vinyl hydride curing system containing the known MED-4011. In one embodiment shown in Table 2, 90 parts MED-4011 can be mixed with 10 parts crosslinker such that the crosslinker comprises 10% of the mixture. The mixture containing MED-6385 can contain 2.5% crosslinker and the mixture of MED-6380 can contain 2.5% or 5% crosslinker.

TABLE 1 drug insert Silicone selection

It has been determined in accordance with the present invention that the type of curing system and silicone material can affect the curing properties of the solid core insert and potentially the output of the anti-glaucoma agent from the core matrix material. In particular embodiments, curing of MED-4011 containing a platinum vinyl hydride system can be inhibited with relatively high concentrations of drug/prodrug, e.g., greater than 20% drug, so that a solid core is not formed. In particular embodiments, curing of MED-6385 or MED 6380 containing a stannoxy system can be slightly inhibited with a relatively high concentration (e.g., 20%) of the drug/prodrug. Such slight inhibition of curing can be compensated by increasing the time or temperature of the curing process. For example, embodiments of the present invention can prepare a drug core comprising 40% drug and 60% MED-6385 (containing the stannoxy system) using appropriate curing times and temperatures. Similar results can be obtained using MED-6380 systems, tin-alkoxy systems and appropriate curing times or temperatures. Even though tin alkoxy cure systems have good results, it has been determined in accordance with the present invention that there may be an upper limit, e.g., 50% drug/prodrug or higher, where the tin-alkoxy cure system does not produce a solid drug core. In many embodiments, latanoprost in the solid core may be at least about 5%, for example in the range from about 5% to 65%, and may be about 20% to about 65% (by weight) of the core. For other anti-glaucoma agents, equivalent therapeutic amounts may be employed, based on therapeutic equivalence with latanoprost. Therapeutic equivalence can be determined by Reference to the "Physician's Desk Reference".

The drug core or other anti-glaucoma agent donor (e.g., impregnated implant body) may comprise one or more biocompatible materials capable of providing sustained release of an agent such as an anti-glaucoma agent (e.g., latanoprost). Although the core has been discussed above primarily with respect to embodiments comprising a matrix comprising a substantially non-biodegradable silicone matrix and latanoprost inclusions disposed therein which are soluble, the core may comprise structures which provide sustained release of a drug (e.g. latanoprost), such as biodegradable matrices, porous cores, fluid cores and solid cores.

The matrix containing latanoprost or other anti-glaucoma agents may be formed from biodegradable or non-biodegradable polymers. The non-biodegradable core may comprise silicone, acrylate, polyethylene, polyurethane, hydrogel, polyester (e.g., dacron. r. available from e.i. du Pont de Nemours and Company of wilmington, terawa)^TMPolypropylene, Polytetrafluoroethylene (PTFE), expanded PTFE (eptfe), Polyetheretherketone (PEEK), nylon, extruded collagen, polymeric foam, silicone rubber, polyethylene terephthalate, ultra-high molecular weight polyethylene, polycarbonate polyurethane (polycarbonaturethane), polyurethane, polyimide, stainless steel, nickel-titanium alloys (e.g., nitinol), titanium, stainless steel, cobalt-chromium alloys (e.g., elgiloy. r, available from Elgin specialty metals, elm, illinois) ^TM1; CONICHROME. R. available from Carpenter Metals, Wyoissing, Pa^TM.)。

The biodegradable core may comprise one or more biodegradable polymers, such as proteins, hydrogels, polyglycolic acid (PGA), polylactic acid (PLA), poly (L-lactic acid) (PLLA), poly (L-glycolic acid) (PLGA), polyglycolide (polyglycolide), poly-L-lactide, poly-D-lactide, poly (amino acids), polydipoly (di-lactide)Alkanone (polydioxanone), polycaprolactone, polygluconate, polylactic acid-polyethylene oxide copolymer, modified cellulose, collagen, polyorthoester, polyhydroxybutyrate, poly (hydroxybutanoate), poly (hydroxyhexanoate), poly (hydroxyalkanoate), poly (hydroxyalk,Polyanhydrides, polyphosphoesters, poly (alpha-hydroxy acids), and combinations thereof. In some embodiments, the core may comprise at least one hydrogel polymer.

Specific implant embodiments:

various embodiments of lacrimal implants that can be used in the lacrimal implant delivery systems and methods described herein are as follows (see also the examples section below). In some embodiments, a drug core insertable into a lacrimal implant comprises a thin-walled polyimide sheath body containing latanoprost or other anti-glaucoma agent dispersed in, for example, Nusil 6385 (cured medical grade solid silicone). The cured silicone served as a solid, non-aggressive matrix from which latanoprost was slowly eluted. The distal end of the drug insert was sealed with a cured film of solid Loctite 4305 medical grade adhesive (cyanoacrylate). The polyimide sheath is inert and, together with the adhesive, can provide structural support and barrier for both lateral drug diffusion and drug diffusion through the distal end of the drug insert. The drug insert may be placed in a hole or other cavity of the lacrimal implant and held in place by an interference fit (interference fit). In some embodiments, the lacrimal implant body is at least partially impregnated with an anti-glaucoma agent (e.g., latanoprost). Optionally, the core may additionally comprise a penetration enhancer (e.g., benzalkonium chloride).

Fig. 2A illustrates one embodiment of a lacrimal implant (e.g., a punctum plug) 200 insertable into a punctum. Insertion of lacrimal implant 200 into the punctum may accomplish one or more of the following: inhibit or block tear flow therethrough (e.g., to treat dry eye), or to deliver an anti-glaucoma agent to the eye on a sustained basis (e.g., to treat one or more of infection, inflammation, glaucoma, or other ocular disease). In this embodiment, lacrimal implant 200 includes an implant body 202 extending from a proximal end portion 204 to a distal end portion 206 and having a retention structure 208.

In various embodiments, the implant body 202 may comprise an elastic material, such as silicone, polyurethane, or other urethane-based material or an acrylic resin having non-biodegradable, partially biodegradable, or biodegradable properties (i.e., corrodible in vivo) that allows at least a portion of the retention structure to deform outward. In some embodiments, the biodegradable elastomeric material comprises a crosslinked polymer, such as poly (vinyl alcohol). In some embodiments, different portions of the implant body 202 are made of different materials. For example, the implant body proximal portion 204 may comprise a silicone/polyurethane copolymer and the implant body distal portion 206 may comprise a polyurethane hydrogel or other solid hydrogel. In some embodiments, the proximal implant body portion 204 can comprise silicone and the distal implant body portion 206 can comprise a hydrophilic silicone mixture. Other copolymers that may be used to form the implant body 302 include silicone/urethane, silicone/poly (ethylene glycol) (PEG), and silicone/2-hydroxyethyl methacrylate (HEMA).

In certain embodiments, the implant body 202 can include a cylindrical structure having a first chamber 210 at or near a proximal end and a second chamber 212 at or near a distal end. A latanoprost core 214 may be disposed in the first chamber 210 and a hydrogel or other expandable retention element 216 having biodegradable or non-biodegradable properties may be disposed in the second chamber 216. In some embodiments, the biodegradable retention element comprises a mixture of salt-based and cellulose-based. In some embodiments, the non-biodegradable retention element comprises a hydrogel or other synthetic polymer. An implant body membrane 218 can be positioned between the first chamber 210 and the second chamber 216 and can be used to inhibit or prevent material transfer between the drug core 214 and the hydrogel retention element 216.

In a different manner, swellable hydrogel retention element 216 may be substantially encapsulated within, for example, a portion of retention structure 208. In various embodiments, retention structure 208 may include a fluid permeable retainer (retainer) that allows hydrogel retention element 216 to accept and absorb or otherwise retain fluid, such as when it is inserted into the punctum. Hydrogel retention element 216 may be configured to expand, for example, to a size or shape that forces one or more outer surface portions of retention structure 208 into contact with the lacrimal canaliculus wall, thereby retaining or assisting in retaining at least a portion of the implant within the punctum. In some embodiments, the fluid permeable retainer may include a fluid permeable aperture 220, for example, disposed in a sidewall of the retention structure 208. In some embodiments, the fluid permeable retainer may include a cap member 222 or other membrane that is fluid permeable or hydrophilic. In some embodiments, the fluid permeable retainer may include a fluid permeable or hydrophilic implant body portion 224. These embodiments of fluid permeable retainers 220, 222, and 224 may also inhibit hydrogel retention element 216 from significantly extending beyond retention structure 208 during and upon expansion.

The implant body 202 can include a feedback or other protrusion 226, such as a laterally extending (e.g., a removable ring) at least partially from or around the proximal end portion 204 of the implant body 202. In some embodiments, the protrusion 226 may comprise a removable ring. In some embodiments, projection 226 can be configured to rest at or near the punctum opening (e.g., via angled portion 260), for example, to inhibit or prevent lacrimal implant 200 from passing entirely through the lacrimal canaliculus, or to provide tactile or visual feedback information about them to the implanting user. In some embodiments, the proximal end of the protrusion 226 may include a convex shape, e.g., to help provide comfort to the subject after implantation. In some embodiments, the protrusion 226 may include a convex radius of about 0.8 millimeters. In some embodiments, the diameter of the protrusion 226 is about 0.7 millimeters to about 0.9 millimeters. In some embodiments, the projections 226 may comprise a non-concave shape having a diameter of about 0.5 millimeters to about 1.5 millimeters and a thickness of 0.1 millimeters to about 0.75 millimeters. In some embodiments, the projections 226 have an airfoil-like shape with a post-like projection extending from the opposite side of the proximal end 204 of the implant. In some embodiments, the projection 226 comprises a partially-pitched ring extending 360 degrees from the outer surface of the implant body about the proximal end 204. In some embodiments, such a protrusion 226 comprises a complete ring extending 360 degrees from the outer surface of the implant body about the proximal end 204. In one embodiment, the projections 226 include a cross-sectional shape similar to a flat disk (i.e., relatively flat top and bottom surfaces). Drug or other agent elution ports 228 may extend through the protrusions 226, for example, to provide sustained release of the agent from the drug core 214 to the eye.

Fig. 2B illustrates a cross-sectional view of an embodiment of a lacrimal implant (e.g., a punctum plug) 200 taken along a line parallel to a longitudinal axis of the implant, such as along line 2B-2B of fig. 2A. As shown in fig. 2B, the lacrimal implant may include an implant body 202 having a retention structure 208 substantially encasing a hydrogel retention element 216 at or near a distal portion 206 of the implant body, and a latanoprost core 214 disposed within the implant body, e.g., at or near a proximal portion 204. In this embodiment, the core 214 is disposed in the first implant body chamber 210 and the hydrogel retention element 216 is disposed in the second implant body chamber 212. As discussed above, hydrogel retention element 216 can be configured to expand to a size or shape that retains or assists in retaining at least a portion of implant 200 within the punctum. In some embodiments, hydrogel retention element 250 can also be coated or otherwise provided on an outer surface portion of implant body 202, providing another (e.g., second) mechanism that retains or assists in retaining at least a portion of implant 200 at least partially within the punctum.

The retention structures 208, which may be used to substantially encapsulate the hydrogel retention elements 216, may be of different sizes relative to the implant body 202 size. In some embodiments, the retention structure 208 is at least about 1/5 a length of the implant body 202. In some embodiments, the retention structure 208 is at least about 1/4 a length of the implant body 202. In some embodiments, the retention structure 208 is at least about 1/3 a length of the implant body 202. In some embodiments, the retention structure 208 is at least about 1/2 a length of the implant body 202. In some embodiments, the retention structure 208 is at least about 3/4 a length of the implant body 202. In some embodiments, the retention structure 208 is about the length of the implant body 202.

As shown in the example embodiment of fig. 2B, the hydrogel retention element 216 may have an unexpanded, "dry" state that aids in passing through the punctum and inserting into the lacrimal canaliculus. Once placed in the lacrimal canaliculus, the hydrogel retention element 216 may absorb or otherwise retain lacrimal or other fluid, such as by fluid-permeable retainers 220, 222, 224 (fig. 2A), forming an expanded structure. In some embodiments, hydrogel retention element 216 may comprise a non-biodegradable material. In some embodiments, hydrogel retention element 216 may comprise a biodegradable material. Other options for hydrogel retention elements 216 may also be used. For example, hydrogel retention elements 216 may be molded together with retention structure 208 as a single piece, or may be formed separately as a single piece and subsequently coupled (coupled) to retention structure 208.

In some embodiments, the core 214 disposed at or near the proximal end portion 204 of the implant body 202 may include a plurality of latanoprost inclusions 252, which may be distributed in a matrix 254. In some embodiments, the inclusion 252 comprises latanoprost in a concentrated form (e.g., a crystalline pharmaceutical dosage form). In some embodiments, the matrix 254 may comprise a silicone matrix or the like, and the distribution of inclusions 252 within the matrix may be non-uniform. In some embodiments, the medicament inclusion 252 comprises droplets of an oil (e.g., latanoprost oil). In other embodiments, the medicament inclusion 252 comprises solid particles. The inclusions can be of various sizes and shapes. For example, the inclusions may be microparticles having a size on the order of about 1 micron to about 100 microns.

In the embodiment shown, the core 214 has a sheath 256 disposed over at least a portion thereof, such as to define at least one exposed surface 258 of the core. Exposed surface 258 can be located at or near proximal portion 204 of the implant body to contact tear fluid or tear film fluid as lacrimal implant 200 is inserted into the punctum and release latanoprost at one or more therapeutic levels for a sustained period of time.

Fig. 2C illustrates a cross-sectional view of an embodiment of lacrimal implant 200 taken along a line parallel to a longitudinal axis of the implant. As shown in fig. 2C, the lacrimal implant includes an implant body 202 that is free of feedback or other protrusions 226 (fig. 2A). In this manner, implant 200 may be fully inserted into the punctum. In some embodiments, the first chamber 210 can comprise dimensions of about 0.013 inch by about 0.045 inch. In some embodiments, the second chamber 212 can comprise dimensions of about 0.013 inch by about 0.020 inch.

Fig. 3A illustrates another embodiment of a lacrimal implant 300 insertable into a punctum. Insertion of the lacrimal implant 300 into the punctum may accomplish one or more of the following: inhibiting or blocking tear flow therethrough (e.g., to treat dry eye), or sustained delivery of anti-glaucoma agents to the eye (e.g., to treat infection, inflammation, glaucoma, or other ocular diseases or disorders), the nasal passages (e.g., to treat sinus or allergic disorders), or the inner ear system (e.g., to treat dizziness or migraine).

In this embodiment, lacrimal implant 300 includes an implant body 302 that includes a first portion 304 and a second portion 306. The implant body 302 extends from a proximal end 308 of the first portion 304 to a distal end 310 of the second portion 306. In various embodiments, the proximal end 308 may define a proximal longitudinal axis 312 and the distal end 310 may define a distal longitudinal axis 314. The implant body 300 can be configured such that, when implanted, there is at least a 45 degree angular intersection 316 between the proximal shaft 312 and the distal shaft 314 for biasing at least a portion of the implant body 302 at least a portion of the lacrimal canaliculus at or distal to the curvature of the lacrimal duct. In some embodiments, the implant body 302 can be configured such that the angled intersection point 316 is between about 45 degrees and about 135 degrees. In this embodiment, the implant body 302 is configured such that the angled intersection point 316 is approximately about 90 degrees. In various embodiments, the distal end 326 of the first portion 304 may be integral with the second portion 306 at or near the proximal end 328 of the second portion 306.

In certain embodiments, the implant body 302 can include an angularly disposed cylinder-like structure comprising one or both of: a first lumen 318 disposed near the proximal end 308, or a second lumen 320 disposed near the distal end 310. In this embodiment, a first lumen 318 extends inwardly from the proximal end 308 of the first portion 304 and a second lumen 320 extends inwardly from the distal end 310 of the second portion 306. A first drug-releasing drug donor 322 may be disposed in the first lumen 318 to provide sustained drug release to the eye, while a second drug-releasing or other agent-releasing drug donor 324 may be disposed in the second lumen 320 to provide sustained drug or other agent release to, for example, the nasal passage or inner ear system. The implant body membrane 330 can be positioned between the first lumen 318 and the second lumen 320 and can be used to inhibit or prevent material transfer between the first drug donor 322 and the second drug donor 324.

In some embodiments, drug or other agent release may occur (at least in part) through the exposed surfaces of the drug donors 322, 324. In some embodiments, a predetermined drug or agent release rate can be achieved by controlling the geometry of the exposed surface. For example, the exposed surface may be constructed with a particular geometry or other technique suitable for controlling the rate of release of a drug or other agent on the eye, such as on an acute basis (acute basis), or on a chronic basis (chronic basis), such as between outpatient patient visits (outubject patient visitors). Additional description of the effective release rate of one or more drugs or other agents from drug donors 322, 324 can be found in commonly owned U.S. application serial No. 11/695,545 to DeJuan et al (filed on 2.4.2007 under the heading of nanoscalel drug systems for drug therapy), which is incorporated herein by reference in its entirety, including its description of achieving a particular release rate. In some embodiments, the exposed surfaces of the drug donors 322, 324 can be flush with or slightly below the proximal end 308 of the first portion 304 or the distal end 310 of the second portion 306, respectively, such that the drug donors do not protrude outside of the implant body 302. In some embodiments, an exposed surface of the drug supply 322, for example, can be positioned above the proximal end 308 such that the drug supply 322 at least partially protrudes outside of the implant body 302.

The implant body 302 can include an integral feedback or other protrusion 332, such as a protrusion extending laterally at least partially from or around the proximal end 308 of the implant body first portion 304. In some embodiments, projection 332 can include a set of wings for removing lacrimal implant 300 from an implantation site. The extraction of the wingset can be configured to not account for movement, as the non-linear configuration of the implant body 302 can prevent movement by assuming the size or shape of the lacrimal curvature and optionally the lacrimal canaliculus. In some embodiments, protrusion 332 can be configured to rest at or near the punctal opening, e.g., to inhibit or prevent lacrimal implant 300 from completely entering the lacrimal canaliculus, or to provide tactile or visual feedback information to the implanting user, e.g., regarding whether the implant is completely implanted. After implantation, the protrusions 332 may project laterally in a direction parallel to the eye or away from the eye. This reduces irritation to the eye compared to the case where the protrusion portion protrudes toward the eye. Additionally, the lateral extension of the projection 332 from the proximal end 308 relative to the distal end 326 of the implant body first portion 304 can be substantially the same as the lateral extension of the second implant body portion 306. This may also avoid extending towards the eye. Drug or other agent elution ports may extend through the loop-protrusions 332 to provide sustained release of the drug donor 322 agent to the eye.

In various embodiments, the implant body 302 can be molded (mold) with an elastomeric material, such as silicone, polyurethane, NuSil (e.g., NuSil 4840 containing 2% 6-4800), or acrylate with non-biodegradable, partially biodegradable, or biodegradable properties (i.e., erodible within the body) to form a non-linearly extended implant body 302. In some embodiments, the biodegradable elastomeric material may include a crosslinked polymer, such as poly (vinyl alcohol). In some embodiments, the implant body 302 can include a silicone/polyurethane copolymer. Other copolymers that may be used to form the implant body 302 include, but are not limited to: silicone/urethane, silicone/poly (ethylene glycol) (PEG), and silicone/2-hydroxyethyl methacrylate (HEMA). Urethane-based polymer and copolymer materials allow for a variety of processing methods and bond well to each other as discussed in commonly owned application serial No. 61/049,317 to Jain et al (filed on 30.4.2008, entitled Drug-releasing Polyurethane latex Insert), which is incorporated herein by reference in its entirety.

Fig. 3B illustrates one embodiment of a cross-sectional view of lacrimal implant 300 taken along a line parallel to the longitudinal axis of the implant, such as along line 3B-3B of fig. 3A. As shown in fig. 3B, lacrimal implant 300 may include an implant body 302 that includes a first portion 304 and a second portion 306. The implant body 302 extends from a proximal end 308 of the first portion 304 to a distal end 310 of the second portion 306. In various embodiments, the proximal end 308 may define a proximal longitudinal axis 312 and the distal end 310 may define a distal longitudinal axis 314. The implant body 300 can be configured such that, when implanted, there is at least a 45 degree angular intersection 316 between the proximal shaft 312 and the distal shaft 314 for biasing at least a portion of the implant body 302 at least a portion of the lacrimal canaliculus at or distal to the curvature of the lacrimal duct. In this embodiment, the implant body 300 is configured such that the angled intersection point 316 is approximately about 90 degrees.

In various embodiments, the distal end 326 of the first portion 304 may be integral with the second portion 306 at or near the proximal end 328 of the second end 326. In some embodiments, the length of the second portion 306 may be a measure less than 4 times the length of the first portion 304. In one embodiment, the second portion 306 may comprise a length of less than about 10 millimeters, for example as shown in fig. 3B. In another embodiment, the second portion 306 may comprise a length of less than about 2 millimeters.

In some embodiments, second portion 306 can include an integral dilator 350 for dilating anatomical tissue 352, such that one or both puncta or canaliculi have a diameter sufficient for implantation of lacrimal implant 300. In this manner, lacrimal implant 300 may be implanted in eye anatomies in different sizes without requiring pre-expansion by a separate dilation tool. Dilator 350 may be formed so that it does not cause trauma to the punctum and lining of the lacrimal duct. In some embodiments, a lubricious coating disposed on or impregnated in the outer surface of implant body 302 can be used to further assist in insertion of lacrimal implant 300 into anatomical tissue 352. In one embodiment, the lubricious coating may include a silicone lubricant.

As shown, the dilator 350 generally narrows from a location near the proximal end 328 of the second portion 306 to the distal end 310 of the second portion 306, for example from a diameter of about 0.6 millimeters to a diameter of about 0.2 millimeters. In some embodiments, the slope of the outer surface of dilator 350 measured from a location near the proximal end 328 of second portion 306 to the distal end 310 of second portion 306 can be about 1 degree to about 10 degrees (e.g., 2 degrees, 3 degrees, 4 degrees, or 5 degrees) relative to the distal longitudinal axis 314. In some embodiments, the taper of the outer surface of dilator 350 can be less than 45 degrees relative to the distal longitudinal axis 314. The desired slope of the dilator 350 for a particular implant location may be determined, among other factors, by balancing the implant body 302 strength required for the implant and the desire to have a soft, flexible, and comfortable implant body after implantation (e.g., to conform to the lacrimal canaliculus anatomy). In some embodiments, dilator tip 354 may be about 0.2 millimeters to about 0.5 millimeters in diameter.

In certain embodiments, the proximal end 328 of the second implant body portion 306 may include a lead extension 356 configured to bias against at least a portion of the lacrimal canaliculus after implantation. In this embodiment, the guide extension 356 extends from near the intersection between the first 304 and second 306 implant body portions, such as in a direction opposite the extension of the dilator 350.

In certain embodiments, the implant body 302 can include a first lumen 318 disposed near the proximal end 308. In this embodiment, the first lumen 318 extends inwardly from the proximal end 308 about 2 millimeters or less and houses a drug donor 322 that releases the first drug or releases the other agent to provide a sustained release of the drug or other agent to the eye. In some embodiments, the drug donor 322 can include a plurality of anti-glaucoma agent inclusions 360, which can be distributed in a matrix 362. In some embodiments, inclusion 360 may comprise an anti-glaucoma agent in a concentrated form (e.g., a crystalline pharmaceutical form). In some embodiments, matrix 362 may comprise a silicone matrix or the like, and the distribution of inclusions 360 within the matrix may be non-uniform. In some embodiments, the pharmaceutical agent inclusion 360 may comprise droplets of an oil (e.g., latanoprost oil). In other embodiments, the medicament inclusion 360 may comprise solid particles, such as bimatoprost particles in crystalline form. The inclusions can be of various sizes and shapes. For example, the inclusions may include particles having a size on the order of about 1 micron to about 100 microns.

In the illustrated embodiment, the drug donor 322 includes a sheath 366 disposed over at least a portion thereof, such as to define at least one exposed surface 368 of the drug donor. Exposed surface 368 can be located at or near proximal end 308 of implant body 302 to contact tear fluid or tear film fluid when lacrimal implant 300 is inserted into the punctum and release the anti-glaucoma agent at one or more therapeutic levels for a sustained period of time.

Fig. 4A illustrates one embodiment of a lacrimal implant 400 insertable into a punctum. In various embodiments, the lacrimal implant 400 includes an implant body 402 including first 404 and second 406 portions, the implant body 402 sized and shaped for at least partial insertion into the punctum. The first portion 404 is formed of a polymer and has a first diameter 408. The second portion 406 is also formed of a polymer and includes a base member 412 (e.g., a mandrel or spine-like member) having a second diameter 410 that is less than the first diameter 408. In one embodiment, the first 404 and second 406 portions are fully coupled and comprise a single implant body 402. In one embodiment, the first 404 and second 406 portions are separate components that may be coupled to each other by, for example, engagement between a coupling void (coupling void) and a coupling arm.

An expandable retention member 414, such as a swellable material, may be bonded or otherwise coupled to the base member 412 such that it at least partially encapsulates a portion of the base member 412. In one embodiment, the expandable retention member substantially encapsulates the base member 412. As the expandable retention member 414 absorbs or otherwise retains tears or other fluids, such as after insertion into a punctum, its size increases and its shape may change, forcing itself against and lightly biasing against the associated tear duct wall. It is believed that the expandable retention member 414 will provide retention comfort to the subject and may improve lacrimal implant 400 implant retention by controlled biasing of the lacrimal duct wall.

Placing the expandable retention member 414 over a portion of the implant body 402 allows the retention member 414 to be freely exposed to tear fluid in situ, thereby achieving a wide range of potential expansion rates. In addition, the base member 412 provides sufficient coupling surface area to which the expandable retention member 414 may be, for example, bonded such that material of the expandable retention member 414 does not remain in the punctum after removal of the lacrimal implant 400 from the subject. As shown in this embodiment, the expandable retention member 414 may include an unexpanded, "dried or dehydrated" state that facilitates passage through the punctum and insertion into the associated lacrimal canaliculus. Once placed in the lacrimal canaliculus, the expandable retention member 414 can absorb or otherwise retain tear fluid to form an expanded structure.

In certain embodiments, the implant body 402 can include a cylinder-like structure including a cavity 416 disposed near a proximal end 418 of the first portion 404. In this embodiment, the lumen 416 extends inwardly from the proximal end 418 and includes a drug donor 420 that releases the first drug or releases the other agent to provide sustained release of the drug or other agent to the eye. Drug or other agent release may occur at least in part through the exposed surface of the drug donor 420. In one embodiment, the exposed surface of the drug donor 420 can be positioned above the proximal end 418 such that the drug donor 420 extends at least partially outside the implant body 402. In certain embodiments, the exposed surface of the drug donor 420 can be flush with the proximal end 418 or slightly below such that the drug donor 420 does not extend outside of the implant body 402.

In certain embodiments, a predetermined drug or pharmaceutical agent release rate may be achieved by controlling the geometry or drug concentration gradient near the exposed surface. For example, the exposed surface may be constructed with a particular geometry or other technique suitable for controlling the rate of release of a drug or other agent on the eye in situations such as on an acute basis, or between outpatient visits on a chronic basis.

The implant body 402 can include an integral feedback or other protrusion 422, such as a protrusion that extends laterally at least partially from or around the proximal end 418 of the implant body first portion 404. In one embodiment, the protrusion 422 comprises a partially-pitched ring that extends 360 degrees from the implant body outer surface about the proximal end 418. In one embodiment, the protrusion 422 comprises a complete ring that extends 360 degrees from the outer surface of the implant body around the proximal end 418. In one embodiment, the projections 422 include a cross-sectional shape that resembles a flat disc (i.e., relatively flat top and bottom surfaces). In various embodiments, the projection 422 can be configured to rest on or near the punctum opening when the second portion 406 of the implant body 402 is positioned within the associated lacrimal canaliculus, for example, to inhibit or prevent the lacrimal implant 400 from completely entering the lacrimal canaliculus, or to provide tactile or visual feedback information to the implantation user (e.g., regarding whether the implant is completely implanted), or to remove the lacrimal implant 400 from the implantation site. In one embodiment, the protrusion 422 includes a portion having a diameter of about 0.5-2.0mm to prevent the lacrimal implant 400 from falling into the lacrimal canaliculus.

Fig. 4B illustrates one embodiment of a cross-sectional view of lacrimal implant 400 taken along a line parallel to the longitudinal axis of the implant, such as along line 4B-4B of fig. 4A. As shown in fig. 4B, the lacrimal implant 400 includes an implant body 402 including a first 404 and a second 406 portion, the implant body 402 sized and shaped to be at least partially inserted into the punctum. The first portion 404 is formed of a polymer and has a first diameter 408. The second portion 406 is also formed of a polymer and includes a base member 412 (e.g., a mandrel or spine-like member) having a second diameter 410 that is less than the first diameter 408. In one embodiment, the base member 412 is at least about 1/3 of the overall length of the implant body 402. In one embodiment, the base member 412 is at least about 1/2 of the overall length of the implant body 402. In the illustrated embodiment, the implant body 402 also includes an integral feedback or other protrusion 422, such as a protrusion that extends laterally at least partially from or around the proximal end 418 of the implant body first portion 404.

In various embodiments, the implant body 402 may be molded (mold) or otherwise formed from an elastomeric material, such as silicone, polyurethane, or other urethane-based materials, or combinations thereof. In one embodiment, one or both of the first 404 and second 406 portions comprise a urethane-based material. In one embodiment, one or both of the first 404 and second 406 portions comprise a silicone-based material, e.g. In one embodiment, one or both of the first 404 and second 406 portions comprise a copolymer material, such as polyurethane/silicone, urethane/carbonate, silicone/polyethylene glycol (PEG), or silicone/2-hydroxyethyl methacrylate (HEMA). In various embodiments, the implant body 402 is configured to be non-absorbable in situ, and is strong enough to address cutting strength (e.g., during insertion and removal of the lacrimal implant 400) and dimensional stabilityAnd (4) the problem of sexual performance.

An expandable retention member 414, such as a swellable material, may be bonded or otherwise coupled to the base member 412 such that it at least partially encapsulates a portion of the base member 412. As the expandable retention member absorbs or otherwise retains tear fluid, such as after insertion into the punctum, its size increases and its shape may change, forcing itself against and lightly biasing against the associated canalicular wall. In various embodiments, the expandable retention member 414 may be molded or otherwise formed from an expandable material. In one embodiment, the expandable retention member 414 comprises a polyurethane hydrogel, for exampleOr other urethane-based hydrogels. In one embodiment, the expandable retention member 414 comprises a thermoset polymer, which may be configured to expand inhomogeneously (anistropic). In one embodiment, the expandable retention member 414 comprises a gel that does not maintain its shape after expansion, but rather adaptively fits the shape of the lacrimal canaliculus wall or other peripheral structures.

In certain embodiments, lacrimal implant 400 includes a base member 412 and an expandable retention member 414, the base member 412 including a polyurethane or other urethane-based material, and the expandable retention member 414 including a polyurethane or other urethane-based expandable material. In one embodiment, the polyurethane hydrogel is coupled directly to an outer surface, e.g., a plasma treated outer surface, of the base member 412.

In some embodiments, lacrimal implant 400 includes an intermediate member 450 positioned between a portion of implant body 402 (e.g., base member 412) and a portion of expandable retention member 414. The intermediate member 450 may comprise a material configured to absorb a greater amount of tear fluid than the polymer of the base member 412, but less tear fluid than the swellable polymer of the expandable retention member 414 when implanted. Intermediate (II)The member 450 can provide the integrity of the lacrimal implant 400, for example, between the substantially non-swelling polymer of the implant body 402 and the swelling polymer of the expandable retention member 414. For example, when the polymer of the expandable retention member 414 swells upon exposure to moisture, the expandable polymer may swell away from the underlying unexpanded polymer of the base member 412 without the intermediate member 450. In one embodiment, the intermediate part 450 comprises And impregnated or otherwise coated on the outer surface of the base member 412. In one embodiment, the intermediate member 450 comprises a polyurethane configured to absorb from about 10% to about 500% water, for exampleNitrogen-based formic acid esters orLiquid-holding grade carbamate. For additional discussion of the application of the intermediate member 450 to be placed between a portion of a first polymeric material and a portion of a second polymeric material (generally different from the first polymeric material), reference may be made to U.S. application serial No. 61/049,329 (filed 4/30 of 2008, entitled Composite rock Insert), commonly owned by Sim et al, which is incorporated herein by reference in its entirety.

In certain embodiments, the implant body 402 may include a cavity 416 disposed near a proximal end 418 of the first portion 404. In one embodiment, the first lumen 416 extends inward from the proximal end 418 about 2 millimeters or less and contains a drug donor 420 that releases a first drug or releases another agent to provide a sustained release of the drug or other agent to the eye. In one embodiment, the first lumen 416 extends through the implant body 402 and houses a drug donor 420 that releases a first drug or releases another agent. In various embodiments, the drug supply 420 stores a pharmaceutical agent and slowly dispenses the pharmaceutical agent to one or both of the eye or nasolacrimal system as the pharmaceutical agent is leached out, for example, by tear film fluid or other tears. In one embodiment, the drug donor 420 includes a plurality of anti-glaucoma agent inclusions 452, which may be distributed in the matrix 454. In one embodiment, inclusion 452 comprises an anti-glaucoma agent in a concentrated form (e.g., a crystalline pharmaceutical form). In one embodiment, the matrix 454 comprises a silicone matrix or the like, and the distribution of the inclusions 452 within the matrix is uniform or non-uniform. In one embodiment, the medicament inclusion 452 comprises droplets of oil (e.g., latanoprost oil). In another embodiment, the medicament inclusion 452 comprises solid particles, such as bimatoprost particles in crystalline form. The inclusions can have many sizes and shapes. For example, the inclusions may include particles having a size on the order of about 1 micron to about 100 microns.

In the embodiment shown, the drug donor 420 includes a sheath 456 disposed over at least a portion thereof, such as to define at least one exposed surface 458 of the drug donor. In one embodiment, the sheath 456 comprises polyimide. Exposed surface 458 may be located at or near proximal end 418 of implant body 402 to contact tear fluid or tear film fluid as lacrimal implant 400 is inserted into the punctum and release the anti-glaucoma agent at one or more therapeutic levels for a sustained period of time.

In certain embodiments, the expandable retention member may include a second drug-releasing or other agent-releasing drug donor 460 to provide sustained release of the drug or other agent to one or both of the lacrimal canaliculus wall or the nasolacrimal system. The drug donor 460 may be configured to store a medicament and slowly dispense the medicament upon contact with tear fluid in the canaliculus punctum. In one embodiment, the agent contained in the expandable retention member may comprise a drug, an anti-glaucoma agent (e.g., latanoprost), or an antimicrobial agent (e.g., silver).

Fig. 5 illustrates one embodiment of a cross-sectional view of lacrimal implant 500 taken along a line parallel to a longitudinal axis of the implant. As shown in fig. 5, lacrimal implant 500 includes an implant body 502. In the illustrated embodiment, the implant body 502 includes an integral feedback or other protrusion 522, such as a protrusion that extends laterally at least partially from or around the proximal end 518 of the implant body 502. The projection 522 is in the form of a loop projection (collarette extension) that extends radially outward from the implant body 502 to an extent sufficient to cause at least a portion of the loop projection to extend beyond and outside of the punctum after insertion of the distal portion of the implant body 502 into the lacrimal duct.

In this embodiment, the implant body 502 is at least partially impregnated with a drug-releasing or other agent-releasing drug donor 520. In certain embodiments, the drug donor 520 is disposed in, distributed throughout, or otherwise contained within the implant body 502. The agent of the Drug donor 520 can be released from the implant body 502 into the tear fluid or nasolacrimal duct system of the eye as discussed in commonly owned application serial No. 10/825,047 to Odrich, which is filed on day 15/4, 200 and entitled Drug Delivery great Plug. In some embodiments, an impermeable sheath is disposed over a portion of the implant body 502 to control release from the drug donor 520.

Preparing a lacrimal implant:

those skilled in the art will be familiar with the various methods that can be used to prepare the lacrimal implants described herein. Specific methods are described in the above-mentioned patent documents, the disclosures of which are incorporated herein by reference in their entirety.

For example, a cartridge as described above may be manufactured in various cross-sectional dimensions of 0.006 inches, 0.012 inches, 0.0125 inches, 0.0165 inches, 0.0220 inches, or 0.025 inches. The wall thickness of the tube may vary; in some embodiments, it may be about 0.005-0.0015 inches. The concentration of drug in the core may be about 5%, about 10%, about 20%, about 30%, about 33%, about 60%, about 63%, or about 93% of the silicone matrix. These cores may be prepared with a syringe barrel and barrel device (cartridge assembly) by mixing latanoprost or other anti-glaucoma agent with silicone and injecting the mixture into a polyimide tube, cutting it to the desired length, and sealing. In some embodiments, the core may be about 0.80 to 0.95mm in length and 0.012 inches (0.32mm) in diameter, corresponding to a total latanoprost or other agent content in the core of about 3.5 micrograms, 7 micrograms, 14 micrograms, 21 micrograms, or 25 micrograms, respectively. In some embodiments, a core of the invention will provide a concentration of therapeutic agent of 5%, 10%, 20%, 30%, 33% and 34% (by weight) relative to the total weight of the components of the core. Optionally, the core may comprise one or more penetration enhancers, for example, benzalkonium chloride.

Syringe barrel and cartridge device: 1. polyimide tubes of different diameters (e.g., 0.006 inches, 0.012 inches, 0.0125 inches, 0.0165 inches, 0.0220 inches, or 0.025 inches) can be used. The wall thickness of the tube may vary from about 0.0005 to about 0.0015 inches. The length of the tube may be about 30cm, or may be cut into 15cm lengths. For example, when preparing a core containing 81 micrograms of latanoprost, a 30cm long polyimide tube may be used. When preparing a core containing 44 micrograms of latanoprost, the tube can be cut into 15cm sections. 2. The polyimide tubing may be inserted into a syringe adapter. 3. The polyimide tubing may be bonded into a luer (luer) fitting (Loctite, low viscosity uv cure). 4. The tip of the device may then be trimmed. 5. The cartridge unit can be cleaned with distilled water, then methanol, and dried in an oven at 60 ℃.

In various embodiments, latanoprost or other anti-glaucoma agents may be mixed with the silicone. Latanoprost may be provided as a 1% solution in methyl acetate. An appropriate amount of the solution can be placed in a tray and the solution evaporated using a nitrogen stream until only the latanoprost or other anti-glaucoma agent remains. The tray with latanoprost oil can be placed under vacuum for 30 minutes. This latanoprost is then combined with silicone and different concentrations of latanoprost (e.g., about 5%, 10%, 20%, 30%, 33%, or 34%) in silicone NuSil 6385 are injected into tubes of different diameters (e.g., 0.006 inch, 0.012 inch, 0.0125 inch, 0.0165 inch, 0.0220 inch, or 0.025 inch) to create a matrix. The percentage of latanoprost to silicone was determined by the total weight of the drug matrix. And (3) calculating: weight of latanoprost/(weight of latanoprost + weight of silicone) × 100 ═ drug percentage.

The tube can then be injected: 1. the cartridge and polyimide tubing set can be inserted into a 1ml syringe. 2. One drop of catalyst (MED-6385 curative) may be added to the syringe. 3. Excess catalyst can be blown out of the polyimide tube with clean air. 4. The syringe may then be filled with the silicone drug matrix. 5. The tube may then be 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 can be sealed and pressure can be maintained until the silicone begins to cure. 7. Curing was carried out at room temperature for 12 hours. 8. The mixture was placed under vacuum for 30 minutes. 9. The tube can then be placed into an appropriately sized trim jig (homemade to clamp different sized tubes) and the drug insert can be cut to length (0.80-0.95 mm).

In some embodiments, the silicone implant body is molded. A filament comprising a solid material, such as a coil, is wound and a filament is heat set. The filament containing the heat set coil is placed in a mold. The implant body is molded with the coil embedded therein. The implant body may comprise a cannula, a tube, a retention structure and/or at least one chamber. The filaments may comprise at least one heat activated material, Nitinol, shape memory material, polymer, polypropylene, polyester, nylon, natural fiber, stainless steel, polymethylmethacrylate, or polyimide. In some embodiments, the filaments can comprise an absorbable thermoplastic polymer, such as at least one of polylactic acid (PLA), polyglycolic acid (PGA), or poly-lactic-co-glycolic acid (PLGA). By suitably controlling the time and/or temperature of the hot filaments, based on empirical data from a sample of filaments (e.g. 10 filaments) that are thermally set, the thermal setting of the filaments can be optimised. The molding of the implant can be optimized in several ways, such as appropriate time and temperature, molding hard ironing (hard ironing), multi-cavity molding and molding equipment parameters. In some embodiments, the filaments used to remove the core insert may be molded with the implant body such that the filaments are embedded in the implant body and located adjacent to the channel that receives the core insert.

In some embodiments, the lacrimal implant body is molded with a coil. Molding the hydrogel stick. The hydrogel rod component is inserted into the channel of the implant body component. The windings of the coil extend beyond the hydrogel rod. The hydrogel rod and the implant body are dip coated, for example in a hydrogel coating solution (which comprises, for example, a 5 wt% hydrogel solution). A needle may be placed in the channel of the implant body to control the body while the hydrogel rod and implant body are immersed in the solution.

In some embodiments of making a drug core insert, an injector device is prepared to inject the drug matrix into a polyimide tube. The drug core matrix is prepared and injected into the tube. The matrix is cured within a polyimide tube. The polyimide tube and cured matrix were cut to length and adhesive was applied.

Known commercially available syringes may be used in the syringe device. The syringe device may comprise a syringe barrel and barrel arrangement. The syringe barrel and barrel 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 to pressurize the tube. The injector device may be used to inject the drug core mixture and/or substance into the polyimide tubing. In some embodiments, multiple syringes may be used, for example for producing drug inserts containing 2 or more drug cores. In some embodiments, the injector device may comprise a manifold (manifold) having 2 or more injection canisters (injection pots) that may be used with separate injectors, wherein each injector comprises a different drug core mixture.

Polyimide tubing for injection was prepared by attaching a 30cm or 15cm long polyimide tubing to a luer fitting. The luer fitting 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 anti-glaucoma agent from the core through the tube, e.g., a material that is substantially impermeable to the flow of the anti-glaucoma agent through the tube, such that the flow of the anti-glaucoma agent is directed toward the exposed end of the core. In some embodiments, such as a drug core insert comprising 2 or more concentric drug cores, the tube may comprise concentric tubes, such as concentric polyimide tubes, with the outer tube arranged to contain the outer drug core mixture and the inner tube arranged to contain the inner drug core mixture. With an annular core as described above, concentric tubes may be used to form the annular core and the inner tube may be removed after the core matrix material has cured.

In some embodiments, the filaments used to remove the core insert may be embedded in the core. The filaments may be passed through a sheath, such as a tube, and the mixture injected into the tube. The matrix material is then cured with the filaments embedded in the matrix.

A drug core mixture is formed comprising an anti-glaucoma agent and a matrix material, such as silicone. In some embodiments, the anti-glaucoma agent may comprise at least one of latanoprost, bimatoprost, or travoprost. Embodiments may use silicones including dimethylsiloxanes such as Med-4011, Med-6385, and Med-6380, each of which is commercially available from NuSil of Rafibott (Lafayette), California. In some embodiments, a mixture of 2 or more cores is prepared, each for injecting separate cores, e.g., 2 mixtures, one for the inner core and one for the outer core.

In a particular embodiment, a drug core mixture is prepared comprising latanoprost oil inclusions in silicone. The anti-glaucoma agent and the drug core matrix material may be prepared and then mixed. In one embodiment, 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 was evaporated using a dry nitrogen stream until only the drop-off prost remained. The tray with latanoprost oil can be placed under vacuum for 30 minutes. In some embodiments, such as those using bimatoprost available as crystals as an anti-glaucoma agent, the anti-glaucoma agent can be prepared without the use of evaporation and vacuum.

In some embodiments where a solid anti-glaucoma agent (e.g., bimatoprost crystals) is used, the anti-glaucoma agent may be milled and passed through a screen and then mixed with the matrix material. In some embodiments, the screen may include a 120 mesh screen (125um) and/or a 170 mesh screen (90 um). Work in connection with embodiments of the present invention indicates that a screen can remove a very small fraction of the anti-glaucoma agent, and many embodiments can be used with inclusions of the anti-glaucoma agent having a size larger than the optional screen. In many embodiments, the release rate is independent of the size and/or size distribution of the inclusions, and the release rate can be independent of the particle size of about 0.1 microns to about 100 microns. In some embodiments, the size and/or size distribution of the particles and/or inclusions may be characterized by at least one of the following: a sieve, light scattering measurements of the core, light microscopy of the core, scanning electron microscopy of the core or transmission electron microscopy of a section of the core. Sieves can generally be used to produce a desired particle size and/or to exclude undesired particle sizes prior to mixing with the matrix. An exemplary screen comprises a fine mesh that passes only particles of a desired size or smaller, thereby limiting the anti-glaucoma agent to finer drug particles. This can be used to produce a more homogenous drug core and/or drug particle size that is easier to mix with the silicone matrix than those with oversized particles, although the particle size may remain significantly varied. Multiple screens may be used. For example, a 120-mesh screen may be used such that the maximum particle size passed is about 0.0049 inches. A # 170 screen can pass through particles having a diameter of 0.0035 inches or less. A 70 mesh screen allows a 0.0083 inch diameter particle size to pass through. The sieve may optionally be used continuously.

In some embodiments, silicones, such as NuSil 6385, can be obtained from the manufacturer in a closed container. Based on the batch of the construction, an appropriate amount of silicone can be weighed. An anti-glaucoma agent (e.g., latanoprost) may be combined with a silicone based on the expected and/or measured percentage of the anti-glaucoma agent in the drug core matrix. The percentage of latanoprost relative to silicone can be determined by the total weight of the drug matrix. The anti-glaucoma agent (e.g., latanoprost) is incorporated into the silicone by weighing out the appropriate amounts of the components. The following formula can be used to determine the percentage of the anti-glaucoma agent in the drug core matrix:

percent drug (drug weight)/(drug weight + silicone weight) X100

For a specific example of latanoprost in silicone, the following formula gives the percentage of latanoprost in silicone:

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

The anti-glaucoma agent (e.g., latanoprost) and silicone are combined and mixed using known methods and devices for mixing silicones. In some embodiments, the anti-glaucoma agent comprising latanoprost oil may form a microemulsion comprising inclusions that can scatter light and appear white.

When an anti-glaucoma agent, such as latanoprost, which is in a liquid physical state at about room temperature (22 ℃) and thus at human body temperature (37 ℃) is used, the agent and matrix material can be mixed by a technique that achieves a high dispersion of liquid latanoprost droplets in the matrix material (in which it may be substantially insoluble). The mixing technique should provide a dispersion of droplets within the matrix material such that when curing occurs, the liquid anti-glaucoma agent is present as relatively small, relatively homogenously dispersed discrete droplets within the matrix of the solid silicone material. For example, mixing may include sonication, i.e., using ultrasonic frequencies, such as produced by an ultrasonic probe. The probe may be placed in contact with a mixture of a matrix material and a liquid anti-glaucoma agent to prepare a close mixture of 2 substantially immiscible materials. See fig. 6 for a graphical representation of the latanoprost content of each 0.95mm segment of the filled precursor sheath. It can be seen that along the entire length of the 13cm precursor sheath (which is subsequently divided into 0.95mm segments), an even distribution of the anti-glaucoma agent latanoprost in the silicone matrix is provided. It is desirable to maintain a uniform level of anti-glaucoma agent in the plurality of drug inserts produced by this method.

In some embodiments, a mixture of the anti-glaucoma agent and the silicone is injected into the tube. A syringe (e.g., a 1ml syringe) may be connected to the syringe barrel and barrel assembly. A drop of silicone compatible catalyst (e.g., MED-6385 curative) may be placed in the syringe and the syringe filled with a mixture of uncured silicone and anti-glaucoma agent or silicone drug matrix. The mixture (i.e., the mixture of uncured silicone and medicament is still a sufficiently fluid or pumpable liquid) can be cooled to a low temperature. For example, the mixture may be cooled to a temperature of less than 20 ℃. For example, the mixture may be cooled to 0 ℃, -5 ℃ or-25 ℃. The polyimide tube was injected with the drug/matrix mixture until the tube was full. The tube and associated devices may also be cooled to maintain the low temperature of the mixture during filling or injecting the sheath with the mixture. In various embodiments, the polyimide tube or sheath is filled with the drug matrix mixture under pressure, for example by using a high pressure pump. For example, a drug/matrix mixture (such as may be obtained in a mixture of latanoprost and MED-6385 part a to which an amount of catalyst part B has been added) may be pumped into the tube at a pressure of at least about 40 psi. The tube may be filled at any suitable rate, for example, at a rate of less than about 0.5 linear centimeters per second. Without being bound by theory, it is believed that relatively rapidly filling the tube under a relatively high pressure head can reduce the degree of phase separation of the substantially immiscible latanoprost oil and silicone monomer material, such that upon polymerization ("curing") to provide the final silicone polymerizate, the latanoprost droplets are finely dispersed in their only sparingly soluble solid matrix.

Curing can occur in the presence of a catalyst ("part B") in the presence of NuSil MED-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. After filling the tube and clamping the end of the filled tube (to prevent void formation and loss of precursor material from the tube end), curing can be initiated directly.

After curing (which may end in about 16-24 hours at 40 ℃ and 80% RH), the clip can be removed from the tube end because the silicone is fully set (set up). The tube may then be cut into segments having a length suitable for use as a drug insert, for example, a length of about 1 mm.

When the extrusion is performed at low temperatures, small and more uniform drug inclusions can be produced. For example, when the agent is latanoprost, a liquid at room temperature, squeezing at-5 ℃, will provide significantly smaller and more uniform droplets of the inclusion. In one embodiment, the cold extrusion produces a core comprising a silicone matrix containing Latanoprost droplets with a mean diameter of 6 μm, with a standard deviation of 2 μm in diameter. In contrast, extrusion at room temperature produced a core comprising a silicone matrix containing Latanoprost droplets of 19 μm mean diameter with a standard deviation of droplet diameter of 19 μm. Clearly, cold extrusion techniques will provide smaller, more uniform inclusions than room temperature extrusion. This in turn results in a more uniform concentration of the drug throughout the core or insert containing the core, which is desirable for medical applications because of the improved uniformity of dosage.

The open end of the polyimide tube can be closed until the silicone begins to cure. In some embodiments having 2 or more cores, 2 or more separate mixtures may be injected separately from each of 2 or more syringes.

The amount of time and temperature of curing can be controlled and empirical data can be generated to determine the desired time and temperature of curing. 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 the anti-glaucoma agent in the core) can affect the optimal time and temperature of curing. In some embodiments, empirical data may be generated for each silicone matrix material and percentage of each anti-glaucoma agent to determine the optimal amount of time to cure the injected mixture. In some embodiments where 2 or more cores are included in the core insert, the 2 or more mixtures may be cured together to cure the cores of the insert.

Release of latanoprost or other anti-glaucoma agent or other agent at effective levels:

the release rate of latanoprost or other anti-glaucoma agent or other agent can be correlated to the concentration of latanoprost or other agent dissolved in the core. In some embodiments, the core comprises a non-therapeutic agent selected to provide a desired solubility of the agent (e.g., latanoprost) in the core. The non-therapeutic agent of the core may comprise a polymer and additives as described herein. The polymer of the core may be selected to provide the desired solubility of latanoprost in the matrix. For example, the core may comprise a hydrogel that may promote solubility of the hydrophilic therapeutic agent. In some embodiments, functional groups may be added to the polymer to provide a desired solubility of latanoprost in the matrix. For example, functional groups can be attached to the silicone polymer. Optionally, one or more excipients, for example, a penetration enhancer (e.g., benzalkonium chloride), may be co-eluted (co-elute) with the latanoprost or other agent used.

Additives may be used to control the concentration of the agent (e.g., latanoprost) by increasing or decreasing the solubility of latanoprost in the drug core, thereby controlling the release kinetics of latanoprost. The solubility can be controlled by providing suitable molecules or substances that increase or decrease the amount of latanoprost in the matrix. The latanoprost content can be correlated to the hydrophobic or hydrophilic nature of the matrix and latanoprost. For example, surfactants and salts may be added to the matrix and the content of hydrophobic latanoprost in the matrix may be increased. Additionally, oils and hydrophobic molecules may be added to the matrix and may increase the solubility of the hydrophobic therapeutic agent in the matrix.

Instead of or in addition to controlling the migration rate based on the concentration of latanoprost dissolved in the matrix, the surface area of the core may also be controlled to achieve the desired rate of migration of the drug from the core to the target site. For example, a larger core exposed surface area will increase the rate of migration of the therapeutic agent from the core to the target site, and a smaller core exposed surface area will decrease the rate of migration of latanoprost from the core to the target site. The exposed surface area of the core may be increased in any number of ways, for example by any of the following: clusters of exposed surfaces (castellations), porous surfaces with exposed channels in communication with tears or tear films, indentations of exposed surfaces, protrusions of exposed surfaces. By adding salt, the salt dissolves and leaves behind porous holes once the salt has dissolved, the exposed surface can be made porous. Hydrogels may also be used, which may be sized to expand to provide a greater exposed surface area. Such hydrogels may also be made porous to further increase the migration rate of latanoprost.

In addition, implants having the ability to deliver 2 or more drugs in combination, such as the structure disclosed in U.S. patent No. 4,281,654(Shell), may be used. For example, in the case of glaucoma treatment, it may be desirable to use various prostaglandins or to use prostaglandins and cholinergic or adrenergic antagonists (beta-blockers) (e.g., alpharoot R)^TMOr treating the subject with latanoprost and a carbonic anhydrase inhibitor. In some embodiments herein, implants are envisioned that will release latanoprost in combination with benzalkonium chloride or other penetration enhancers or artificial tears.

Additionally, drug impregnated meshes (mesh) such as those disclosed in U.S. patent publication No. 2002/0055701 (serial No. 77/2693), or a biostable polymer layer as described in U.S. patent publication No. 2005/0129731 (serial No. 97/9977), the disclosures of which are incorporated herein in their entirety, may be used. Latanoprost may be incorporated into the devices of the present invention using certain polymer processes; for example, so-called "self-delivering drugs" or polymeric drugs (PolymerixCorporation, Piscataway, n.j.) are designed to degrade only into therapeutically useful compounds and physiologically inert linker molecules, as further detailed in U.S. patent publication No. 2005/0048121 (serial No. 86/1881; East), which is incorporated herein by reference in its entirety. Such delivery polymers may be used in the devices of the present invention to provide release rates that are the same as the polymer erosion and degradation rates, and are constant over the course of treatment. Such delivery polymers may be used as a device coating or in the form of microspheres for an injectable drug depot (e.g., a reservoir of the invention). Alternative polymer delivery technologies may also be constructed into the devices of the present invention, such as those described in U.S. patent publication No. 2004/0170685 (serial No. 78/8747; Carpenter), and those available from Medivas (san Diego, Calif.).

In particular embodiments, the drug core matrix comprises a solid material, such as silicone, which encapsulates the inclusion of a drug (e.g., latanoprost). The drug comprises a molecule that is poorly soluble in water and slightly soluble in the matrix surrounding the drug core. The inclusions encapsulated by the core may be microparticles having a size of about 1 micron to about 100 microns in diameter. The drug inclusions may comprise droplets of an oil (e.g. latanoprost oil). The drug inclusions may be dissolved in the solid core matrix and the core matrix substantially saturated with the drug, e.g. dissolution of latanoprost oil in the solid core matrix. The drug dissolved in the matrix of the core is often transported by diffusion from the exposed surface of the core into the tear film. Since the drug core is substantially saturated with drug, in many embodiments, the rate limiting step in drug delivery is the transport of drug from the surface of the drug core matrix exposed to the tear film. Since the drug core matrix 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 drug transport from the drug core into the tear film can be substantially constant. It has been determined in accordance with the present invention that the solubility of latanoprost in water and the molecular weight of the drug can affect the transport of the drug from the solid matrix to the tear fluid. In many embodiments, latanoprost is practically insoluble in water, and has a solubility in water of about 0.03% to 0.002% (by weight), and has a molecular weight of about 400 g/mol to about 1200 g/mol.

In many embodiments, latanoprost has very low solubility in water, e.g., from about 0.03% (by weight) to about 0.002% (by weight), has a molecular weight of from about 400 grams/mole (g/mol) to about 1200g/mol, and is readily soluble in organic solvents. Latanoprost is a liquid oil at room temperature, has a water solubility of 50 micrograms/mL or about 0.005% (by weight) in water at 25 ℃, and has a molecular weight of 432.6 g/mol.

It has been determined in accordance with the present invention that surfactants naturally present in the tear film (e.g., surfactant D and phospholipids) can affect the transport of drug dissolved in the solid matrix from the drug core to the tear film. The drug core can be configured to respond to a surfactant in the tear film to provide sustained delivery of latanoprost into the tear film at a therapeutic level. For example, empirical data can be obtained from a population of subjects, e.g., 10 subjects, collecting their tears and analyzing surfactant levels. The elution profile of a sparingly water-soluble drug in collected tears can also be measured and compared to the elution profile in buffer and surfactant to form an in vitro model of tear surfactant. In vitro surfactant-containing solutions based on this empirical data can be used to modulate the center of the drug in response to the surfactant of the tear film.

Fig. 7 illustrates a method 700 for producing a drug core comprising, for example, about 44 micrograms of latanoprost. At 702, latanoprost is combined with an organosilicon formulation. In various embodiments, the silicone formulation includes a two-part system, such as part a and part B. Part a may include silicone and a crosslinker, while part B may contain a tin catalyst, for example, to promote crosslinking. In one embodiment, the 2 fractions are combined in a final ratio of 200: 1 (fraction A: fraction B). Additional cross-linking agents may be added to aid in the formation of the solid core. The cross-linking agent used in this system may be tetrapropylorthosilicate (tetrapropylorthosilicate), which may be purchased from NuSil, among others, as part of a three-part system (MED5-6382), the cross-linking agent being supplied separately. At 704, appropriate amounts of latanoprost, crosslinker, and MED6385 portions a and B can be dispensed onto a slide and mixed using a plastic microtome for about 2 minutes.

After thoroughly mixing the silicone/latanoprost, the mixture can be loaded into the barrel of a syringe extrusion system at 706. The plunger is inserted and excess air is removed. The extrusion apparatus may be a tube with an all stainless steel jacket in a tube-clean welded heat exchanger and include a gas scrubber (gas purge) that is internally cooled by crimping inside the coolant side of the heat exchanger. The operating temperature of the cooling system may be 5 to-20 ℃, depending on the settings and capacity of the recycle cooler used. The temperature inside the heat exchanger should be relatively stable, within ± 2.5 ℃ of the extrusion temperature. The steady state temperature of the cooling system can be confirmed prior to insertion of the injector and tubing.

In various embodiments, the tubes inside the heat exchanger are cooled in the direction toward the sight glass, and the inner surface is kept dry and protected by a gas purge of a small amount of residual pressure nitrogen. The top of the injector cooling system may be connected to the HP7x high pressure injector adapter, which is connected to the EFD, with three clips. The EFD is connected to a compressed air source.

After assembly, at 708, the EFD is activated and the silicone/latanoprost mixture is extruded down the length of the polyimide tube. The pressure may be gradually increased from 5psi to 40psi over a period of about 3 minutes and maintained at 40psi until the mixture reaches the end of the tube. Once the mixture reaches the bottom of the tube, the syringe containing the tube may be removed from the cooling system. The syringe can be removed by cutting the tube with a safety blade; the tube may then be clamped at both ends, at 710. The clamped tube segments can be placed in a humidity chamber at 712, for example, for curing at 40 deg.C/80% RH for about 16-24 hours. After curing, the tube may be cut into 0.95mm long sections at 714, a cyanoacrylate glue may be applied at 716 and cured to one end of the insert, and then inserted into the punctal plug at 718 to produce the final product, for example. The final product may then be packaged at 720 and optionally sterilized at 722.

In one embodiment, a core comprising about 44 micrograms of latanoprost is prepared using the following method. A silicone/latanoprost mixture was prepared by combining 16.8mg latanoprost, 33.2mg silicone MED6385 part a, 0.15 μ L silicone MED6385 part B, and 1.0 μ L additional crosslinker on a slide. The components were mixed using a small plastic spatula for approximately 2 minutes. After mixing, the mixture was loaded into the barrel of a syringe extrusion system, a plunger was inserted, and pressed to remove excess air. The syringe was then loaded into a cooled extrusion apparatus and allowed to equilibrate to an extrusion temperature of-10 ℃ for 2 minutes. The EFD was activated and the pressure was gradually increased from 5psi to 40psi until the mixture was extruded down the length of the polyimide tube to the end. The syringe is then removed from the extruder and the tube is cut with a safety blade and then clamped at both ends. The tubes were then cured at 40 ℃/80% RH for approximately 16-24 hours in a controlled humidity and temperature chamber. After curing, the tube was released and cut into 0.95mm long sections. The glue is applied and cured to one end of the insert and then checked for length and physical properties. The insert is inserted into the lumen of the punctal plug. The assembled punctum plugs were packaged into Tyvec bags and heat sealed. The Tyvec bags were then packaged into aluminum foil bags, back-filled with nitrogen, and then heat sealed. The packaged lacrimal plug is then sent to electron beam irradiation for sterilization.

The drug core may also be modified to utilize carrier vehicles such as nanoparticles or microparticles depending on the size of the molecule to be delivered, such as the composite and latent reactive nanofiber composition of the Surface of the nanosubground (Innovative Surface Technologies, LLC, st. paul, Minn.), nanostructured porous silicon (known as biosilicon. r.)^TM.) including microNanometer-sized particles, membranes, woven fibers, or miniaturized implantable devices (pSividia, Limited, UK) and protein nanocage (chiceracore) systems that target selective cells for drug delivery.

In many embodiments, the drug insert comprises a thin-walled polyimide sheath with a drug core comprising latanoprost dispersed in NuSil6385 (MAF 970), which NuSil6385 is a medical grade solid silicone used as a drug delivery matrix. The distal end of the drug insert was sealed with a cured film of solid Loctite 4305 medical grade adhesive. The drug insert can be positioned within the lumen of the lacrimal implant without the Loctite 4305 adhesive contacting the tissue or tear film. The inner diameter of the drug insert may be 0.32 mm; the length may be 0.95 mm. In embodiments of the invention, different latanoprost concentrations may be employed in the final pharmaceutical product: the core may comprise 3.5, 7, 14, 21, 44 or 81 micrograms of latanoprost in a concentration of 5, 10, 20, 30 or 34% by weight respectively. Assuming a total elution rate of about 100 ng/day, a drug core comprising 14 microclatanoprost is constructed to deliver the drug for approximately at least 100 days, e.g., 120 days. The total weight of the core (containing latanoprost) may be about 70 micrograms. The drug insert weight, including the polyimide sleeve (sleeve), may be about 100 micrograms.

In many embodiments, the core may elute latanoprost at a high level initially, followed by a substantially constant elution of latanoprost. In many cases, the amount of latanoprost released from the core per day may be below therapeutic levels and still provide benefit to the subject. High levels of eluted latanoprost may produce residual amounts of latanoprost, or combined with subtherapeutic amounts of latanoprost, providing relief to the subject. In embodiments where the therapeutic level is about 80 ng/day, a device containing a 44 microgram drug core may deliver about 1500ng-3000ng on the first day, 500-1000ng on days 2-7, and thereafter 300-500ng latanoprost for a total of at least 90 or 120 days. Because the amount of drug delivered can be precisely controlled, the initial high dose does not produce complications or adverse events to the subject.

In certain embodiments, the methods of the present invention result in a percentage reduction in intraocular pressure of about 28%. In some embodiments, the methods of the present invention result in a percentage reduction or reduction in intraocular pressure of about 30%, about 29%, about 28%, about 27%, about 26%, about 25%, about 24%, about 23%, about 22%, about 21%, or about 20%. In certain embodiments, the methods of the present invention result in a percentage reduction or reduction in intraocular pressure of at least 30%, at least 29%, at least 28%, at least 27%, at least 26%, at least 25%, at least 24%, at least 23%, at least 22%, at least 21%, at least 20%, at least 15%, or at least 10%.

In certain embodiments, the methods of the present invention reduce intraocular pressure from baseline by about 9mmHg, about 8.5mmHg, about 8mmHg, about 7.5mmHg, about 7mmHg, about 6.5mmHg, about 6mmHg, about 5.5mmHg, about 5mmHg, about 4.5mmHg, about 4mmHg, about 3.5mmHg, about 3mmHg, about 2.5mmHg, or about 2 mmHg. In certain embodiments, the methods of the present invention reduce intraocular pressure from baseline by at least 2mmHg, at least 3mmHg, at least 4mmHg, at least 5mmHg, at least 6mmHg, or at least 7 mmHg. In some embodiments, the intraocular pressure is reduced to less than or equal to 21mmHg, less than or equal to 20mmHg, less than or equal to 19mmHg, less than or equal to 18mmHg, less than or equal to 17mmHg, less than or equal to 16mmHg, less than or equal to 15mmHg, less than or equal to 14mmHg, less than or equal to 13mmHg, or less than or equal to 12 mmHg.

In one embodiment, the implants and methods of the invention provide a 90-day treatment course. In some embodiments, an effective level of latanoprost is released during the entire course of treatment. In another embodiment, the variability of intraocular pressure over the course of treatment is less than about 1mm Hg. In other embodiments, the variability of intraocular pressure over the course of treatment is less than about 2mm Hg. In other embodiments, the variability of intraocular pressure over the course of treatment is less than about 3mm Hg.

The implants described herein can be inserted into the superior punctum, the inferior punctum, or both, and can be inserted into one or both eyes of a subject. In some embodiments, the lacrimal implant delivery system is inserted bilaterally into the inferior (inferior) punctum of the eye.

Lacrimal implants with excipients:

the present invention also relates to various embodiments of a therapeutic agent-containing lacrimal implant for use in an implant body (which is adapted for placement in a body tissue, body fluid, body cavity, or duct) that contains one or more excipients disclosed herein that can alter one or more of several properties of the implant. These properties include: the amount of therapeutic agent that may be substantially uniformly dispersed in the matrix, the rate at which the agent is released from the matrix after placement in living tissue, and the pharmacokinetic behavior of the agent in the tissue.

The implant may be adapted to be positioned in or near the eye of a patient. The implant will release the agent into the body, e.g., into the eye or surrounding tissue or both, for a period of time for treating a condition of the patient that medically dictates the use of the therapeutic agent. The invention also relates to various embodiments of methods of producing the drug insert, and methods of treating a patient using an implant containing the drug insert.

The cores, implants, and methods of their production described herein may take any of a number of different designs, configurations, or arrangements, for example, as described in the following patent documents, each of which is incorporated herein by reference in its entirety: U.S. application Ser. No. 60/871,864 (filed on 26.12.2006, entitled Nasolarix Drainage System for drug therapy); U.S. application Ser. No. 11/695,537 (filed on 2.4.2007 under the heading drug delivery Methods, Structures, and Compositions for Nasolacrimal System); U.S. application Ser. No. 60/787,775 (filed 3/31/2006 under the heading Nasolarimal Drainage System for Drug Therapy); U.S. application Ser. No. 11/695,545 (filed on 2.4.2007 under the heading Nasolarix Drainage System for Drug Therapy); U.S. application serial No. 60/970,696 (filed on 7/9/2007 under the heading Expandable Nasolacrimal Drainage systems implants); U.S. application Ser. No. 60/974,367 (filed on 21/9/2007 under the heading Expandable Nasolarix Drainage System Implants); U.S. application Ser. No. 60/970,699 (filed on 7.9.2007, entitled manufacturing of Drug Cores for Sustainated releases of Therapeutic Agents); U.S. application Ser. No. 60/970,709 (filed on 7/9/2007 under the heading Nasolarix Drainage systems Implants for Drug Delivery); U.S. application Ser. No. 60/970,720 (filed on 7/9/2007 under the heading of the Manual of Expandable Nasolanicial Drainage systems Implants); U.S. application Ser. No. 60/970,755 (filed on 7/9/2007 under the heading Prostaglandin analogs for expression Devices and Methods); U.S. application Ser. No. 60/970,820 (filed on 7/9/2007 under the heading Multiple drug delivery Systems and Combinations of Drugs with Punctal Implants); U.S. application Ser. No. 61/049,347 (filed on 30.4.2008, entitled Laclimale implants and Related Methods); U.S. application Ser. No. 61/049,360 (filed on 30.4.2008, entitled Lacrial Implants and Related Methods); U.S. application serial No. 61/209,630 (filed 3/9/2009 under the heading Lacrimal Implants and related Methods); unknown U.S. application serial No., docket No. 2755.023PV9 (filed herewith under the title Lcriml Implt d filtered Method); U.S. application Ser. No. 61/036,816 (filed 3/14/2008, entitled Lacrial Implants and RelatedMethods); U.S. application Ser. No. 61/049,337 (filed on 30.4.2008, entitled Lacrial Implants and Related Methods); U.S. application serial No. 61/049,329 (filed on 30/4/2008, entitled Composite Laccrimal Insert); U.S. application serial No. 61/049,317 (filed on 30.4.2008, entitled Drug-Releasing Polyurethane latex Insert); U.S. application serial No. 61/050,901 (filed 5/6/2008, entitled larlimit protection); U.S. application Ser. No. 12/231,989 (filed on 5.9.2008, entitled Laclimale implants and Related Methods); U.S. application Ser. No. 61/134,271 (filed on 8.7.2008, entitled Lacrial image Body incorporating Comforting agent); U.S. application Ser. No. 12/231,986 (filed on 5.9.2008, titled drug cores for Sustanated Release of Therapeutic Agents); U.S. application Ser. No. 10/825,047 (filed 4/15/2004 under the heading Drug Delivery via Punctal plug); international published application WO 2006/014434; international application Ser. No. PCT/US2007/065789 (filed 3.31.2006, published as WO 2007/115259, titled Nasolacrimal Drainage System for Drug Therapy); international application Ser. No. PCT/US2008/010487 (filed 5.9.2008, titled drug cores for Sustainated Release of Therapeutic Agents); international application Ser. No. PCT/US2008/010479 (filed on 8.9.2008, titled Lacamidal Implants and related Methods); U.S. application Ser. No. 61/139,456 (filed on 19.12.2008, entitled Substance rendering efforts improvements and Methods).

It has been surprisingly found that the addition of certain excipients to a core consisting of a polymer matrix and a therapeutic agent can unexpectedly alter the properties or behaviour of the core (when placed in vivo). For example, it has been unexpectedly found that certain excipients can increase the release rate of the pharmaceutical agent (after placement of an implant containing a drug core in vivo, such as in a punctum of a human eye). Other excipients may act to delay release of the agent under the same conditions.

Some excipients may provide benefits in the administration of agents (such as latanoprost) to tissues (such as the eye) in a manner that results in a longer residence time of the agent adjacent to the implant (e.g., in the tear fluid or disposed on the surface of the eye). Alternatively, some excipients may enhance penetration of the agent into adjacent tissue after implant placement, for example, increasing corneal penetration of prostanoids.

In some embodiments, a high degree of homogeneity of the therapeutic agent throughout the drug core matrix is provided. Many pharmaceutical agents do not dissolve in the polymeric material in any appreciable concentration, but rather form inclusions within the polymer matrix as solid particles or droplets. It is desirable to maintain a high degree of uniformity in the dispersion of the medicament within the matrix at the sub-millimeter level to provide uniformity of often physically small (e.g., 1mm length) drug cores, such as those suitable for placement in the punctum. On the other hand, high concentration levels of the agent or drug in the matrix can be advantageously achieved to provide an effective amount to the target tissue over a period of time (e.g., a period of days or weeks).

It has been surprisingly found that certain excipients of the present invention can allow for higher loading of therapeutic agents within a drug core matrix while retaining the desired homogeneity of dispersion of the inclusion bodies within the polymer matrix.

In various embodiments, the present invention provides a core adapted to be disposed within a sheath, and the core with the sheath is disposed within the implant body to provide a complete implant assembly. The implant is adapted for placement in or near the eye of a patient for providing sustained release of a therapeutic agent to the eye or surrounding tissue or both, wherein the sheath serves to spatially limit the release of the agent into the surrounding tissue. For example, a cylindrical sheath open at only one end may limit release of the agent to the open end, as long as the sheath is itself substantially impermeable to diffusion of the agent therethrough.

In some embodiments, the core comprises a therapeutic agent, one or more excipients disclosed herein, and a matrix, wherein the matrix comprises a polymer, wherein the amount of therapeutic agent in one volume portion (volumetric portion) of the core is similar to the amount of therapeutic agent in any other same volume portion of the core.

In some embodiments, the core comprises an excipient that modulates the release rate of the agent to body tissue (such as by increasing or decreasing the release rate), or increases the residence time of the agent in adjacent tissue, or provides enhanced tissue penetration, such as corneal penetration of the eye. Excipients may also allow higher drug loads to be achieved in the drug core composition while maintaining the desirable properties of substantially homogeneous distribution of the drug inclusions within the core-forming polymer matrix.

In various embodiments, the present invention provides an implant configured for placement within or near a body cavity, tissue, tube, or fluid, the implant comprising:

a core comprising:

(a) a matrix including a polymer;

(b) a therapeutic agent dissolved or dispersed in the matrix, and

(c) an excipient dissolved or dispersed within the matrix, the excipient configured for any one of the following uses:

(1) modulating the release rate of the therapeutic agent into the body cavity, tissue, tube, or fluid as compared to an equivalent release rate in the absence of the excipient; or

(2) Increasing the loading of the therapeutic agent substantially uniformly dissolved or dispersed within the matrix as compared to an equivalent loading of the therapeutic agent substantially uniformly dissolved or dispersed in the absence of the excipient;

(3) increasing retention of the agent at or near a site of release in vivo, or increasing penetration of the agent into adjacent body tissue, or both, as compared to retention or penetration from a comparable implant in the absence of the excipient, or both;

or any combination thereof;

wherein the amount of therapeutic agent in one volume portion of the matrix is similar to the amount of therapeutic agent in any other same volume portion of the matrix;

And, optionally, an implant body adapted to receive a core therein for placement within a body cavity, tissue, tube or fluid.

The drug core comprises a matrix and a therapeutic agent as disclosed in published PCT application PCT/US2008/010487 (filed on 5/9/2008, published as WO 2009/035562 on 19/3/2009, and incorporated herein by reference). As disclosed and claimed herein, the drug core may additionally comprise excipients which unexpectedly modulate the properties of the drug core, for example in the manner of the achievable drug loading in the core, and the release of drug from the drug core after placement within or near the living tissue of a patient.

Therapeutic agents or drugs 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 (CAIs, both systemic and local), parasympathomimetics, prostaglandins (such as latanoprost) and hypotensive lipids (hypotensive lipids) and combinations thereof); antimicrobial agents (e.g., antibiotics, antiviral agents, antiparasitic agents (antiparastic), antimycotic agents (antimycotic), etc.); corticosteroids or other anti-inflammatory agents (e.g., NSAIDs or other analgesics and pain treatment compounds such as cyclosporine or olopatadine); decongestants (e.g., vasoconstrictors); agents that prevent or modulate allergic responses (e.g., antihistamines, cytokine inhibitors, leukotriene inhibitors, IgE inhibitors, immunomodulators such as cyclosporine); mast cell stabilizers; a cycloplegic agent; mydriatic or the like.

Examples of agents additionally include, but are not limited to: a thrombin inhibitor; an antithrombotic agent; dissolving the blood suppository; a fibrinolytic agent; an inhibitor of vasospasm; a vasodilator; an antihypertensive agent; antimicrobial agents, such as antibiotics (e.g., tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, cephalexin, terramycin, chloramphenicol, rifampin, ciprofloxacin, tobramycin, gentamicin, erythromycin, penicillin, sulfonamides, sulfadiazine, sulfacetamide, sulfamethizole, sulfisoxazoleAzole, nitrofurazone, sodium propionate), antifungal agents (e.g., amphotericin B and miconazole) and antiviral agents (e.g., idoxuridine trifluorothymidine, acyclovir, ganciclovir, interferon); surface glycoprotein receptorsThe inhibitor of (1); anti-platelet agents; an anti-mitotic agent; a microtubule inhibitor; an antisecretory agent; an activity inhibitor; remodeling inhibitors (remodelling inhibitors); an antisense nucleotide; antimetabolites (anti-metabolites); antiproliferative agents (including anti-angiogenic agents); an anti-cancer chemotherapeutic agent; anti-inflammatory agents (e.g., cyclosporin, olopatadine, hydrocortisone acetate, dexamethasone 21-phosphate, fluocinolone, medrysone, methylprednisolone, prednisolone 21-phosphate, prednisolone acetate, fluorometholone, betamethasone, triamcinolone acetonide); non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., salicylates, indomethacin, ibuprofen, diclofenac, flurbiprofen, piroxicam indomethacin, ibuprofen, naproxen, piroxicam, and nabumetone). Examples of such anti-inflammatory steroids contemplated for use in the punctal plugs of the invention include triamcinolone acetonide and corticosteroids that include, for example, triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone, p-flumethasone, and derivatives thereof; antiallergic drugs (e.g. sodium cromoglycate, antazoline, metapyriline, chlorpheniramine, cetirizine, pyrilamine, pheniramine); antiproliferative agents (e.g., 1, 3-cis retinoic acid, 5-fluorouracil, paclitaxel, rapamycin, mitomycin C, and cisplatin); decongestants (e.g., phenylephrine, naphazoline, tetrahydrozoline); miotics and anticholinesterases (e.g., pilocarpine, salicylate, carbachol, acetylcholine chloride, physostigmine, irinotecan, diisopropyl fluorophosphate, iodoecoxite, dimeglumine); antineoplastic agents (e.g., carmustine, cisplatin, fluorouracil); immunopharmaceuticals (e.g., vaccines and immunostimulants); hormonal agents (e.g., estrogen, estradiol, progestational agents, progesterone, insulin, calcitonin, parathyroid hormone, peptide, and vasopressin hypothalamic releasing factor); immunosuppressants, growth hormone antagonists, growth factors (e.g., epidermal growth factor, fibroblast growth factor, platelet derived growth factor, transforming growth factor beta, growth hormone, fibronectin); angiogenesis inhibitors (e.g., angiostatin, anecortave acetate, thrombospondin, anti-VEGF antibody); a dopamine agonist; radiotherapeutic agent (ii) a A peptide; a protein; an enzyme; an extracellular matrix; preparing components; an ACE inhibitor; a free radical scavenger; a chelating agent; an antioxidant; anti-polymerase (antipolymerase); a photodynamic therapeutic agent; a gene therapy agent; and other therapeutic agents such as prostaglandins, anti-prostaglandins, prostaglandin precursors, including anti-glaucoma drugs 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, danus; neuroprotective agents such as lubeluzole, nimodipine and related compounds; and parasympathomimetics such as pilocarpine, carbachol, physostigmine, and the like.

Other agents that may be used with the lacrimal implants of the present invention include, but are not limited to, drugs that have been approved under United States Federal Food, Drug, and Cosmetic Act, Section 505 or under Public Health Service Act, some of which may be found in the United States Food and Drug Administration (FDA) website http:// www.accessdata.fda.gov/scripts/cd/Drug atfda/index. The punctal plugs of the invention can also be used with drugs listed in the Orange Book paper or electronic (Orange Book) that can be found in the FDA Orange Book website (http:// www.fda.gov/cder/ob /) and which has or records data at the same, earlier, or later date as the filing date of this patent document. For example, these drugs may include, among others, dorzolamide, olopatadine, travoprost, bimatoprost, cyclosporin, brimonidine, moxifloxacin, tobramycin, brinzolamide, acyclovir, timolol maleate, ketorolac tromethamine, prednisolone acetate, sodium hyaluronate, nepafenac, bromfenac, diclofenac, flurbiprofen, suprofen (suprofnac), binoxan, patarol, dexamethasone/tobramycin combinations, moxifloxacin, or acyclovir.

In various embodiments, the agent may be a prostaglandin analog, such as latanoprost, bimatoprost, or travoprost, and the amount of agent in the drug insert may be about 10-100 μ g. In various embodiments, the core (excluding the sheath, if present) may comprise from about 0.1% to about 50% by weight of an agent such as latanoprost.

The matrix may comprise a polymeric material, for example, the matrix may comprise silicone, polyurethane, or any non-biodegradable polymer in which the agent has at least sufficient solubility to diffuse therein. The matrix may comprise other materials including, but not limited to, other types of polymers such as polyolefins, polyamides, polyesters, polyvinyl alcohol or acetate, ethylene-vinyl acetate copolymers, polysaccharides (such as cellulose or chitin, etc.), as long as the materials are biocompatible. Thus, the material of the matrix may be selected based at least in part on the agent selected for a particular intended use, such that a sufficient degree of solubility of the agent in the matrix may be achieved that therapeutic levels of the agent may be maintained in the target tissue for a period of time. In various embodiments, the present invention provides an implant, wherein the matrix comprises silicone (which is optionally crosslinked) or a polyurethane polymer. For example, the matrix may comprise MED6385 silicone polymer crosslinked with tetraethyl orthosilicate.

In various embodiments, the implant can comprise a sheath partially surrounding the core, at least a portion of the sheath being intermediate the surface of the core and the wall of the lumen of the implant body. The core may be partially covered by a sheath, but whether or not a sheath is present, the core may be located within a lumen of the implant body adapted to receive it. The implant body may then be positioned within or adjacent to living tissue of the patient to achieve a controlled or sustained release of the agent therefrom. For example, the implant body may be adapted to be positioned within a punctum of a human eye.

In various embodiments, the core comprising the complex of the therapeutic agent and the matrix is partially contained within or surrounded by a sheath that is substantially impermeable to the agent. The sheath may cover a portion (but not all) of the surface of a core comprising the drug and the matrix material, the core having an exposed surface such that the therapeutic agent may be released from the surface. In various embodiments, the sheath may comprise: a polymer comprising at least one of polyimide, PMMA, or PET, wherein the polymer is extruded or cast; or metals including stainless steel or titanium.

The core and its sheath together are adapted to be contained within an implant structure which is itself adapted to be implanted within a patient, such as within a body cavity, tissue, tube or fluid. For example, the implant may be an ocular implant suitable for placement in or around the eye, such as a punctal plug, which is suitable for placement in the lacrimal canaliculus of the eye such that the agent may be released through the punctum of the eye to contact the eyeball and surrounding tissues, such as the sclera, conjunctiva, posterior fornix of the eyelid, trabecular meshwork, ciliary body, cornea, choroid, suprachoroidal space, or tissues within the eyeball, such as the vitreous humor, aqueous humor, and retina.

In various embodiments, the implant may be an ocular implant adapted to be positioned within a punctum of a human eye to release a therapeutic agent therefrom.

In various embodiments, the therapeutic agent is substantially uniformly and homogeneously dissolved in the matrix, or the agent is at least partially formed into solid or liquid inclusions having an average diameter of less than about 50 microns, the inclusions being substantially uniformly dispersed in the matrix on a sub-millimeter scale.

In various embodiments, the agent is not sufficiently soluble in the matrix to form a solid solution. In these embodiments, the agent may be dispersed throughout the matrix at least in part as a plurality of solid or liquid inclusions comprising: at a temperature of about 20 ℃, droplets of the agent of no more than about 50 μm in diameter (when the agent is a liquid at about 20 ℃), or particles of the agent of no more than about 50 μm in diameter (when the agent is a solid at about 20 ℃); wherein the inclusion of the medicament is dispersed throughout each core.

The size and size distribution of the inclusions can affect the rate of release of the pharmaceutical agent from the core to the patient. For example, smaller, more uniform inclusions can be used to more effectively infuse a large volume of matrix with a medicament at a higher rate due to a more favorable surface area to volume ratio. Thus, the method of the invention provides for the control or adjustment of the average inclusion diameter or the distribution of inclusion diameters. In various embodiments, the distribution of inclusion diameters may be a monodisperse distribution. In various embodiments, the inclusions comprise predominantly cross-sectional dimensions in the range of about 0.1 μm to about 50 μm. It is believed that a tight or monodisperse distribution of inclusion diameters is advantageous from a therapeutic point of view of the drug core or drug insert containing the drug core.

Various embodiments of the present invention also provide a drug core or an insert containing a drug core, wherein the pharmaceutical agent forms inclusions in the matrix that are in a liquid physical state at about 20 ℃. For example, substantially all of the inclusions may be droplets of the agent having a diameter of less than about 50 μm within the matrix. An example of an agent 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 containing a drug core, wherein the pharmaceutical agent forms inclusions in the matrix that are in a solid physical state at about 20 ℃. For example, substantially all of the inclusions may be particles of the pharmaceutical agent having a diameter of less than about 50 μm within the matrix. For example, the average particle size within the matrix may be about 5-50 μm. Examples of pharmaceutical agents that are in a solid physical state at about 20 ℃ include bimatoprost, olopatadine, or cyclosporine.

In various embodiments, the therapeutic agent (such as latanoprost) is contained in the matrix such that the amount of therapeutic agent in one volume portion of the core is similar to the amount of therapeutic agent in any other same volume portion of the core. For example, the amount of therapeutic agent in one volume portion of the core may differ by no more than about 30% from the amount of therapeutic agent in any other same volume portion of the core. For example, the amount of therapeutic agent in one volume portion of the core may differ by no more than about 20% from the amount of therapeutic agent in any other same volume portion of the core. For example, the amount of therapeutic agent in one volume portion of the core may differ by no more than about 10% from the amount of therapeutic agent in any other same volume portion of the core. For example, the amount of therapeutic agent in one volume portion of the core may differ by no more than about 5% from the amount of therapeutic agent in any other same volume portion of the core. Additionally, the concentration of the therapeutic agent in one volumetric portion of the core may be the same as any other same volumetric portion of the core, including in certain embodiments, embodiments wherein the agent is present as a homogeneous, homogeneous dispersion, and in embodiments wherein the agent is present as a solid or liquid inclusion throughout the matrix.

In various embodiments, the core may comprise an excipient comprising a phospholipid, a polyol, a polyethylene glycol, or any combination thereof. The excipient may modulate the release rate of the agent into the tissue (after placement within or near the tissue), or the excipient may alter the pharmacokinetic properties of the agent within the tissue, such as tissue residence time or penetration. For example, excipients may increase the degree of corneal penetration of agents released in the tear fluid of the ocular surface.

For example, the excipient may modulate the release rate of the drug, where the release rate is the rate of release of the therapeutic agent from an implant disposed in the punctum of the patient into the tear fluid, and the release rate is increased compared to the release rate in the absence of the excipient. More specifically, the release rate may increase over a period of about 1 to about 10 days after placement of the ocular implant within the punctum.

In various embodiments, when the therapeutic agent inclusions in the core are present in the matrix, the inclusions are of a more uniform size and are more uniformly dispersed in the matrix than the size and dispersion of the inclusions within the matrix in an equivalent core having an equivalent drug loading in the absence of an excipient.

In some embodiments, the excipient may increase the achievable drug loading such that the therapeutic agent is present in the matrix of the drug core at a higher loading or concentration in the presence of the excipient than would be achievable with a reasonably homogeneous dispersion in a comparable matrix in the absence of the excipient. As discussed above, high homogeneity of dispersion of the agent within the matrix is desirable, and cores that do not maintain adequate uniformity are not suitable for use as controlled or sustained release implants in living tissue. At higher drug loadings within the matrix, it is difficult to achieve substantially uniform dispersion of the drug within the matrix. Phase separation may occur. Referring to figures 13 and 14, it can be seen that cores containing latanoprost in cross-linked MED6385 silicone (prepared as described in example 2 ("control"), without excipients) exhibited a significant heterogeneity of latanoprost dispersion in the presence of cores of the present invention without excipients (figure 14). After extruding the silicone/latanoprost mixture into a polyimide sheath, discrete droplets of latanoprost were observed within the filled sheath. At comparable latanoprost loading within the same matrix, it was surprisingly found that the presence of the excipients DMPC or EPG resulted in the maintenance of a substantially uniform or homogeneous dispersion of latanoprost droplets within the matrix, such that the droplets visible to the naked eye were not visible, as shown in fig. 13.

In various embodiments, the excipient may be adapted to enhance corneal penetration of the therapeutic agent, or may be adapted to enhance retention of the therapeutic agent on the ocular surface or within ocular tissue. For example, the excipient may act as a penetration enhancer for a drug (such as latanoprost) into corneal tissue where the drug may exert its anti-glaucoma effect. Alternatively or additionally, the excipient may delay tear fluid clearance of the agent from the ocular surface, such as by increasing absorption of the drug on the corneal surface.

In various embodiments, the core of the implant of the present invention may comprise a phospholipid. The phospholipid may be a negatively charged phospholipid, for example, the phospholipid may be Egg Phosphatidylglycerol (EPG). EPG is a negatively charged lipid because the molecule contains an anionic phosphate group, but no cationic group. As shown in figures 9 and 10, it has been unexpectedly found that EPG increases the rate of release of latanoprost from the silicone matrix (formulation 2) into aqueous media, such as tear fluid, compared to the rate of release of latanoprost in the absence of excipients.

In various embodiments, the phospholipid may comprise a zwitterionic phospholipid containing a fatty acyl moiety of 16 carbon atoms or less. For example, the phospholipid excipient may be Dimyristoylphosphatidylcholine (DMPC). DMPC is a zwitterionic phospholipid because the molecule contains a negatively charged phosphate oxygen atom and a positively charged choline (trimethyl ammonium carbinol) moiety. Formulation 1 (example 1) contained DMPC and as can be seen from figures 9 and 10, DMPC increased the rate of release of latanoprost from the silicone matrix into an aqueous medium such as tear fluid compared to the rate of release of latanoprost in the absence of excipient.

In various embodiments, the excipient may be a polyol, such as glycerol. Figure 9 shows the rate of release of latanoprost from a cross-linked silicone matrix in the presence of 10% glycerol. It is evident that this rate is increased compared to the control.

In various embodiments, the excipient may include polyethylene glycol, such as PEG-400. Figure 9 shows the rate of release of latanoprost from a cross-linked silicone matrix in the presence of 5% PEG 400. It is evident that this rate is increased compared to the control.

In various embodiments, the present invention provides a method of making an ocular implant of the present invention, wherein the matrix polymer is a cross-linked silicone, the therapeutic agent is latanoprost, and the excipient comprises a phospholipid, a polyol, or a polyethylene glycol, or any combination thereof, the method comprising:

combining silicone part a, latanoprost and excipient under agitation, then

Adding the silicone part B and the crosslinker under stirring, and then

Extruding the mixture under pressure (e.g., at low temperature) into a tube containing an impermeable substance, and then

Curing the mixture in the tube, and then

The cured, filled tube is cut into segments, each segment being a core for an implant.

In various embodiments, the crosslinking agent may be tetraethylorthosilicate.

In various embodiments, the phospholipid is a phosphatidylglycerol, or is dimyristoylphosphatidylcholine.

In various embodiments, the polyol is glycerol.

In various embodiments, the polyethylene glycol is PEG 400.

In various embodiments, for a core of an implant made by the method of the present invention, the release rate is the release rate of the therapeutic agent from the implant disposed in the punctum of the patient to tear fluid, and the release rate is increased compared to the release rate in the absence of the excipient. For example, the release rate may increase over a period of about 1 to about 10 days after placement of the ocular implant within the punctum.

In various embodiments, for the core of an implant made by the method of the present invention, the therapeutic agent is present in the core matrix at a higher loading or concentration in the presence of the excipient than would be achievable with a reasonably homogeneous dispersion in a comparable matrix in the absence of the excipient.

In various embodiments, for cores of implants made by the methods of the invention, the therapeutic agent inclusions in the core are present in the matrix, the inclusions are of a more uniform size and are more uniformly dispersed in the matrix than the size and dispersion of the inclusions in the matrix in an equivalent core with a comparable drug loading in the absence of excipients.

In various embodiments, for the core of the implant made by the method of the present invention, the excipient is adapted to enhance corneal penetration of the therapeutic agent, or to enhance retention of the therapeutic agent on the ocular surface or within ocular tissue.

In various embodiments, for a core of an implant made by the method of the present invention, the amount of therapeutic agent in one volume fraction of the matrix differs from the amount of therapeutic agent in any other same volume fraction of the matrix by no more than about 30%, or by no more than about 20%, or by no more than about 10%, or by no more than about 5%.

The foregoing detailed description includes references to the accompanying drawings, which form a part hereof. Which show by way of illustration specific embodiments in which the invention may be practiced. These embodiments are also referred to herein as "examples".

All publications, patents, and patent documents mentioned in this document are incorporated by reference in their entirety into this specification, as if individually incorporated by reference. In the event of inconsistent usages between this document and those documents so incorporated by reference, the usage in the incorporated references should be considered supplementary to the usage in this document; for inconsistent inconsistencies, this document controls.

Concentrations, amounts, etc. of the various components of the invention are often presented herein in a range format. The description in scope is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, descriptions such as a range of about 42 micrograms to about 44 micrograms of latanoprost should be considered as having specifically disclosed sub-ranges, e.g., about 42 micrograms to about 43 micrograms, about 43 micrograms to about 44 micrograms, etc., as well as individual numbers within that range, e.g., 42 micrograms, 43 micrograms, and 44 micrograms. Such a configuration is applicable to all aspects of this patent document, regardless of the breadth of the range.

The above description is intended to be illustrative, and not restrictive. For example, the above-described embodiments (or one or more features thereof) may be used in combination with each other. For example, other embodiments may be used by those of ordinary skill in the art upon reading the above description. Moreover, in the foregoing detailed description, various features may be grouped together to simplify the present disclosure. This should not be interpreted as implying that an unclaimed disclosed feature is essential to any claim. Rather, inventive subject matter may lie in less than all features of a particular disclosed embodiment. Thus the following claims are hereby incorporated into the detailed description, with each claim standing on its own as a separate embodiment. The scope of the invention should be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled.

Abbreviations used herein include:

the following non-limiting examples may further illustrate the invention.

Example 1

An open-label (open-label) phase 2 trial of a latanoprost punctum plug delivery system (L-PPDS) lacrimal implant containing a core comprising 44 microclatanoprost was performed in subjects with Ocular Hypertension (OH) or Open Angle Glaucoma (OAG). After a washout period appropriate from the previous treatment (or no washout if first treated), approximately 40 subjects were worn (fit) with L-PPDS and subsequently evaluated for safety and efficacy for 12 weeks.

Administering to the subject following treatment with L-PPDS(Latanoprost ophthalmic solution, 0.005%) for 4 weeks a regression (run-out) phase was performed to confirm the response to topical prostaglandin treatment.

Brief introduction:

the L-PPDS formulation in this example contained 44 μ g of latanoprost and used a proprietary punctum plug design that had been designed to have improved retention characteristics. This is an open label test to collect preliminary safety and efficacy data for 44 μ g strength L-PPDS consisting of a new punctal plug design.

The total amount of latanoprost (44. mu.g) in L-PPDS used in this experiment corresponded to 29 dropsAnd is intended to be delivered within a few months.

Test protocol and evaluation:

the test and treatment lacrimal duct suppository consists of medical-grade organic silicon, polyimide and cyanoacrylate medical-grade adhesive.

At the start of the trial, each subject had L-PPDS inserted bilaterally into the lower punctum and examined later at each visit. At week 12 visit, L-PPDS was removed. After termination of L-PPDS treatment, subjects were assignedAnd instructs to drop 1 drop into each eye at night.(Latanoprost ophthalmic solution, 0.005%) was supplied as a 2.5mL solution. Is a commercially available product.Comprises benzalkonium chloride (antiseptic), sodium chloride, sodium dihydrogen phosphate monohydrate, anhydrous disodium hydrogen phosphate and water.

IOP has a well characterized pattern of diurnal patterns (secondary pattern) that peaks in the early morning hours (Liu et al 1999); thus, the time point of IOP measurement in this experiment was fixed. In addition, in this trial, diurnal IOP was monitored at selected visits to gather information about the effect of sustained release L-PPDS on IOP patterns. The primary and secondary IOP variables were summarized using mean, standard deviation, minimum, median, maximum and 95% Confidence Intervals (CI). In addition, frequency distributions of some IOP variables can also be prepared.

The relationship between changes in IOP from baseline and other variables such as TBUT, tear volume or other statistical features is evaluated. Differences in IOP variation from baseline between treatment groups were summarized using mean, standard deviation, minimum, maximum and 95% CI.

4 weeks preliminary results:

60 patients diagnosed with OAG/OH were enrolled with a mean age of 65 years (30-90 years). The mean baseline IOP for the patient population was 24.5 ± 2.4 mmHg. Of the 60 patients enrolled, 47 (78%) completed a 4-week follow-up, IOP measurements were taken at week 4, and L-PPDS was retained in both eyes for 4 weeks. In this interim data analysis, 13 patients (22%) discontinued L-PPDS treatment early: 11 patients (18%) were due to loss of L-PPDS and 2 patients (3%) were due to inadequate IOP control.

Preliminary 4-week intermediate results from an ongoing phase II clinical trial of the 44-micron latanoprost punctum plug delivery system (L-PPDS) indicated that at week 4 visit, the mean change from baseline in intraocular pressure (IOP) was-3.52 ± 2.77mmHg (ranging from-8.9 to 3.5, excluding 2 subjects who had lost or had removed L-PPDS from both eyes). 36% of patients have a reduction in IOP from baseline of greater than or equal to 5 mmHg.

The L-PPDS was well tolerated during the test period. Based on the 4-week preliminary data, the total adverse events ranged from 1.7% to 11.7%. The most common adverse events were ocular itching (common to the initial punctal plug wear, usually partially accommodated) and ocular irritation (11.7% and 8.3%, respectively). Increased lacrimation (tear production) and ocular discomfort were reported in 6.7% and 1.7% of patients using 44- μ g L-PPDS. Superficial punctate keratitis was reported in 1 patient (1.7%). No conjunctival or ocular congestion was observed. Week 4 patients with 44 micrograms of L-PPDS-reported comfort and tear scores were as follows: 88% of patients rated L-PPDS comfort as ` unconscious ` or ` weakly conscious ` and 76% of patients rated lacrimation as ` none `.

TABLE 2

Adverse ocular events	Percentage of subjects (N ═ 60)
		Increased lacrimation	4(6.7)
Eye pruritus (pruritus)＊＊	7(11.7)
		Discomfort of the eye＊＊	1(1.7)
Eye irritation	5(8.3)
		Conjunctival congestion	0
Bleeding of conjunctiva	2(3.3)
		Blurred vision	2(3.3)
Device movement	0
		Feeling of foreign body	0
Granuloma	0
		Superficial punctate keratitis	1(1.7)
All others	＜2

^＊＊Usually partially adapted to the initial wearing of the punctum plug

TABLE 3

Example 2

An open label, randomized, parallel group trial was performed in approximately 40 subjects with Ocular Hypertension (OH) or Open Angle Glaucoma (OAG). After a washout period appropriate from the previous treatment (no washout if first treated), subjects were enrolled and randomized (1: 1) into trial treatments using either the 44 microclatanoprost punctum plug delivery system (L-PPDS) or the 44 microclatanoprost punctum plug delivery system + benzalkonium chloride-containing artificial tears (L-PPDS + AT-BAK). Subjects were followed for 6 weeks to monitor safety and efficacy.

Administering to the subject following treatment with L-PPDS(Latanoprost ophthalmic solution, 0.005%) for a 4-week washout (run-out) period to confirm response to topical prostaglandin treatment.

Brief introduction:

the L-PPDS formulation in this example contained 44 μ g of latanoprost and used a proprietary punctum plug design that had been designed to have improved retention characteristics. This is an open label test to collect preliminary safety and efficacy data for 44 μ g strength L-PPDS consisting of a new punctal plug design.

The total amount of latanoprost (44. mu.g) in L-PPDS used in this experiment corresponded to 29 dropsAnd is intended to be delivered within a few months.

Another objective of this assay is to test the effect of parallel administration of BAK-containing artificial tears (AT-BAK) on the IOP response of, for example, L-PPDS.

Test protocol and evaluation:

each subject had L-PPDS inserted bilaterally into the lower punctum. Dispensing an artificial tear solution containing the preservative BAK to subjects randomized to receive HypoTears^TM(preserved with 0.01% BAK; Novartis Ophthalmics) as an adjunct treatment to L-PPDS. Subjects were instructed to instill 2 drops into each eye, at least 5 minutes apart, 2 times per day: every morning and every evening. During the trial, the subject may not be administered any other IOP lowering drug or other lubricant or artificial tears. Other products containing benzalkonium chloride are prohibited.

The primary IOP efficacy variable is the change in IOP from baseline. The secondary IOP efficacy variable is IOP and the percentage change in IOP from baseline.

Preliminary results at 6 weeks:

65 subjects were screened for enrollment, and of these, 40 subjects were randomized to treatment trials with L-PPDS (n-20) alone or L-PPDS + AT-BAK (n-20).

In the L-PPDS-only treatment group, 11 subjects completed the trial treatment session and 9 subjects prematurely discontinued treatment for the following reasons: L-PPDS was detached from both eyes (5 subjects), inadequate IOP control (2 subjects) and other causes (2 subjects). The subjects in the L-PPDS + AT-BAK treatment group were similarly treated, with 11 subjects completing the trial treatment period and 9 subjects prematurely discontinued treatment. The reasons for premature discontinuation of treatment in the L-PPDS + AT-BAK group were: L-PPD detached from both eyes (7 subjects), improper IOP control (1 subject) and other causes (1 subject). Table 4 shows the preliminary IOP results (ITT) of this experiment.

TABLE 4 Primary mean change from baseline IOP and percent change from baseline IOP (ITT)

Preliminary analysis of the data indicated that the mean IOP was reduced from baseline in both treatment groups throughout the experiment. In the L-PPDS treated group alone, a decrease of about 3-4mmHg from baseline was observed, and in the L-PPDS + AT-BAK group, a decrease of about 4-5mmHg was observed. This is equivalent to: the percent reduction from baseline was about 12% to 16% in the L-PPDS alone group and 17% to 19% in the L-PPDS + AT-BAK treated group.

According to preliminary analysis, the most common adverse events reported in this trial were local adverse events known to be associated with topical ocular latanoprost, such as conjunctival congestion and ocular pruritus (the incidence of each event is 10%). No systemic safety issues were observed.

Preliminary results indicate that there is no higher incidence of ocular itching in subjects treated concurrently with L-PPDS and AT-BAK (15% of subjects and 7 events, relative to 5% of subjects and 1 event). In subjects treated with L-PPDS alone, ocular itching was not considered to be associated with treatment.

Example 3

The partially masked test was performed in approximately 10 evaluable subjects with Ocular Hypertension (OH) or Open Angle Glaucoma (OAG). After a washout period appropriate from the previous treatment (or no washout if first treated), the subject was fitted with a latanoprost punctum plug delivery system (L-PPDS) to the upper and lower punctum of both eyes. In each subject, the right eye received a total latanoprost dose of 44 μ g (L-PPDS with a latanoprost dose of 44 μ g in the lower punctum, a punctum without a drug core tied in the upper punctum), and the left eye received a total latanoprost dose of 65 μ g (L-PPDS with a latanoprost dose of 44 μ g in the lower punctum, L-PPDS with a latanoprost dose of 21 μ g in the upper punctum). Subjects were followed for 6 weeks to monitor safety and IOP response.

During the test, the L-PPDS and the punctal plugs, which did not contain the drug core, were not replaced. The subject remained in the trial as long as L-PPDS and/or punctum plugs remained in the upper and lower punctum of one eye. Administering to the subject following treatment with L-PPDS(Latanoprost ophthalmic solution, 0.005%) in order to confirm the response to topical prostaglandin treatment.

Brief introduction:

this example is a partially masked experiment to collect preliminary IOP response data at a higher latanoprost dose of 65 μ g.

The purpose of this test was to evaluate the presence of 65. mu.g of latanoprost (equivalent to about 43 drops)Amount of (1) of L-PPDS. The trial included a 6 week follow-up, so the amount of latanoprost in the L-PPDS was only slightly lower than the amount of aptata the subject would receive over the same period of timeAmount in number of drops. This experiment used L-PPDS in two puncta (44 μ g latanoprost in the lower puncta and 21 μ g latanoprost in the upper puncta) to achieve a 65 μ g latanoprost dose. This test also compares 65 muThe g latanoprost dose and the 44 μ g latanoprost dose, simultaneously occluding 2 puncta, to alleviate any effect of double punctal occlusion on IOP response.

Test protocol and evaluation:

This is a partially masked test, as IOP is measured by an independent evaluator. Such masking is intended to reduce preference when comparing different latanoprost doses administered. Otherwise, the trial is open label (i.e., the primary trial person and subject are aware of the treatment administered).

IOP variables were analyzed by latanoprost dose and differences between both eyes of the same subjects. Analysis of Intent To Treat (ITT) data sets included all data from all subjects with at least 1 follow-up IOP measurement. For analysis using the EVAL (EVAL) data set, if L-PPDS is lost (spontaneously extruded or dislocated) at any time, IOP data from the eye is excluded from the first loss. If L-PPDS is removed by the test person, IOP data from the eye is excluded from the visit after removal.

The primary and secondary IOP variables were summarized using mean, standard deviation, minimum, median, maximum and 95% CI. In addition, frequency distributions of some IOP variables can also be prepared.

Example 4

An open-label assay for latanoprost punctum plug delivery system (L-PPDS) containing 81 mccarat prost was performed in subjects with Ocular Hypertension (OH) or Open Angle Glaucoma (OAG). After a washout period appropriate from previous treatment (or no washout if first treated), approximately 40 subjects were subjected to L-PPDS and subsequently evaluated for safety and efficacy for 12 weeks.

Administering to the subject following treatment with L-PPDS(Latanoprost ophthalmic solution, 0.005%) for a 4-week washout (run-out) period to confirm response to topical prostaglandin treatment.

Brief introduction:

the L-PPDS formulation in this example contained 81 μ g of latanoprost and used a proprietary punctum plug design that has been designed to have improved retention characteristics. This is an open label test to collect preliminary safety and efficacy data for 81 μ g strength L-PPDS consisting of a new punctal plug design.

The total amount of latanoprost (81. mu.g) in the L-PPDS used in this test corresponded to 54 dropsAnd is intended to be delivered within a few months.

Test protocol and evaluation:

the test and treatment lacrimal duct suppository consists of medical-grade organic silicon, polyimide and cyanoacrylate medical-grade adhesive.

At the start of the trial, each subject had L-PPDS inserted bilaterally into the lower punctum and examined later at each visit. At week 12 visit, L-PPDS was removed. After termination of L-PPDS treatment, subjects were assignedAnd instructs to drop 1 drop into each eye at night.(Latanoprost ophthalmic solution, 0.005%) was supplied as a 2.5mL solution. Is a commercially available product.Comprises benzalkonium chloride (antiseptic), sodium chloride, sodium dihydrogen phosphate monohydrate, anhydrous disodium hydrogen phosphate and water.

If extrusion occurs during the trial, the subject may replace one L-PPDS in each eye. If a subject loses 2L-PPDS of the same eye, the eye will remain untreated and the subject is followed according to the schedule until week 6 (or the second L-PPDS of the contralateral eye is lost). At the discretion of the medical professional, the L-PPDS can be removed from the contralateral eye and immediately startedAnd (5) clearing and retreating.

IOP has a well characterized pattern of diurnal effusions, peaking several hours in the early morning (Liu et al 1999); thus, the time point of IOP measurement in this experiment was fixed. In addition, in this trial, diurnal IOP was monitored at selected visits to gather information about the effect of sustained release L-PPDS on IOP patterns. The primary and secondary IOP variables were summarized using mean, standard deviation, minimum, median, maximum and 95% CI. In addition, frequency distributions of some IOP variables can also be prepared.

The relationship between changes in IOP from baseline and other variables such as safety, TBUT, tear volume or other statistical features was evaluated. Differences in IOP variation from baseline between treatment groups were summarized using mean, standard deviation, minimum, maximum and 95% CI.

Example 5

Production of latanoprost/silicone mixture:

the silicone formulation (MED6385) is a two-part system. Part a contains silicone and a crosslinker, while part B contains a tin catalyst to promote crosslinking. The 2 fractions were combined in a final ratio of 200: 1 (fraction A: fraction B). The required amount of latanoprost, selected excipients (DMPC or EPG), cross-linker, MED6385 parts a and B were weighed onto a slide and mixed using a plastic mini-spatula for about 2 minutes. The amounts used in the preparation of the specific examples are shown below.

Preparation of syringe extrusion system:

the tubing sections were connected in series (threaded) through a plastic luer fitting and bonded in place using a cyanoacrylate adhesive. A 1mL syringe was modified by cutting the plunger tip flat. The previously assembled tubing/connector segments were inserted into the syringe barrel and connected in series through the luer outlet and mounted in place.

Extrusion into a polyimide tube:

after the silicone/latanoprost mixing was complete, the mixture was loaded into the barrel of a syringe extrusion system. The plunger is inserted and excess air is removed. The syringe is then loaded into the compression device.

After installation, the extrusion system was activated and the silicone latanoprost mixture was extruded down the length of the polyimide tube. After the mixture reached the bottom of the tube, the tube was cut with a safety blade and clamped at both ends.

And (3) curing:

the clamped tube sections were placed in a humidity chamber to be cured.

Release characteristics:

samples (including those shown in figures 9-12) were analyzed for elution by immersion in PBS (phosphate buffered saline) elution medium. The temperature was maintained at 37 ℃ with shaking at 100 cpm. The elution medium was changed daily for the first 2 weeks (except weekends) and weekly thereafter. The elution medium samples were analyzed by reverse phase chromatography. Samples for HPLC analysis were prepared as follows: add 200. mu.L of internal standard solution (2.4. mu.g/ml butylated hydroxyanisole in isopropanol) and vortex mix. The amount of eluted latanoprost was determined using a Waters SunFire C18, 3.5 μm, 3.0x100mm column and the following detection conditions using reverse phase HPLC uv detection: flow rate of 1.0mL/min, injection volume of 200 μ L, wavelength detected at 210nm, column temperature set point at 50 ℃ using a solvent gradient containing 0.1% aqueous phosphoric acid (mobile phase a) and ACN (mobile phase B) (time zero 63% mobile phase a, 37% mobile phase B, time 4.9 min 35% a, 65% B, time 5 min 63% a, 37% B) over a 6 min run time.

Latanoprost/silicone L-PDDS formulation 1:

^＊density 1.29 ^＊＊Density 0.916

Latanoprost/silicone L-PDDS formulation 2:

^＊density 1.29^＊＊Density 0.916

Figure 10 shows the release profile over time for both formulations compared to the formulation without excipients.

Example 6-drug loading comparison with and without excipients:

silicone part B, crosslinker, API and excipients (DMPC or EPG) were weighed onto glass slides. The materials were mixed for 2-5 minutes until thoroughly mixed. Silicone part a was then added and mixed for 2 minutes. The mixture was extruded into a polyimide tube at about 5 ℃. The extrudate is then solidified (extrusion).

The results are shown in FIG. 13.

Comparison:

the components (silicone parts a and B, crosslinker and API) were weighed onto a glass slide. The materials were mixed for 2 minutes and then extruded into polyimide tubing at about 5 ℃. The extrudate is then solidified.

The results are shown in FIG. 14.

Example 7-open label phase 2 testing of formulations 1 and 2 of latanoprost punctum plug delivery system:

a phase 2 trial of an open label of a latanoprost punctum plug delivery system (L-PPDS) lacrimal implant containing a drug core comprising 95 micrograms (μ g) of latanoprost was performed in subjects with Ocular Hypertension (OH) or Open Angle Glaucoma (OAG). The L-PPDS used was one of two formulations-formulation 1 or formulation 2. After a washout period appropriate from the previous treatment (or no washout if first treated), about 30 subjects were wearing L-PPDS formulation 1 and about 30 other subjects were wearing L-PPDS formulation 2 (total of about 60 subjects).

Subjects were evaluated for safety and efficacy for 6 weeks. Monitoring safety by one or more of: intraocular pressure (IOP), Snellen corrected good visual acuity (BCVA), biomicroscopy, subject lacrimation and comfort assessment, automated visual field examination, and ophthalmoscopy. Tear characteristics were evaluated throughout the experiment using Schirmer's and tear film break-up time (TBUT) tests. Ocular surface evaluation was performed using lissamine green staining. In addition, photographs were taken at baseline to record the placement of the L-PPDS.

Treating with L-PPDSAfter treatment, the subject is administered(latanoprost ophthalmic solution, 0.005%) 4 weeks washout period to confirm response to topical prostaglandin treatment.

Brief introduction:

the L-PPDS formulation in this example contained 95 μ g of latanoprost and used a proprietary punctum plug design that has been designed to have improved retention characteristics. This is an open label test to collect preliminary safety and efficacy data for 95 μ g strength L-PPDS consisting of the new punctal plug design and formulations 1 and 2.

The total amount of latanoprost (95. mu.g) in the L-PPDS used in this test corresponded to approximately 62-63 dropsAnd is intended to be delivered within a few months.

Test protocol and evaluation:

the test and treatment lacrimal duct suppository consists of medical-grade organic silicon, polyimide and cyanoacrylate medical-grade adhesive.

At the start of the trial, each subject had L-PPDS inserted bilaterally into the lower punctum and examined later at each visit. If the L-PPDS is spontaneously expressed, a maximum of 1L-PPDS change per subject is allowed. At week 6 visit, L-PPDS was removed.

Subjects received trial treatment on day 0 and were followed at weeks 1, 2, 3, 4 and 6.

The primary efficacy variable is the change from baseline in IOP measurements.

Reference book eye

See Allen rc, medical management of glaucoma, see: albert DM, Jakobiec FA, eds. Principles and Practice of Ophthalmology Philadelphia, PA: WB Saunders and Co.; 1994: 1569-1588.

AlphaMed lacrimal implant[product label].Wauwatosaa，WI：AlphaMed.

American Academy of Ophthallogogy, Primary Open-AngleGlaucoma, Preferred Practice Pattern, san Francisco: american academy of Ophthematology, 2005. see in detail: http:// www.aao.org/ppp.2008, 10 month 22 day visit.

Anderson DR，Chauhan B，Johnson C，Katz J，Patella VM，DranceSM.Criteria for progression of glaucoma in clinical management and inoutcome studies.Am J Ophthalmol 2000；130(6)：827-829.

Anderson DR.Collaborative normal tension glaucoma study.CurrOpin Ophthalmol.2003；14(2)：86-90.

Bailey IL，Lovie JE.New design principles for visual acuity lettercharts.Am J Optom Physiol Opt 1976 Nov；53(11)：740-745.

Balaram M，Schaumberg DA，Dana MR.E fficacy and tolerabilityoutcomes after punctal occlusion with silicone plugs in dry eye syndrome.Am J Ophthalmol.2001；131(1)：30-36.

Baudouin C，Rouland JF，Nordmann JP，Bron A，Pelen F.Efficacyof first-or second-line latanoprost on intraocular pressure and ocularsymptoms in subjects with open-angle glaucoma or ocular hypertension[in French].J Fr Ophtalmol.2006；29(6)：615-624.

Bengtsson B，Heijl A.A long-term prospective study of risk factorsfor glaucomatous visual field loss in subjects with ocular hypertension.JGlaucoma.2005；14(2)：135-138.

Brown MM，Brown GC，Spaeth GL.Improper topicalself-administration of ocular medication among subjects with glaucoma.Can J Ophthalmol.1984：1；2-5.

Callender M，Morrison PE.A quantitative study of human tearproteins before and after adaption to non-flexible contact lenses.Am JOptom Physiol Opt.1974；51(12)：939-945.

Coleman AL.Glaucoma.Lancet 1999；354：1803-10.

Dasgupta S，Oates V，Bookhart BK，Vaziri B，Schwartz GF，Mozaffari E.Population-based persistency rates for topical glaucomamedications measured with pharmacy claims data.Am J Manag Care.2002；8(suppl 10)：S255-S261.

Dieselhorst M, Schaefer CP, besterien KM, et al, persisten and clinical oligonucleotides associated with lateronoptist and beta-blockmenopause: evidence from a European retroactive cohot study. EurJ Ophthalmol.2003; 13(suppl 4): S21-S29.

Fiscella RG，Geller JL，Gryz LL，Wilensky J，Viana M.Costconsiderations of medical therapy for glaucoma.Am J Ophthalmol.1999；128(4)：426-433.

Fremont AM, Lee PP, Mangione CM, et al, Patterns of card for open-angle glaucomma in managed card, Arch Ophthalmol.2003; 121(6): 777-783.

Fukano Y，Asada H，Kimura A，Kawazu K.Influence ofbenzalkonium chloride on the penetration of latanoprost into rabbitaqueous humor after ocular instillations.AAPS Journal.2006；8(S2).http://www.aapsj.org/abstracts/AM_2006/AAPS2006-001397.pdf.Accessed October 22，2008

Gordon MO, Beiser JA, Brandt JD, et al, The ocular hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. 120(6): 714 and 720; discission 829 and 830.

Gordon MO，Kass MA.The Ocular Hypertension Treatment Study：design and baseline description of the participants.Arch Ophthalmol1999；117(5)：573-583.

Goskonda VR，Hill RA，Khan MA，Reddy IK.Permeability ofchemical delivery systems across rabbit corneal(SIRC)cell line andisolated corneas：a comparative study.Pharm Dev Technol.2000；5(3)：409-416.

Gurwitz JH, Glynn RJ, Monane M, et al, Treatment for glaucoma: adherence by the elderly.am J Public health.1993; 83(5): 711-716.

Heijl A，Leske MC，Bengtsson B，Hyman L，Bengtsson B，Hussein M，for the Early Manifest Glaucoma Trial Group.Reduction of intraocularpressure and glaucoma progression：results from the Early ManifestGlaucoma Trial.Arch Ophthalmol.2002；120(10)：1268-1279.

Higginbotham EJ, Gordon MO, Beiser JA, et al, The Ocular Hypertension Treatment Study: topical medical delivery or prevenssprimary open-angle glaucoma in African American indiciduals, ArchOphalmol.2004; 122(6): 813-820.

Horwath-Winter J，Thaci A，Gruber A，Boldin I.Long-termretention rates and complications of silicone punctal plugs in dry eye.AmJ Ophthalmol.2007；144(3)：441-444.

Safety Information.Novartis Ophthalmics，EastHanover，NJ.http://www.miochol.org/hcp/products/hypotears-hcp-si.jsp.Accessed：October 22，2008

Javitt JC，Metrick S，Wang F：Costs of glaucoma in the UnitedStates.Invest Ophthalmol Vis Sci 1995；36：S429.

Kass MA，Gordon MO，Kymes SM.Incorporating the results of theOcular Hypertension Treatment Study into clinical practice.ArchOphthalmol.2005；123(7)：1021-1022.

Kass MA, Heuer DK, Higginbotham EJ, et al, The Ocular Hypertension Treatment Study: a random three decisions of the positive annular medium of the negative equilibrium deletion or previous of the negative absolute open-angle glaucoma, Arch Ophthalmol 2002; 120(6): 701-713.

Kim BM，Osmanovic SS，Edward DP.Pyogenic granulomas aftersilicone punctal plugs：a clinical and histopathologic study.Am JOphthalmol.2005；139(4)：678-684.

Kobelt-Nguyen G，Gerdtham UG，Alm A：Costs of treating primaryopen-angle glaucoma and ocular hypertension：a retrospective，observational two-year chart review of newly diagnosed subjects inSweden and the United States.J Glaucoma 1998；7：95.

Leibowitz HM, Krueger DE, Mauder LR, et al, the Framingham Eye Study monograph: the anatomical and anatomical study of cataracts, glaucomas, metabolic retentations, and visual access in a genetic disposition of 2631adults, 1973-1975.Surv Ophthalmol.1980; 24 (Suppl): 335-610.

Leonard R.Statistics on Vision Impairment：A Resource Manual(5thEdition).New York：Arlene R.Gordon Research Institute of LighthouseInternational；2002.

Leske MC，Heijl A，Hyman L，Bengtsson B，Komaroff E.Factors forprogression and glaucoma treatment：the Early Manifest Glaucoma Trial.Curr Opin Ophthalmol.2004；15(2)：102-106.

Leung EW，Medeiros FA，Weinreb RN.Prevalence of ocular surfacedisease in glaucoma subjects.J Glaucoma.2008；17(5)：350-355.

Lichter PR，Musch DC，Gillespie BW，et al，and the CIGTS StudyGroup.Interim clinical outcomes in the Collaborative Initial GlaucomaTreatment Study comparing initial treatment randomized to medicationsor surgery.Ophthalmology.2001；108(11)：1943-1953.

Liu JHK, Kripke DF, Twa MD, et al, Twenty-four-hour pattern of intraocular compression in the imaging position, invest Ophthalmol Vis Sci.1999: 40(12): 2912-2917.

Maier PC，Funk J，Schwarzer G，Antes G，Falck-Ytter YT.Treatment of ocular hypertension and open angle glaucoma：meta-analysis of randomised controlled trials.BMJ.2005；331(7509)：134.Epub 2005 Jul 1.

See Mindel js. pharmacokinetics, see: tasman W, Jaeger EA, eds Duane's Foundations of Clinical ophthalmology. Vol.3: lippincott Williams & Wilkins, 1995: 1-17.

Musch DC，Lichter PR，Guire KE，Standardi CL，The CIGTS StudyGroup.The Collaborative Initial Glaucoma Treatment Study Design，Methods，and Baseline Characteristics of Enrolled Subjects.Ophthalmology 1999；106：653-662.

Nakamura T, Yamada M, Teshima M, et al, electrophysiology biology analysis of right joint path of jaw core area with optical molecular analysis issues, biol Pharm Bull.2007; 30(12): 2360-2364.

Nordstrom BL，Friedman DS，Mozaffari E，Quigley HA，WalkerAM.Persistence and adherence with topical glaucoma therapy.Am JOphthalmol.2005；140(4)：598-606.

Norell SE， PA.Self-medication with pilocarpine amongoutsubjects in a glaucoma clinic.Br J Ophthalmol.1980Feb；64(2)：137-41.

O′Donoghue EP，and the UK and Ireland Latanoprost Study Group.A comparison of latanoprost and dorzolamide in subjects with glaucomaand ocular hypertension：a 3 month，randomised study.Br J Ophthalmol.2000；84：579-582.

Osterberg L，Blaschke T.Adherence to Medication.N Engl J Med.2005：353(5)：487-497.

Parrish RK，Palmberg P，Sheu WP，XLT Study Group.Acomparison of latanoprost，bimatoprost，and travoprost in subjects withelevated intraocular pressure：a 12-week，randomized，masked-evaluatormulticenter study.Am J Ophthalmol.2003；135(5)：688-703.

Patel SS，Spencer CM.Latanoprost.A review of its pharmacologicalproperties，clinical efficacy and tolerability in the management ofprimary open-angle glaucoma and ocular hypertension.Drugs Aging.1996；9(5)：363-378.

Pawar PK，Majumdar DK.Effect of formulation factors on in vitropermeation of moxifloxacin from aqueous drops through excised goat，sheep，and buffalo corneas.AAPS PharmSciTech.2006；7(1)：E13.

Preferred practice pattern - Primary Open-Angle Glaucoma.American Academy of Ophthalmology.(Limited Revision).2005.

Quigley HA：The number of persons with glaucoma worldwide.Br JOphthalmol 1996；80：389.

Reardon G，Schwartz GF，Mozaffari E.Subject persistency withpharmacotherapy in the management of glaucoma.Eur J Ophthalmol.2003；13(suppl 4)：S44-S52.

Regnier, et al, Ocular Effects of Topical 0.03% Latanoprost solution in Normotive Feline eyes.vet Ophthalmol 2006; 9(1): 39-43.

Rossetti L, Gandolfi S, Traverso C, et al, An evaluation of the rate of nonresponsors to latenoprost therapy.J. Glaucoma.2006: 15(3): 238-243.

Rouland JF，Berdeaux G，Lafuma A.The economic burden ofglaucoma and ocular hypertension：implications for subject management：a review.Drugs Aging 2005；22(4)：315-321.

Sakamoto A，Kitagawa K，Tatami A.Efficacy and retention rate oftwo types of silicone punctal plugs in subj ects with and withoutSyndrome.Cornea.2004；23(3)：249-254.

Scholz M，Lin JE，Lee VH，Keipert S.Pilocarpine permeabilityacross ocular tissues and cell cultures：influence of formulationparameters.J Ocul Pharmacol Ther.2002；18(5)：455-468.

Schwartz GF，Reardon G，Mozaffari E.Persistency with latanoprostor timolol in primary open angle glaucoma suspects.Am J Ophthalmol.2004；137(suppl 1)：S13-S16.

Shaya FT，Mullins CD，Wong W，Cho J.Discontinuation rates oftopical glaucoma medications in a managed care population.Am JManag Care.2002；8(suppl 10)：S271-S277.

Silliman NP.Xalatan Ophthalimic Solution 0.005％(50mg/mL)(Pharmacia)06/06/1996 Approval：Statistical Review.1995.

Spooner JJ, Bullano MF, Ikeda LI, et al, Rates of discontination and change of glaucopia therapy in a managed care setting. am J MahagCare.2002; 8(suppl 10): S262-S270.

The AGIS Investigators.The Advanced Glaucoma InterventionStudy(AGIS)：7.The relationship between control of intraocular pressureand visual field deterioration.Am J Ophthalmol.2000；130(4)：429-440.

Thomas JV. Primary open angle glaucoma. see: albert DM, Jakobiec FA, eds. Principles and Practice of Ophthalmology Philadelphia, PA: WB Saunders and Co.; 1994: 1342-1345.

Thylefors B，Negrel A-D，Pararajasegaram R，Dadzie KY：Globaldata on blindness.Bull World Health Org 1995；73：115-121.

Touitou，Elka，Barry，Brian W.Enhancement in Drug Delivery.Taylor & Francis Group；2007：527-548.

Urquhart J.The odds of the three nons when an aptly prescribedmedicine isn′t working：non-compliance，non-absorption，non-response.Br J Clin Pharmacol.2002；54(2)：212-220.

Waldock A，Snape J，Graham CM.Effects of glaucoma medicationson the cardiorespiratory and intraocular pressure status of newlydiagnosed glaucoma subjects.Br J Ophthalmol.2000；84(7)：710-713.

Whitcup SM, et al, A random, double masked, multicenter three-dimensional composition and time for the treatment of glaucoma and acetic high tension. Br J Ophthalmol 2003; 87: 57-62.

Winfield AJ, et al, A study of the house of non-complex by systematic objects expressed eyedrops, Br J Ophthalmol.1990 Aug; 74(8): 477-80.

Woodward DF, et al, pharmaceutical charateristic of a NovelAntiglaucoma Agent, (AGN 192024). J Pharmacology and Experimental therapeutics 2003; 305(2): 772-785.

(latanoprost ophthalimic solution)(50μg/mL)ProductMonograph.Pfizer Canada Inc.；2003.http://www.pfizer.ca/english/our％20products/prescription％20pharmaceuticals/default.asps＝1&id＝18&doc is the annual graph.2008, day 10 and day 22.

(latanoprost ophthalimic solution)(50μg/mL)ProductMonograph.Pfizer Canada Inc.；2003.http://www.pfizer.ca/english/our％20products/prescription％20pharmaceuticals/default.asps＝1&id＝18&doc is the annual graph.2008, day 10 and day 22.

(latanoprost ophthalimic solution)0.005％(50μg/mL)prescribing information.Division of Pfizer Inc.New York，NY：Pharmacia &Upjohn Company; http:// www.xalatan.com/consumer/descriscrinbingfo. asp.2007, month 10, day 1 visit.

Claims (23)

1. An implant configured for placement within or adjacent to a body cavity, tissue, tube or fluid, the implant comprising:

a core, the core comprising:

(a) a matrix comprising a non-biodegradable polymer;

(b) a therapeutic agent dissolved or dispersed in the matrix, and

(c) an excipient dissolved or dispersed within the matrix, the excipient configured for any one of the following uses:

(1) modulating the release rate of the therapeutic agent into the body cavity, tissue, tube, or fluid as compared to an equivalent release rate in the absence of the excipient;

(2) increasing the loading of the therapeutic agent substantially uniformly dissolved or dispersed within the matrix as compared to an equivalent loading of the therapeutic agent substantially uniformly dissolved or dispersed in the absence of the excipient;

(3) increasing retention of the therapeutic agent at or near a site of release in vivo, or increasing penetration of the therapeutic agent into adjacent body tissue, or both, as compared to retention or penetration from a comparable implant in the absence of the excipient, or both;

or any combination thereof.

2. The implant of claim 1, wherein the implant is an ocular implant adapted for passage through a punctum and placement within a lacrimal canaliculus of a human eye for release of a therapeutic agent from the implant.

3. The implant of claim 1, wherein the therapeutic agent is substantially uniformly and homogeneously dissolved in the matrix, or the therapeutic agent at least partially forms solid or liquid inclusions having an average diameter of less than 50 microns, the inclusions being substantially uniformly dispersed in the matrix on a sub-millimeter scale.

4. The implant of claim 1, wherein the matrix comprises a silicone or polyurethane polymer.

5. The implant of claim 1, further comprising an implant body having a lumen and a sheath partially surrounding the core, at least a portion of the sheath being intermediate the surface of the core and the wall of the implant body lumen.

6. The implant of claim 5, wherein the sheath comprises: a polymer comprising at least one of polyimide, PMMA, or PET, wherein the polymer is extruded or cast; or metals including stainless steel or titanium.

7. The implant of claim 5, wherein the implant body comprises first and second portions and extends from a proximal end of the first portion to a distal end of the second portion; the proximal end of the first portion defines a longitudinal proximal axis and the distal end of the second portion defines a longitudinal distal axis; the implant body is configured such that, when implanted in a lacrimal canaliculus, there is an angled intersection between the proximal and distal axes for biasing at least a portion of the implant body against at least a portion of the lacrimal canaliculus at or distal to a curvature of the lacrimal canaliculus; and wherein the second portion of the implant body comprises a longitudinal length having a measure of less than 4 times a longitudinal length of the first portion of the implant body.

8. The implant of claim 1, wherein the excipient comprises a phospholipid.

9. The implant of claim 8, wherein the phospholipid comprises dimyristoylphosphatidylcholine.

10. The implant of claim 4, wherein the core comprises 51.4 wt% silicone MED6385 part A, 39.1 wt% latanoprost, 0.4 wt% silicone MED6385 part B, 1.8 wt% crosslinker, and 7.3 wt% dimyristoylphosphatidylcholine, wherein part A contains silicone and crosslinker and part B contains tin catalyst.

11. The implant of claim 1, wherein the therapeutic agent is latanoprost, travoprost, bimatoprost, an anti-glaucoma agent, or a non-steroidal anti-inflammatory drug.

12. The implant of claim 1, wherein the core comprises 95 μ g latanoprost.

13. The implant of claim 1, wherein the core comprises about 46 μ g latanoprost.

14. The implant of claim 1, wherein the core comprises 5% to 65% by weight of a therapeutic agent that is latanoprost.

15. The implant of claim 1, wherein the core comprises 20% to 65% by weight of a therapeutic agent that is latanoprost.

16. A drug insert adapted to be positioned in or near an eye of a subject, the drug insert comprising:

a core, the core comprising:

a polymer matrix, and

an anti-glaucoma agent, wherein the anti-glaucoma agent is homogeneously dispersed in the matrix in an amount of about 42 micrograms, about 44 micrograms, about 65 micrograms, or about 81 micrograms, and wherein the amount of the anti-glaucoma agent in one volume portion of the drug insert is similar to the amount of the anti-glaucoma agent in any other same volume portion of the drug insert.

17. The drug insert of claim 16 wherein the polymer matrix comprises a silicone or polyurethane polymer.

18. The drug insert of claim 16 wherein the anti-glaucoma agent comprises a prostaglandin analog.

19. The drug insert of claim 18 wherein the prostaglandin analog is latanoprost.

20. The drug insert of claim 19 wherein the latanoprost is about 46 micrograms.

21. The drug insert of claim 19 wherein the latanoprost is 95 micrograms.

22. The drug insert of claim 16 wherein the anti-glaucoma agent is latanoprost, travoprost, bimatoprost, an anti-glaucoma agent, or a non-steroidal anti-inflammatory drug.

23. A sustained release ophthalmic formulation comprising:

51.4 wt% silicone MED6385 part a containing silicone and crosslinker;

0.4 wt% silicone MED6385 part B, which contains tin catalyst;

39.1 wt% latanoprost;

1.8 wt% crosslinker; and

7.3 wt.% dimyristoylphosphatidylcholine.