HK1158951A - Sustained release delivery of active agents to treat glaucoma and ocular hypertension - Google Patents

Description

Sustained release delivery of active agents for the treatment of glaucoma and ocular hypertension

Priority declaration

Priority benefits of U.S. provisional patent application serial No. 61/052,068 entitled "stationary Release Delivery of Latanoprost to Treat Glaucoma" filed on 9.5.2008, U.S. provisional patent application serial No. 61/052,113 entitled "stationary Release Delivery of Latanoprost to Treat Glaucoma" filed on 9.5.2008, and U.S. provisional patent application serial No. 61/108,777 entitled "stationary Release Delivery of Latanoprost to Treat Glaucoma" filed on 27.10.2008, the descriptions of which are incorporated herein by reference in their entireties, are hereby claimed.

Background

Glaucoma is a collection of conditions characterized by progressive visual field loss due to optic nerve damage. In the united states, it is the leading cause of blindness, affecting 1-2% of individuals aged 60 years and older. Although there are many risk factors (age, race, myopia, family history and injury) associated with the development of glaucoma, elevated intraocular pressure (also known as ocular hypertension) is the only 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 often need to 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 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 many cases, the topically applied agent has the highest ocular effect for about two hours, after which the agent should be applied again to maintain the therapeutic benefit. PCT publication WO 06/014434(Lazar), incorporated herein by reference in its entirety, may be related to these and other problems associated with eye drops.

With the difficulty of compound eye treatment, patients often do not use their eye drops according to the prescription. Recalcitrance rates of typically at least 25% have been reported. The poor compliance may be due to, for example, the initial stinging or burning sensation caused by eye drops and experienced by the patient. 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 patients may have additional drip problems due to arthritis, instability and impaired vision. It also has difficulties for pediatric and psychiatric populations.

In view of the foregoing, there is a need for an improved drug delivery system that overcomes at least some of the above-mentioned disadvantages.

Disclosure of Invention

The present invention provides methods for sustained release delivery of therapeutic agents from a patient's punctum (punctum) into ocular tissue using implants to treat diseases, particularly ocular diseases. In one embodiment, the therapeutic agent is latanoprost. In one aspect, the invention provides a method of delivering latanoprost and/or one or more other therapeutic agents to an eye having an associated tear fluid, the method comprising placing a topical formulation (topicalformulation) comprising latanoprost and/or one or more other therapeutic agents into a punctum of the eye. In one embodiment, the topical formulation is in the form of a drug core, optionally disposed in a punctal implant body configured to be at least partially inserted into a punctum or lacrimal duct (canaliculus) of an eye. In some embodiments, the core may comprise a matrix and inclusions of the therapeutic agent within the matrix, in some embodiments the therapeutic agent is latanoprost. A portion of the core may be exposed to tear fluid so as to release latanoprost or other therapeutic agent into the tear fluid. The latanoprost or other therapeutic agent may be dissolved or dispersed in the matrix and release the latanoprost or other therapeutic agent at therapeutic levels over a sustained period of time via the exposed core portion. In another aspect, the invention provides a method of delivering latanoprost or other therapeutic agent to an eye having an associated tear fluid, the method comprising placing a topical formulation consisting essentially of latanoprost or other therapeutic agent and a polymer into a punctum of the eye. In one embodiment, the topical formulation is impregnated (impregnate) within a preformed punctal implant (punctalipmplant), or is made in the form of a punctal implant consisting of a mixture of latanoprost or other therapeutic agent and a polymer.

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

The present invention provides the use of latanoprost or one or more other therapeutic agents for treating elevated intraocular pressure. In some embodiments, the present invention provides the use of latanoprost for the treatment of glaucoma. In some embodiments, the present invention provides the use of one or more therapeutic agents other than latanoprost for the treatment of glaucoma. In some embodiments, there is provided the use of latanoprost for reducing intraocular pressure. Certain embodiments provide the use of latanoprost or one or more other therapeutic agents for the treatment of an ocular disease. In some embodiments, the use of a combination of therapeutic agents for the treatment of an eye disease is provided. The invention also provides the use of an anti-glaucoma drug for the treatment of glaucoma and/or elevated intraocular pressure. In some embodiments, the present invention provides the use of a prostaglandin or a prostaglandin analog for the treatment of an eye condition.

The invention further provides the use of an intraocular pressure-reducing therapeutic agent in the manufacture of a medicament for reducing intraocular pressure in the eye of a patient in need thereof. In some embodiments, the drug is a sustained release topical formulation. In some embodiments, the intraocular pressure-reducing therapeutic agent is capable of being continuously released over time to the eye. In certain embodiments, the intraocular pressure of the patient is reduced by at least 10% from baseline. In certain embodiments, the intraocular pressure is reduced by at least 15% from baseline, at least 20% from baseline, or at least 25% from baseline.

In specific embodiments, the intraocular pressure-reducing therapeutic agent is released for a period of time of at least about 30 days, at least about 60 days, or at least about 90 days. In some embodiments, the intraocular pressure-reducing therapeutic agent is an anti-glaucoma agent, such as an adrenergic agonist, an adrenergic antagonist, a beta-blocker, a carbonic anhydrase inhibitor, a parasympathomimetic, a prostaglandin analog, a hypotensive lipid, a neuroprotective agent, or a combination thereof. In one embodiment, the anti-glaucoma drug is latanoprost.

In many embodiments, the formulation is disposed in and eluted from an ocular implant (e.g., a punctal implant). In some embodiments, the formulation is impregnated within the punctal implant such that at least one surface of the implant is coated with the formulation. In some embodiments, the formulation is contained within a sustained release core disposed within the punctal implant.

It is contemplated that the punctal implant can contain an amount of intraocular pressure-reducing therapeutic agent of about 3.5 micrograms, about 14 micrograms, about 21 micrograms, or about 44 micrograms. In some embodiments, the punctal implant is inserted into one punctum of each of both eyes of the patient.

The formulation may be administered approximately every 90 days, and the intraocular pressure-reducing therapeutic agent may be released to the eye for a period of time 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, continuously.

In certain embodiments, about 25 ng/day to about 250 ng/day of the intraocular pressure-reducing therapeutic agent is released. In one embodiment, the intraocular pressure is at least about 20mm Hg prior to administration of the intraocular pressure-reducing therapeutic agent. In some embodiments, the reduction in intraocular pressure is maintained for the following consecutive time periods: up to about 7 days, up to about 14 days, up to about 21 days, up to about 28 days, up to about 56 days, up to about 84 days, or up to about 105 days.

In some embodiments, patient noncompliance is significantly reduced as compared to eye drops of intraocular pressure-reducing therapeutic agents.

In certain embodiments, the intraocular pressure is associated with ocular hypertension. In some embodiments, intraocular pressure is associated with glaucoma.

Also provided herein is the use of an intraocular pressure-reducing agent in the manufacture of a medicament for reducing intraocular pressure in an eye of a patient in need thereof, wherein the medicament is suitable for use in an implant inserted into at least one punctum of the eye, wherein the implant comprises a sustained release core comprising the intraocular pressure-reducing agent, wherein the intraocular pressure-reducing therapeutic agent is capable of being continuously released over time to the eye, and wherein the intraocular pressure is reduced at least about 10% from baseline.

In some embodiments, the intraocular pressure is reduced from baseline by an amount selected from the group consisting of: at least 15%, at least 20% and at least 25%. In certain embodiments, the intraocular pressure-reducing therapeutic agent is released for a period of time selected from the group consisting of: at least about 30 days, at least about 60 days, and at least about 90 days.

In some embodiments, the sustained release core is disposed in an implant body (implantable body). In certain embodiments, the patient is suffering from glaucoma. In certain embodiments, the implant, the sustained release core, or both are at least partially coated with an impermeable coating. In some embodiments, the impermeable coating comprises parylene. In one embodiment, the intraocular pressure-reducing therapeutic agent is latanoprost.

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

In some embodiments, the implant releases latanoprost or other therapeutic agent 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 implant insertion. In some embodiments, the implant releases about 25 ng/day to about 250 ng/day of latanoprost or other therapeutic agent. In other embodiments, the implant can release at least 250 ng/day of latanoprost or other therapeutic agent. In other embodiments, the implant can release at least 350 ng/day or more of latanoprost or other therapeutic agent. In certain embodiments, the implant can release about 0.75 micrograms/day, about 1.0 micrograms/day, or about 1.5 micrograms or more/day of latanoprost or other therapeutic agent. In some embodiments, the implant topical formulation comprising latanoprost or other therapeutic agent is administered to the eye of the subject less than 10 times, less than 5 times, or less than 3 times over the continuous period of time.

In one embodiment, the present invention provides a method of lowering intraocular pressure (IOP) by inserting an implant into at least one punctum of a patient having an IOP of about 22 mmHg. The implant may be at least partially impregnated with latanoprost or other therapeutic agent, or may comprise a sustained release core containing at least latanoprost or other therapeutic agent, and release of latanoprost or other therapeutic agent from the implant results in a reduction in IOP from about 22mm Hg to about 16mm Hg.

In certain embodiments, the present invention provides methods of reducing intraocular pressure by inserting an implant into at least one punctum of a patient having an intraocular pressure (IOP) of about 21mm Hg, about 20mm Hg, about 19mm Hg, about 18mm Hg, about 17mm Hg, about 16mm Hg, about 15mm Hg, about 14mm Hg, about 13mm Hg, about 12mm Hg, about 11mm Hg, or about 10mm Hg. 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 invention provides methods of treating normal 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.

In certain embodiments, the variability in intraocular pressure over the course of treatment after 1 week is less than about 1 mmHg. In other embodiments, the variability in intraocular pressure over the course of treatment after 1 week is less than about 2 mmHg. In other embodiments, the variability in intraocular pressure over the course of treatment after 1 week is less than about 3 mmHg. In one embodiment, once the intraocular pressure is reduced by about 6mm Hg, the variability of intraocular pressure at any particular time point during the remainder of the treatment session is less than about 1mm Hg.

The invention described herein also provides a method of lowering intraocular pressure by inserting a sustained release implant into at least one punctum of a patient, wherein the intraocular pressure of the eye concerned is lowered by at least about 25%.

In some embodiments, the present invention provides methods of treating a patient having ocular hypertension by administering a topical formulation consisting of latanoprost or other therapeutic agent that is eluted from a drug core or other implant body configured to be at least partially inserted into at least one punctum of the patient, 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 an ocular implant. In other embodiments, the ocular implant is a punctal implant, such as a punctal plug (punctal plug).

In one embodiment, the method of the invention results in a reduction in intraocular pressure of at least 10% within 1 day after insertion of the implant, or at least 20% within 7 days after insertion of the implant. 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 of the punctal implant.

In one embodiment, the intraocular pressure is at least 20mmHg prior to insertion of the punctal implant. In some embodiments, the intraocular pressure is about 16mm Hg at about 7 days after insertion of the implant.

The methods of the invention described herein also provide implants that are at least partially impregnated with a therapeutic agent or have a sustained release core comprising a non-biodegradable polymer. In some embodiments, the sustained release core comprises silicone.

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.

The implant may contain at least 3 micrograms, at least 10 micrograms, at least 20 micrograms, at least 30 micrograms, at least 40 micrograms, or about 3.5-135 micrograms of latanoprost or other therapeutic agent. In other embodiments, the implant may contain more than 40 micrograms of latanoprost or other therapeutic agent. In other embodiments, the implant may contain a therapeutic agent, such as one or more prostaglandin derivatives, such as travoprost, bimatoprost, and the like, or other therapeutic agents useful for treating elevated intraocular pressure, such as beta blockers, carbonic anhydrase inhibitors, alpha adrenergic antagonists, and the like. In some embodiments, the amount of therapeutic agent released from the implant is sufficient to treat an ocular condition for a sustained period of time, e.g., about 7 days or more, about 30 days or more, about 45 days or more, about 60 days or more, about 75 days or more, about 90 days or more. In some embodiments, the implant contains about 3.5 micrograms, about 14 micrograms, about 21 micrograms, about 42 micrograms, or about 44 micrograms of latanoprost or other therapeutic agent. In other embodiments, the implant contains about 50, about 60, about 70, or about 80 micrograms of latanoprost or other therapeutic agent. In other embodiments, the implant contains a sufficient amount of the therapeutic agent for sustained release at therapeutic levels for a desired therapeutic period.

The present invention further provides a method of treating elevated intraocular pressure by inserting an implant into at least one punctum of a patient, wherein the implant is impregnated with about 14 micrograms of latanoprost or other therapeutic agent, or has a sustained release core containing about 14 micrograms of latanoprost or other therapeutic agent, wherein the implant remains inserted for at least 90 days, and wherein the intraocular pressure is substantially reduced, as shown in fig. 1.

In some embodiments, a topical formulation consisting essentially of latanoprost or other therapeutic agent and a pharmaceutically acceptable vehicle (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 patient, wherein the formulation is capable of lowering intraocular pressure for at least 90 days.

The invention further provides for a reduction in patient non-compliance as compared to eye drops of latanoprost and other therapeutic agents. A single insertion procedure provides continuous administration of latanoprost or other therapeutic agent for a sustained period of time, avoiding patient noncompliance associated with eye drop administration.

The present invention further provides methods of lowering intraocular pressure, and in some embodiments, reducing the occurrence of adverse effects resulting from the topical administration of therapeutic 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 therapeutic agents from implants, including but not limited to the implants disclosed herein, to the eye. In one embodiment, such an implant may be partially or completely impregnated with the therapeutic agent. For example, the implant body may comprise a matrix of polymeric components and one or more therapeutic agents. The one or more therapeutic agents may be substantially dispersed throughout the matrix and released over time. In another embodiment, such an implant may comprise a sustained release core containing the therapeutic agent.

Drawings

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.

Figure 1 illustrates the average intraocular pressure of subjects treated with a 14 μ g latanoprost punctal plug delivery system.

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

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

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

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

Fig. 3B illustrates an embodiment of a cross-sectional view of the punctal implant taken along a line parallel to the 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 punctal implant configured to be at least partially retained within the punctum or lacrimal duct anatomy.

Fig. 4B illustrates one embodiment of a cross-sectional view of the punctal implant taken along a line parallel to the 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 punctal implant configured to be at least partially retained within the punctum or lacrimal duct anatomy.

Figure 6 illustrates intraocular pressure values over the 3 months of follow-up.

Figure 7 illustrates intraocular pressure values followed for more than 3 months.

Figure 8 illustrates the change from baseline (± standard deviation) of the mean intraocular pressure over a 3 month period.

Figure 9 illustrates the change from baseline in mean IOP in CORE studies.

Figure 10 illustrates the change from baseline in mean IOP in the CORE study.

FIG. 11 illustrates the reduction in IOP at week 12 in the CORE study.

FIG. 12 illustrates the percent reduction in IOP in CORE studies compared to published Latanoprost and Timolol eye drop studies (source: American Latanoprost research group. Rate of Response to Latanoprost or Timolol in Patents with Ocular Hypertension or Glaucoma. J Glaucoma 2003; 12: 466-. It should be noted that the percentage of latanoprost and timolol was estimated from the figures in the sources.

FIG. 13 illustrates the percent reduction in IOP in CORE studies compared to published Latanoprost, Timolol and Bimatoprost eye drop studies (ref: Rate of Response to Latanoprost or Timolol in Patientswitch Ocular Hypertension or Glaucoma. J Glaucoma 2003; 12: 466) 469; A Six-singled Randomized Clinical Trial Trial matching the intracellular pressure-viewing impact of Bimatoprost and Latanoprost in Patients with Ocular Hypertension or Glaucoma. am. J Ophthalmol 2003; 135: 55-63). The percentage of latanoprost and timolol was estimated from the graph.

Figure 14 illustrates the absolute reduction of IOP in the CORE study compared to the published latanoprost and timolol eye drop study. The source is as follows: the U.S. latanoprost research group. Rate of response to Latanoprost or Timolol in documents with Ocular hypertension or Glaucoma.J Glaucoma 2003; 12: 466-469. It should be noted that the percentage of latanoprost and timolol was estimated from the figures in the sources.

Figure 15 illustrates the percentage of patients who reached the target IOP in the CORE study compared to the published latanoprost and timolol eye drop study. The source is as follows: the U.S. latanoprost research group. Rate of Response to Latanoprost or Timolol in documents with Ocular hypertension or Glaucoma.J Glaucoma 2003; 12: 466-469. It should be noted that the percentage of latanoprost and timolol was estimated from the figures in the sources.

Figure 16 illustrates ocular Adverse Events (AEs) in the CORE study.

Figure 17 illustrates ocular adverse events in the CORE study compared to the latanoprost eye drop study. Adlida ophthalmic solution 0.005% (50mg/mL) (Pharmacia) approved 6/5/1996: medical Officers Review, pages 93, 98-100. Provided by FOI Services. A Six-single randomised Clinical laboratory Comparing the interferometric Pressure-lower effect of Bimatoprost and Latanoprostin Patents with Ocular Hypertension or Glaucomma. Am J Ophthalmol 2003; 135: 55-63. Other adverse events include eyelash growth. Medical Officers Review was approved in 6.5.1996 in 98 patients (98 with 0.005% (50mg/mL) of the Pradata ophthalmic solution).

Figure 18 illustrates ocular adverse events in the CORE study compared to the eye drop study of latanoprost, travoprost, timolol, and bimatoprost. (1) Travoprost supplied With Latanoprost and Timolol in documents With Open-angleGlaucoma or Ocular Hypertension, am J Ophthalmol 2001; 132: 472-484. Other adverse events include ocular pain, cataracts, dry eye, blepharitis, blurred vision.

(2) A Six-month randomised Clinical logic composing the interferometric Pressure-lower effect of Bimatoprost and Latanoprostin titles with Ocular Hypertension or Glaucoma.Am J Ophthalmol 2003; 135: 55-63. other adverse events include eyelash growth.

(3) One-Yeast, random student company and ethanol in Glaucoma and Ocular hypertension Arch opthalmol V120Oct.20021286-1293. The bim group (higher incidence of adverse events) was also included than horse prost.

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 patient undergoing therapeutic treatment (including drugs and/or medical devices) in a clinical trial or clinical practice. Adverse events include changes in the condition or laboratory outcome of the patient, which have or may have a deleterious effect on the patient's health or well-being. 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, visual deterioration, 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, 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 modified to form 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" as used herein refers to a structure that can be configured to contain or be impregnated with a drug, such as via 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), and that is capable of releasing an amount of an active agent (e.g., latanoprost or other therapeutic agent) into tear fluid over a sustained release period when the structure is implanted in a target site along the patient's tear pathway. The terms "implant," "plug," "punctal plug," and "punctal 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 implants described herein can be inserted into a punctum of a subject, or passed through the punctum into the lacrimal duct. The implant can also be a drug core or drug matrix itself that is configured to be inserted into the punctum without being disposed in a carrier (e.g., a punctal implant obturator), e.g., having a polymeric component and a latanoprost or other therapeutic agent component, without additional structure encasing the polymeric component and latanoprost or other therapeutic agent component.

As used herein, "effacement loss" (LoE) is defined as the increase in IOP of either or both eyes to baseline (post-flush) IOP while wearing a (wear) latanoprost punctal plug delivery system (L-PPDS) continuously 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: polymeric matrices, 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 the superior and inferior lacrimal canaliculi, which terminate at the superior and inferior puncta, 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 terms "subject" and "patient" refer to an animal such as a mammal, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, and the like. In many embodiments, the subject or patient is a human.

"therapeutic agent" may include drugs and may be any of the following or their equivalents, derivatives or analogs, including: anti-glaucoma agents (e.g., adrenergic agonists, adrenergic antagonists (β -blockers), carbonic anhydrase inhibitors (CAIs, both systemic and topical), parasympathomimetics (e.g., cholinergics), prostaglandins, and hypotensive lipids, and combinations thereof), antimicrobial agents (e.g., antibiotics, antivirals, antiparasitics, antifungals, 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, cycloplegics, and the like. Examples of conditions that may be treated with therapeutic agents include, but are not limited to, glaucoma, pre-and post-operative treatment, ocular hypertension, dry eye, and allergies. In some embodiments, the therapeutic agent may be a lubricant or surfactant, such as a lubricant for treating dry eye.

Exemplary therapeutic agents 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); inhibitors of surface glycoprotein receptors; 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., 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).Such anti-inflammatory steroids (steroids) contemplated for use in the methods of the present invention include: triamcinolone acetonide (common name) and corticosteroids including, 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 3; immunopharmaceuticals (e.g., vaccines and immunostimulants), hormonal agents (e.g., estrogen, -estradiol, progestational agents, progesterone, insulin, calcitonin, parathyroid hormone, peptides, and vasopressin hypothalamic releasing factor), immunosuppressive agents, 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, thrombin sensitive protein, anti-VEGF antibodies), dopamine agonists, radiotherapeutic agents, peptides, proteins, enzymes, extracellular matrices, components, ACE inhibitors, free radical scavengers, chelators, anti-oxidants, anti-polymerase (anti-myelomerase), photodynamic therapeutics, gene therapeutics, and other therapeutics such as prostaglandins, retinoids, growth hormone antagonists, growth factors, 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(ii) a And parasympathomimetics such as pilocarpine, carbachol, physostigmine, and the like.

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, as used herein, also include formulations that can release a therapeutic 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.

The implants described herein are expected to be useful in treating a variety of diseases, including, but not limited to, diseases or disorders of the eye (malconditiontion). These diseases or conditions include diabetic retinopathy, uveitis, intraocular inflammation, keratitis, dry eye, macular edema, including cystoid macular edema, infection, macular degeneration, blurred vision, herpetic conjunctivitis, blepharitis, retinal or choroidal neovascularization, and other proliferative ocular diseases. Treatment of other diseases is also contemplated herein, including, but not limited to, rheumatic diseases, dizziness, infectious diseases, including upper respiratory tract infections (cold/flu), chest/angina, heart disease, muscle/joint/back pain, autoimmune diseases, inflammation, cancer or other proliferative diseases, infections, vascular diseases, diabetes, and central nervous system diseases, including migraine. Local and systemic delivery of therapeutic agents from the plugs described herein may be employed.

The present invention provides the use of latanoprost or one or more other active agents for the treatment of: diabetic retinopathy, uveitis, intraocular inflammation, keratitis, dry eye, macular edema, including cystoid macular edema, infection, macular degeneration, blurred vision, herpetic conjunctivitis, blepharitis, retinal or choroidal neovascularization, and other proliferative eye diseases. Also provided herein is the use of latanoprost or other active agents for the treatment of: rheumatic diseases, dizziness, infectious diseases, including upper respiratory tract infections (cold/flu), chest pain/angina pectoris, heart disease, muscle/joint/back pain, autoimmune diseases, inflammation, cancer or other proliferative diseases, infections, vascular diseases, diabetes and central nervous system diseases, including migraine. In some embodiments, the invention provides the use of anti-glaucoma agents for the treatment of the above-mentioned diseases. In certain embodiments, the use of a prostaglandin or prostaglandin analog for the treatment of the above-mentioned diseases is provided.

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 the 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:

a preferred therapeutic 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.

"YinshiLatanoprost ophthalmic solutions are commercially available products suitable for lowering elevated IOP in patients with open angle glaucoma or ocular hypertension. Commercially available product aptitudeThe 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 to maintain therapeutic benefit. Low patient compliance can compromise (compound) these effects.

Patient non-compliance:

many studies have been published that show high recalcitrance of patients treated with eye drops for various eye disorders. One study showed that only 64% of patients were prescribed eye drops (Winfield et al, 1990). Another study showed that 41% of patients 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 a method of treating glaucoma that avoids the problem of non-compliance associated with eye drop administration. In some embodiments, the methods of the invention significantly reduce patient 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 patient noncompliance of the methods described herein is about 5%, about 10%, about 15%, about 20%, or about 25%.

Patient noncompliance can occur if the implant of the present invention is intentionally removed by the patient, or if the patient does not want to reinsert the implant after the implant has been unintentionally detached from the patient's punctum. Patient compliance is considered to be met if the implant is intentionally removed and the patient wants to reinsert in less than about 48 hours. Patient compliance is also considered to be met if the implant is intentionally removed and the patient wants to reinsert within less than about 24 hours of removing or detaching the implant.

Adverse events in clinical trials and clinical practice:

based on aptlyProduct 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.

The treatment method comprises the following steps:

the invention described herein provides methods of treating glaucoma, elevated intraocular pressure, and glaucoma-associated elevated intraocular pressure with therapeutic agents. In many embodiments, methods of treating an eye with latanoprost are provided. In some embodiments, the therapeutic 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 an 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 includes inserting an implant through the punctum, the implant having a body impregnated with a therapeutic agent. In some embodiments, 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 therapeutic 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 latanoprost or other therapeutic agents are provided, the methods comprising 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 latanoprost or other therapeutic 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 latanoprost or other therapeutic agent at therapeutic levels over a sustained period of time.

A replacement implant, or in other embodiments, a replacement core, which may be attached to the retention structure in some embodiments or include its own retention structure, may be attached to the retention structure approximately every 90 days, allowing for continuous release of the drug to the eye 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. 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 therapeutic 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 or other therapeutic agent at therapeutic levels. In some embodiments, the sustained release delivery of latanoprost or other therapeutic agent is for up to 90 days.

In many embodiments, a method of treating an eye with latanoprost or other therapeutic agent is provided, the method comprising inserting a distal end of an implant 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 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 to inhibit expulsion of the implant. Latanoprost or other therapeutic agent is delivered from the proximal end of the implant to the tear fluid adjacent the eye. Distal to the proximal end, delivery of latanoprost or other therapeutic agent is inhibited.

The methods of the invention provide for the sustained release of latanoprost or other therapeutic agent. In some embodiments, the active agent 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 some embodiments, the active agent is latanoprost. In one embodiment, latanoprost or other therapeutic agent is released for at least 12 weeks. In another embodiment, the treatment method according to the invention described above further comprises delivering an eye drop solution of latanoprost (e.g., dulex)) The adjuvant therapy of (1).

The amount of latanoprost or other therapeutic agent 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 or other therapeutic agent is at least that amount which is effective to achieve the desired physiological or pharmacological local or systemic effect upon release from the device.

Certain embodiments of the implants of the present invention may be configured to deliver latanoprost or other therapeutic agent at a daily rate similar or equivalent to a therapeutically effective form of drop therapy. Other embodiments of the implants of the invention may be configured to deliver latanoprost or other therapeutic agent at a daily rate that exceeds the therapeutically effective form of drop therapy.

Embodiments of the implants of the present invention may also be configured to deliver latanoprost or other therapeutic agent at a daily rate substantially lower than therapeutically effective drop treatment forms, 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 elution phase of about 1-3 days, the implant can elute latanoprost or other therapeutic 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., Belgium) are usedDrops) delivered about 1.5 micrograms of latanoprost. In contrast, in one embodiment, the implants of the present invention can deliver a significantly smaller amount of drug than the conventional drop administration described above. In other embodiments, sustained release of latanoprost in excess of 100 ng/day, e.g., up to 1.5 micrograms per day, may be administered. Although the sustained release 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% 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. Generally, for placement, the size of the punctal implant to be used can be determined by using the appropriate magnification, or, if provided, sizing tools accompanying the punctal implant. The patient's punctum can be dilated, if necessary, to fit the punctal 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. The process may be repeated for the other eye of the patient. To remove the implant, small 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 some embodiments, latanoprost or other therapeutic agent is administered for a period of time via a drug matrix core, which may or may not be associated with the implant body structure alone. In certain embodiments, an implant for use in the methods described herein is provided. The implant can be configured to release an amount of latanoprost or other therapeutic agent into the tear fluid daily for a period of days, weeks, or months when implanted at a target site along the tear channel of a patient. The implant may be one of many different designs that release latanoprost or other therapeutic agent over a sustained period of time. The disclosures of the following patent documents, which describe example implant structures or process 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 Methods for Nasolarization System); U.S. application Ser. No. 60/787,775 (filed 3/31/2006 under the heading Nasolarimal Drainage System Implantsfor 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. 11/571,147 (filed on 21.12.2006, entitled Treatment Medium Delivery Device and Methods for Delivery of Such therapeutic substances to the Eye Using S

Typically, the implant comprises a 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 patient. The implant body may be at least impregnated with, or otherwise contain, latanoprost or other therapeutic agent, for example in a matrix core that is inserted within the implant body. Exposure of the matrix core or impregnated body to tear fluid results in effective release of latanoprost or other active agent 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 or other therapeutic agent 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 (integral feedback) 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 full or partial (e.g., trim) head portion attached around the sheath near the proximal end of the core. The head portion 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. For example, in some embodiments, the implant may include a body formed with a Drug eluting matrix (e.g., silicone) and a prostaglandin or other therapeutic agent (in some embodiments, latanoprost), wherein the therapeutic agent is impregnated in a portion or all of the implant body, such as those described in U.S. application serial No. 10/825,047 (filed 4/15/2004, entitled Drug Delivery via plunger). In some embodiments, the core comprises a latanoprost or other therapeutic agent matrix, including a pharmaceutically acceptable vehicle, such as a non-bioabsorbable polymer, such as silicone in a heterogeneous mixture containing latanoprost or other therapeutic agent. The heterogeneous mixture in the core may comprise a silicone matrix saturated with latanoprost or other therapeutic agent or saturated with inclusions of latanoprost or other therapeutic agent. The contents of the core are a concentrated form of latanoprost or other therapeutic agent, and the silicone matrix surrounds the contents of the core. In particular embodiments, latanoprost or other therapeutic agent inclusions encased in a silicone matrix comprise a heterogeneous mixture of inclusions encased in a silicone matrix. The core inclusion may contain latanoprost oil.

It is also within the scope of the present invention to modify or adapt the implant device to deliver a high release rate, a low release rate, a bolus release, an explosive 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 all of the latanoprost or other therapeutic agent is released at once. The explosive release of latanoprost or other therapeutic agents 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 therapeutic agents may be achieved by porous membranes, soluble gels (such as those in typical ophthalmic solutions), particulate 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 therapeutic agent from the 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 therapeutic agent, such that the rate of migration of latanoprost or other therapeutic agent is controlled to a large extent by the exposed surface area of the core that is not covered by the sheath. In many embodiments, the migration of latanoprost or other therapeutic agent through the sheath can be about 1/10 or less, often 1/100 or less, of latanoprost or other therapeutic agent through the exposed surface of the core. In other words, migration of latanoprost or other therapeutic agent through the sheath is at least about 1 order of magnitude less than migration of latanoprost or other therapeutic agent through the exposed surface of the core. Suitable sheath materials include polyimide, polyethylene terephthalate (hereinafter "PET"). In some embodiments, the sheath has a thickness of about 0.00025 "to about 0.0015" as defined from a sheath surface adjacent the core to an opposing sheath surface distal from the core. In some embodiments, the overall diameter of the sheath extending across the core is in the range of about 0.2mm 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 patient. 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 may 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 may be readily observed by the patient. 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 non-shape memory alloys, can be used 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:

in some embodiments, the core may be inserted into the implant body, or may serve as the implant itself, without any other structural components, or may be configured to take the shape of a punctal plug or the like. The core comprises latanoprost or other therapeutic agent and material to provide sustained release of latanoprost or other therapeutic agent. In some embodiments, the core comprises a sustained release formulation consisting of, or consisting essentially of, latanoprost or other therapeutic agent and silicone as a carrier. Latanoprost or other therapeutic agent migrates from the drug core to the target tissue (e.g., ciliary muscle of the eye). The core may optionally comprise latanoprost or other therapeutic agent in a matrix, wherein the latanoprost or other therapeutic agent is dispersed or dissolved within the matrix. Latanoprost or other therapeutic agents may be only sparingly soluble in the matrix, such that small amounts are dissolved in the matrix and released from the surface of the core. As latanoprost or other therapeutic agent diffuses from the exposed surface of the core to the tear or tear film, the rate of migration from the core to the tear or tear film can be correlated to the concentration of latanoprost or other therapeutic agent dissolved in the matrix. Additionally or in combination, the rate of migration of latanoprost or other therapeutic agent 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 therapeutic agent is dissolved.

In one embodiment, the topical formulation or core does not contain a preservative. Preservatives include, for example, benzalkonium chloride and EDTA. In one embodiment, the implants of the invention may be hypoallergenic and may have reduced chemosensitivity compared to formulations containing these preservatives.

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 latanoprost or other therapeutic agent dissolved in the core can be controlled to provide a desired release rate of latanoprost or other therapeutic agent. The latanoprost or other therapeutic agent contained in the core may include latanoprost or other therapeutic agent in liquid (e.g., oil), solid gel, solid crystalline, solid amorphous, solid particulate, or dissolved form. In some embodiments, the core may comprise liquid or solid inclusions, such as droplets of liquid latanoprost or other therapeutic agent 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 1, 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 affect the output of therapeutic agent from the core matrix material. In particular embodiments, curing of MED-4011 containing a platinum vinyl hydride system can be inhibited with 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 high concentration (e.g., 20%) of 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, the latanoprost or other therapeutic agent in the solid core may be at least about 5%, for example ranging from about 5% to 50%, and may be about 20% to about 40% (by weight) of the core.

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

The matrix containing latanoprost or other therapeutic agent may be formed from biodegradable or non-biodegradable polymers. Non-biodegradable cores may include silicone, acrylates, polyethylene, polyurethane, hydrogels, polyester (e.g., dacron. rtm. from e.i. du Pont de Nemours and Company of wilmington, tlahua), polypropylene, Polytetrafluoroethylene (PTFE), expanded PTFE (eptfe), Polyetheretherketone (PEEK), nylon, extruded collagen, polymeric foams, silicone rubber, polyethylene terephthalate, ultra high molecular weight polyethylene, polycarbonate polyurethane (polycarbonate urethane), polyurethane, polyimide, stainless steel, nickel-titanium alloys (e.g., nitinol), titanium, stainless steel, cobalt-chromium alloys (e.g., elgiloy. rtm. from Elgin Specialty Metals of elm, illinois; conhrome. rtm. from carpent Metals of wyosissing, tx).

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)Alkanones (polydioxanones), polycaprolactones, polygluconates, polylactic acid-polyethylene oxide copolymers, modified celluloses, collagens, polyorthoesters, polyhydroxybutyrates, 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 implants that can be used in the methods described herein are as follows (see also the examples section below). In some embodiments, the drug insert comprises a thin-walled polyimide sheath with latanoprost or other therapeutic agent dispersed in Nusil6385 (cured medical grade solid silicone). The cured silicone acts as a solid, non-aggressive matrix from which latanoprost or other therapeutic agent is 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, provides structural support and barrier for both lateral drug diffusion and drug diffusion through the distal end of the drug insert. The drug insert is placed in the cavity of the punctal implant and is held in place by an interference fit (interference fit). In some embodiments, the implant body is at least partially impregnated with a therapeutic agent (e.g., latanoprost or other therapeutic agent).

Fig. 2A illustrates one embodiment of a punctal implant 200 that can be inserted into a punctum. Insertion of punctal implant 200 into the punctum can accomplish one or more of the following: inhibit or block tear flow therethrough (e.g., to treat dry eye), or to deliver a therapeutic 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, punctal implant 200 includes implant body 202 that extends from proximal portion 204 to distal portion 206 and has 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 or other therapeutic agent 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 punctal 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, for example, to help provide comfort to the patient 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 includes a partially-pitched head portion that extends 360 degrees from the outer surface of the implant body about the proximal end 204. In some embodiments, such a protrusion 226 includes an integral head portion that extends 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 punctal implant 200 taken along a line parallel to the longitudinal axis of the implant, such as along line 2B-2B of fig. 2A. As shown in fig. 2B, the punctal implant can include an implant body 202 having a retention structure 208 that substantially encases a hydrogel retention element 216 at or near a distal portion 206 of the implant body, and a latanoprost or other therapeutic agent 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 can include a plurality of latanoprost or other therapeutic agent inclusions 252, which can be distributed in a matrix 254. In some embodiments, inclusion 252 comprises latanoprost or other therapeutic agent in a concentrated form (e.g., a crystalline 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 or tear film fluid as punctal implant 200 is inserted into the punctum and release latanoprost or other therapeutic agent at one or more therapeutic levels over a sustained period of time.

Fig. 2C illustrates a cross-sectional view of an embodiment of punctal implant 200 taken along a line parallel to the longitudinal axis of the implant. As shown in fig. 2C, the punctal 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 punctal implant 300 that can be inserted into a punctum. Insertion of the punctal implant 300 into the punctum can accomplish one or more of the following: inhibiting or blocking tear flow therethrough (e.g., to treat dry eye), or sustained delivery of therapeutic agents to the eye (e.g., to treat infection, inflammation, glaucoma, or other ocular diseases or disorders), the nasal passages (e.g., to treat sinuses or allergic disorders), or the inner ear system (e.g., to treat dizziness or migraine).

In this embodiment, punctal 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 (outpatient 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 punctal implant 300 from the 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, projection 332 can be configured to rest at or near the punctal opening, e.g., to inhibit or prevent punctal 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 head portion-protrusions 332 to provide sustained release of 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 an acrylate having 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 punctal 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, the punctal implant 300 can 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 4 times smaller measure (magnitude) than 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 certain 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 punctal implant 300. In this manner, punctal implant 300 can be implanted in eye anatomy 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 into the outer surface of the implant body 302 can be used to further assist in the insertion of the punctal implant 300 into the 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, drug donor 322 can include a plurality of therapeutic agent inclusions 360, which can be distributed in matrix 362. In some embodiments, inclusion 360 may comprise a therapeutic 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 as punctal implant 300 is inserted into the punctum and release therapeutic agent at one or more therapeutic levels over a sustained period of time.

Fig. 4A illustrates one embodiment of a punctal implant 400 that can be inserted into a punctum. In various embodiments, the punctal implant 400 includes an implant body 402 that includes a first 404 and a second 406 portion, the implant body 402 being 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 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 punctal 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 bonded, for example, such that material of the expandable retention member 414 does not remain in the punctum after removal of the punctum 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, for example, between outpatient visits on an acute basis (acute basis), or on a chronic basis (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 includes a partially-pitched head portion that extends 360 degrees from the implant body outer surface about the proximal end 418. In one embodiment, the protrusion 422 includes an integral head portion that extends 360 degrees from the implant body outer surface about 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 punctal implant 400 from fully entering the lacrimal canaliculus, or to provide tactile or visual feedback information to the implanting user (e.g., regarding whether the implant is fully implanted), or to remove the punctal 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 punctal implant 400 from falling into the lacrimal canaliculus.

Fig. 4B illustrates one embodiment of a cross-sectional view of punctal 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 punctal implant 400 includes an implant body 402 that includes a first 404 and a second 406 portion, the implant body 402 being 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.OrIn 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 issues of cutting strength (e.g., during insertion and removal of the punctal implant 400) and dimensional stability.

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 conforms to the shape of the lacrimal canaliculus lumen wall or other peripheral structureAnd (4) forming.

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

In certain embodiments, the punctal implant 400 includes an intermediate member 450 that is placed between a portion of the implant body 402 (e.g., the base member 412) and a portion of the 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. The intermediate member 450 can provide the integrity of the punctal 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 comprisesAnd 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 exampleCarbamate orSolution grade carbamate. With respect to a portion disposed on a first polymeric material and a second polymeric material (generally different from the first polymeric material)Polymeric materials), see commonly owned U.S. application serial No. 12/432,553 (filed 4/29, 2009, entitled Composite laser Insert and release methods), which is incorporated by reference herein 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 therapeutic agent inclusions 452, which may be distributed in a matrix 454. In one embodiment, inclusion 452 comprises a therapeutic 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 pharmaceutical agent inclusions 452 comprise droplets of an oil (e.g., latanoprost or other therapeutic agent 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 can be located at or near proximal end 418 of implant body 402 to contact tear fluid or tear film fluid as punctal implant 400 is inserted into the punctum and release therapeutic agent at one or more therapeutic levels over 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, a therapeutic agent, or an antimicrobial agent (e.g., silver).

Fig. 5 illustrates one embodiment of a cross-sectional view of punctal implant 500 taken along a line parallel to the longitudinal axis of the implant. As shown in fig. 5, punctal 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. Projection 522 is in the form of a head portion that extends radially outward from implant body 502 to an extent sufficient to cause at least a portion of the head portion to extend beyond and outside of the punctum after insertion of the distal end portion of 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. For example, the implant body 502 may comprise a matrix of polymeric components and a drug donor 520 that releases one or more pharmaceutical agents. The drug donor 520 releasing the one or more agents may be substantially distributed throughout the matrix and released over time. In this manner, the implant body 502 can effectively provide long-term delivery of one or more therapeutic agents to the eye (e.g., to an external surface of the eye). As shown in fig. 5, the implant body 502 can be sized, shaped, or otherwise configured to be at least partially retained in the lacrimal canaliculus while releasing a therapeutic agent. As discussed in the commonly owned application serial No. 10/825,047 to Odrich (filed on day 4/15 200 under the title Drug Delivery virtual punch) incorporated herein by reference in its entirety, the medicament of the Drug donor 520 may be saturated in the implant body 502 and released from the latter, for example into the tear fluid of the eye or the nasolacrimal duct system.

In various embodiments, an impermeable sheath or coating is disposed over one or more portions of the implant body 502 to control release from the drug donor 520. For example, a substantially drug impermeable donor 520 non-biodegradable polymer can be coated around the periphery of the implant body 502. In some embodiments, at least one surface of the implant body 502 is uncoated or unsheathed to allow the drug donor 520 stored in the body 502 to be released to surrounding bodily tissue or structures. In some embodiments, the impermeable sheath or coating includes at least one aperture extending from the outer surface of the coating to the outer surface of the implant body 502. The at least one aperture may be sized, shaped, or otherwise configured to allow the drug supply 520 stored in the body 502 to be released to surrounding body tissue or structures, such as to the eye unit. In some embodiments, the at least one hole is etched into the coating, for example using a laser. In some embodiments, the at least one hole is formed into the coating after dissolution of the salt-impregnated portion of the implant. In one embodiment, the impermeable sheath or coating comprises parylene.

Preparing an implant:

those skilled in the art will be familiar with the various methods that can be used to prepare the 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, the cartridges described above may be manufactured in different cross-sectional sizes of 0.006 inches, 0.012 inches and 0.025 inches. The concentration of drug in the core may be 5%, 10%, 20%, 30% of the silicone matrix. These cores can be prepared with a syringe barrel and barrel device (cartidgeassambly), mixing latanoprost or other therapeutic agent with silicone and injecting the mixture into a polyimide tube, cutting it to the desired length, and sealing. 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 therapeutic agent content in the core of about 3.5 micrograms, 7 micrograms, 14 micrograms, and 21 micrograms, respectively, for concentrations of 5%, 10%, 20%, and 30%.

Syringe barrel and cartridge device: 1. polyimide tubes of different diameters (e.g., 0.006 inch, 0.0125 inch, and 0.025 inch) can be cut into 15cm lengths. 2. The polyimide tubing may be inserted into a syringe adapter. 3. The polyimide tubing may be bonded into a 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 ℃.

Latanoprost or other therapeutic agents may be mixed with the silicone. Latanoprost or other therapeutic agent may be provided as a 1% solution in methyl acetate. An appropriate amount of the solution can be placed in a dish and the solution evaporated using a nitrogen flow until only the latanoprost or other therapeutic agent remains. The plates containing the latanoprost or other therapeutic oil may be placed under vacuum for 30 minutes. The latanoprost or other therapeutic agent was then mixed with silicone and 3 different concentrations of latanoprost or other therapeutic agent (5%, 10% and 20%) in silicone NuSil6385 were injected into tubes of different diameters (0.006 inch, 0.012 inch and 0.025 inch) to produce a 3 x 3 matrix. The percentage of latanoprost or other therapeutic agent relative to silicone is determined by the total weight of the drug matrix. And (3) calculating: the weight of latanoprost or other therapeutic agent/(the weight of latanoprost or other therapeutic agent + the 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).

Release of latanoprost or other therapeutic agent at effective levels:

the release rate of latanoprost or other therapeutic agent can be correlated to the concentration of latanoprost or other therapeutic agent dissolved in the core. In some embodiments, the core comprises a non-therapeutic agent selected to provide a desired solubility of latanoprost or other therapeutic agent 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 a desired solubility of latanoprost or other therapeutic agent 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 or other therapeutic agent in the matrix. For example, functional groups can be attached to the silicone polymer.

Additives may be used to control the concentration of latanoprost or other therapeutic agent by increasing or decreasing the solubility of latanoprost or other therapeutic agent in the drug core, thereby controlling the release kinetics of latanoprost or other therapeutic agent. Solubility can be controlled by providing appropriate molecules or substances that increase or decrease the amount of latanoprost or other therapeutic agent in the matrix. The latanoprost or other therapeutic agent content can be correlated to the hydrophobic or hydrophilic nature of the matrix and latanoprost or other therapeutic agent. 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 or other therapeutic agent dissolved in the matrix, the surface area of the core can also be controlled to achieve a 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 or other therapeutic agent 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 are 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 or other therapeutic agents.

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 treat the patient with various prostaglandins or with prostaglandins and cholinergic or adrenergic antagonists (β -blockers) (e.g., afar. RTM.) or with latanoprost and carbonic anhydrase inhibitors.

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. Certain polymer processes can be used to incorporate latanoprost or other therapeutic agents into the devices of the present invention; for example, so-called "self-delivering drugs" or polymeric drugs (Polymer Corporation, 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 (Ser. 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, that encapsulates the inclusion of latanoprost or other therapeutic agent. 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. Naturally occurring surfactants may affect the solubility of latanoprost or other therapeutic agent in water, and the molecular weight of the drug may affect the transport of the drug from the solid matrix to the tear fluid. In many embodiments, latanoprost or other therapeutic agent is practically insoluble in water, has a solubility in water of about 0.03% to 0.002% (by weight), and has a molecular weight of about 400 grams/mol to about 1200 grams/mol.

In many embodiments, latanoprost or other therapeutic agent 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.

Surfactants naturally present in the tear film (e.g., surfactant D and phospholipids) may affect the transport of drug dissolved in the solid matrix from the drug core to the tear film. In some embodiments, the drug core can be configured to respond to a surfactant in the tear film to provide sustained delivery of latanoprost or other therapeutic agent into the tear film at therapeutic levels. For example, empirical data can be obtained from a patient population, e.g., 10 patients, collecting their tears and analyzing surfactant levels. The elution profile of sparingly water-soluble drugs 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.

Drug cores can also be modified to utilize carrier vehicles such as nanoparticles or microparticles, depending on the size of the molecule to be delivered, such as composite materials and latent reactive nanofiber compositions on the Surface of the nanosomes (LLC, st. paul, Minn.), nanostructured porous silicon (known as biosilicon. rtm.), including micron-sized particles, membranes, woven fibers or micro-computerized implants (pSividia, Limited, UK), and protein nanocage (Chimeracore) systems that target selective cells to deliver drugs.

In many embodiments, the drug insert comprises a thin-walled polyimide sheath with a drug core containing latanoprost dispersed in Nusil6385 (MAF 970), which 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 placed within the cavity of the punctal 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. At least 4 latanoprost concentrations can be employed in the final drug product: the core may comprise 3.5, 7, 14 or 21 micrograms of latanoprost in a concentration of 5, 10, 20 or 30% 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 or other therapeutic agent) 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 the latanoprost or other therapeutic agent at an initial high level followed by a substantially constant elution of the latanoprost or other therapeutic agent. In many cases, the amount of latanoprost or other therapeutic agent released from the core per day may be below therapeutic levels and still provide benefits to the patient. High levels of eluted latanoprost or other therapeutic agent may result in residual amounts of latanoprost or other therapeutic agent, or in combination with subtherapeutic amounts of latanoprost or other therapeutic agent, providing relief to the patient. In embodiments where the therapeutic level is about 80 ng/day, the device may deliver about 100 ng/day during the initial delivery phase. When latanoprost or other therapeutic agent is released at a level below therapeutic levels (e.g., 60 ng/day), more than 20ng delivered per day can have a beneficial effect. Because the amount of drug delivered can be precisely controlled, the initial high dose does not produce complications or adverse events to the patient.

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 drop 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 6mm Hg, about 5mm Hg, about 4mm Hg, about 3mm Hg, or about 2mm Hg during the treatment period. In certain embodiments, the methods of the present invention reduce intraocular pressure from baseline by at least 2mm Hg, at least 3mm Hg, at least 4mm Hg, at least 5mm Hg, at least 6mm Hg, or at least 7mm Hg. In some embodiments, the intraocular pressure is reduced to less than or equal to 21mm Hg, less than or equal to 20mm Hg, less than or equal to 19mm Hg, less than or equal to 18mm Hg, less than or equal to 17mm Hg, less than or equal to 16mm Hg, less than or equal to 15mm Hg, less than or equal to 14mm Hg, less than or equal to 13mm Hg, or less than or equal to 12mm Hg.

In one embodiment, the implants and methods of the invention provide a 90-day treatment course. In other embodiments, the implants and methods of the invention provide a 60-day treatment course. In other embodiments, the implants and methods of the invention provide a 45-day treatment course. In other embodiments, the implants and methods of the invention provide a 30-day course of treatment, depending on the disease to be treated and the therapeutic agent to be delivered. Other embodiments include treatment for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks. In some embodiments, an effective level of latanoprost or other therapeutic agent 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.

As described below, the study was conducted with 5 test subjects ≧ 18 years of age, who had a diagnosis of ocular hypertension or glaucoma at baseline. A sustained release implant comprising 14 micrograms of latanoprost is inserted into the punctum of the subject. An average decrease of 6mm Hg in intraocular pressure was observed within 7 days. This decrease was maintained for more than about 3 months.

The following non-limiting examples may illustrate the invention.

Example 1

A label published (open-label), promising study was performed on patients, following up to 3 months after placement. The patient is a male or female aged 18 or older diagnosed with ocular hypertension or glaucoma, for whom 2 consecutive measurements (at least 48 hours apart) of intraocular pressure of 22mmHg or higher are made after an appropriate drug clearance period (see Table 2 below).

Implant: a punctal plug drug delivery system (PPDS) consisting of a drug insert configured to be placed into a suitable commercially available punctal implant having a pre-formed cavity (pre-existing bore). All materials used in the construction of the drug insert were medical grade materials that passed a series of safety/toxicity experiments. The drug insert was a thin-walled polyimide tube containing latanoprost dispersed in Nusil6385 (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 sleeve is inert and, together with the adhesive, provides structural support and barrier for both lateral drug diffusion and drug diffusion through the distal end of the drug insert. The drug insert is disposed in the cavity of the punctal implant and is held in place by an interference fit. The assembled system is packaged and sterilized.

Procedure: after the first visit to confirm ocular hypertension, the patient was fitted with a punctal implant. In a later review (diagnosis) the patient is evaluated to determine if the punctal implant is still in place. After a subsequent baseline visit, one punctal plug drug delivery system was installed in each of the lower punctum of both eyes of the subject. If the punctal implant is not in place as found in any of the examinations, a new punctal plug drug delivery system is inserted. After an appropriate washout period as defined in table 2 below, the delivery system is placed in the lower or upper punctum. If during a subsequent visit the punctal tether system is not present, a replacement device is inserted.

The punctal plug drug delivery system is placed and removed in the same manner as other commercially available punctal implants. Typically, for placement, the size of the punctal implant to be used is determined by using the appropriate magnification, or sizing tools accompanying the punctal implant if provided. The patient's punctum can be dilated, if necessary, to fit the punctal implant. If necessary, a drop of lubricant may be applied to facilitate placement of the implant into the punctum. The implant is inserted into the upper or lower punctum of the eye using a suitable placement tool. After placement, the cap of the implant is visible. The procedure is repeated for the other eye of the patient. To remove the implant, small forceps are used to securely grasp the portion of the tube of the implant below the cap. The implant is gently removed using a gentle distraction motion.

TABLE 2 recommended washout period

During the course of the study, intraocular pressure was measured by goldmann applanation tonometry measurements. Local anesthetic and fluorescein were administered. This is achieved by using a combination product (e.g., sodium fluorescein solution)Butroxyprocaine and fluorescein) or by separate administration of a local anesthetic and fluorescein for corneal evaluation. The intraocular pressure was then measured immediately using the applanation method. Efficacy was assessed as a change in IOP from baseline.

In vitro drug release kinetics: several in vitro experiments have been performed with several medical grade silicone formulations to demonstrate the ability to control the elution rate of latanoprost. In the interest of commercially available productsThe amount of latanoprost in (a) is about 1.5 micrograms/droplet. Thus, a punctal implant delivery system that elutes about 100 ng/day of latanoprost is only delivered at the point of benefitAbout 6% of the amount of drug in (a). For this reason, the punctal implant devices do not pose any drug safety risks to the patient.

Adverse events: the risk associated with the device is possible ocular irritation due to punctal implants or ineffective relief of ocular hypertension. The total drug content of the punctal implant system is equivalent to 10-20 drops of dulcinSafety was assessed by assessing ocular signs, intraocular pressure (IOP), visual acuity under slit lamp examination, and by determining the incidence and severity of adverse events.

As a result: IOP per subject is the average IOP of both eyes unless only 1 eye is treated. Thus, 10 eyes equals 5The subject was placed. On days 0-28, N-10 eyes, on day 52, N-9 eyes, on days 88-105, N-6 eyes (2 subjects were excluded on day 88, and use of alism was later started in contralateral eyes where the implant had been lost(ii) a Thus 3 subjects remained in the study on days 88-105). At day 105, 1 of the 3 subjects lost efficacy (IOP within 2mmHg at baseline).

As shown in figure 1 and table 3, the mean baseline IOP after washout was 22.9 ± 0.9 mmHg. The mean IOP was reduced to 16.1 + -1.1 mmHg 7 days after PPDS placement and remained stable throughout the follow-up period. On day 88, the mean IOP was 16.5. + -. 1.2mmHg, representing a 28% pressure drop from baseline (p < 0.05). These results demonstrate that the sustained release punctal implant delivery system is safe and effective for treatment in the subject population studied.

Table 3: average intraocular pressure in subjects treated with 14 μ g latanoprost punctal plug delivery system

Days of study	N	Average IOP	Standard deviation of
				0	5 bit (10 eyes)	22.9	0.9
1	5 bit (10 eyes)	19.7	1.2
				7	5 bit (10 eyes)	16.1	1.1
14	5 bit (10 eyes)	15.8	1.2
				21	5 bit (10 eyes)	15.8	1.6
28	5 bit (10 eyes)	16.2	1.4
				52	5 bit (9 eyes)	15.9	0.7
88	3 bit (6 eyes)	16.8	1.4
				105	3 bit (6 eyes)	19.0	3.0

Example 2

A randomized, blinded phase II study ("CORE study") was conducted to evaluate the IOP-lowering effect of a latanoprost punctal plug delivery system (L-PPDS) containing a sustained release drug-eluting drug CORE. Patients with open angle glaucoma at position 61 with post-clearance IOP between 21 and 30mmHg or ocular hypertension were likewise randomized to one of 3L-PPDS treatment groups containing latanoprost doses of 3.5, 14 or 21 μ g followed for up to 12 weeks. The primary outcome measure is IOP change from baseline and safety.

Efficacy results: the analysis of primary efficacy was based on the proportion of subjects in each treatment group who did not lose efficacy at each visit, IOP, and IOP changes and percent changes from baseline. The intent-to-treat (ITT) data set included data from all randomized subjects. No subject is excluded because of protocol violations. The ITT data set was used to analyze all study variables.

The results of the study showed that there was an IOP-lowering effect at all 3 doses, with an average reduction from baseline at week 12 of 20%. The average IOP at screening was 16.8 mmHg; after washout, the mean IOP was 24.4. + -. 2.1 mmHg. Figures 9 and 10 show the mean IOP changes from baseline at weeks 4, 8 and 12 for 3.5, 14 and 21 microgram implants. On week 8, in the 3.5, 14 and 21 μ g groups (n ═ 17, 15 and 15), the patients' average IOP reductions were-3.6 ± 2.4, 4.2 ± 3.7 and 4.4 ± 2.4mmHg, respectively. At week 12, the mean IOP reduction was-5.4 ± 2.7, -4.8 ± 3.2 and-4.9 ± 2.1(n ═ 13, 12 and 13), respectively, representing a 20% reduction from baseline at week 12. The retention ratio of L-PPDS was 75%.

Figure 11 shows the IOP drop from baseline at week 12 for each treatment group. Some decrease in IOP is shown on the X-axis. The percentage of patients showing those reductions in each treatment group is shown on the Y-axis.

Figures 12-15 compare the efficacy of L-PPDS with other topical glaucoma medications.

Safety results: the L-PPDS was well tolerated during the test period (see FIG. 16). The total adverse events ranged from 1.6% to 14.8%, and were not dose-dependent. The most common adverse events were increased lacrimation (tear production) and ocular discomfort (14.8% and 9.8%, respectively), which were mild and transient in nature and most likely resolved during the adaptation period for punctal implant wear. The proportion of ocular hyperemia and punctate keratitis was 1.6%. At week 12, 89% of patients rated L-PPDS comfort as "no detection", 8% as "light detection", and lacrimation as "no" (78%), "occasional" (14%) or "light" (5%). The remaining 3% of patients did not receive comfort and tear assessments at week 12. Due to the loss of efficacy/inadequate IOP control, 19 patients discontinued visits before week 12.

Figure 16 shows adverse events associated with L-PPDS for each treatment group and all treatment groups. Reported adverse events included conjunctival hyperemia, ocular pruritus, eyelid margin crusting, foreign body sensation, increased lacrimation, ocular discomfort, ocular hyperemia, and punctate keratitis.

Figures 17 and 18 compare the adverse events of L-PPDS with those previously reported for eye drops of other agents, including travoprost, timolol, latanoprost, and bimatoprost. The following documents are used for L-PPDS comparison and are incorporated herein by reference in their entirety: travoprot supplied With Latanoprost and Timolol in documents With open-angle Glaucoma 0r Ocular Hypertension. am J Ophthalmol 2001; 132: 472-484 (other reported adverse events include ocular pain, cataracts, dry eye, blepharitis, blurred vision); a Six-month randomised Clinical logic composing the interferometric Pressure-lower effect of Bimatoprost and Latanoprostin Properties With Ocular hyper tension or Glaucoma.Am J Ophthalmol 2003; 135: 55-63 (other reported adverse events include eyelash growth); One-Yeast, random student comprehensive Bimatoplast and Timolol in Glaucomaand Ocular Hypertension. Arch opthalmol V120Oct.20021286-1293 (other reported adverse events include eyelash growth, dry eye, and Ocular pain; also including the BiD group, and confirmed a higher adverse event incidence than Marek; and 0.005% (50mg/mL) of an ophthalmic solution of Prideda (Pharmacia) approved 6/5 th 1996: medical Officers Review, pages 93, 98-100, is provided by FOI Services.

To summarize: CORE is the first known randomized, parallel group, multicenter us trial of a sustained and controlled punctal implant drug delivery system to study glaucoma. At 3 months, a 20% reduction in average IOP was observed. Ocular implants are well tolerated; no significant safety issues were observed.

Bibliography

1.Allen RC.Medical management of glaucoma.In：Albert DM，Jakobiec FA，eds.Principles and Practice of Ophthalmology.Philadelphia，PA：WB Saunders and Co.；1994：1569-1588.

2.AlphaMed punctum plug[product label].Wauwatosa，WI：AlphaMed.

3.Anderson DR，Chauhan B，Johnson C，Katz J，Patella VM，Drance SM.Criteria forprogression of glaucoma in clinical management and in outcome studies.Am J Ophthalmol2000；130(6)：827-829.

4.Anderson DR.Collaborative normal tension glaucoma study.Curr OpinOphthalmol.2003；14(2)：86-90.

5.Bailey IL，Lovie JE.New design principles for visual acuity letter charts.Am JOptom Physiol Opt 1976 Nov；53(11)：740-745.

6.Balaram M，Schaumberg DA，Dana MR.Efficacy and tolerability outcomes afterpunctal occlusion with silicone plugs in dry eye syndrome.Am J Ophthalmol.2001；131(1)：30-36.

7.Baudouin C，Rouland JF，Nordmann JP，Bron A，Pelen F.Efficacy of first-orsecond-line latanoprost on intraocular pressure and ocular symptoms in patients withopen-angle glaucoma or ocular hypertension[in French].J Fr Ophtalmol.2006；29(6)：615-624.

8.Bengtsson B，Heijl A.A long-term prospective study of risk factors forglaucomatous visual field loss in patients with ocular hypertension.J Glaucoma.2005；14(2)：135-138.

9.Brown MM，Brown GC，Spaeth GL.Improper topical self-administration of ocularmedication among patients with glaucoma.Can J Ophthalmol.1984；19(1)：2-5.

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

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

12.Diestelhorst M，Schaefer CP，Beusterien KM，et al.Persistency and clinicaloutcomes associated with latanoprost and beta-blocker monotherapy：evidence from aEuropean retrospective cohort study.Eur J Ophthalmol.2003；13(suppl 4)：S21-S29.

13.Fiscella RG，Geller JL，Gryz LL，Wilensky J，Viana M.Cost considerations ofmedical therapy for glaucoma.Am J Ophthalmol.1999；128(4)：426-433.

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

15.Gordon MO，Beiser JA，Brandt JD，et al.The Ocular Hypertension TreatmentStudy：baseline factors that predict the onset of primary open-angle glaucoma.ArchOphthalmol.2002；120(6)：714-720；discussion 829-830.

16.Gordon MO，Kass MA.The Ocular Hypertension Treatment Study：design andbaseline description of the participants.Arch Ophthalmol 1999；117(5)：573-583.

17.Gurwitz JH，Glynn RJ，Monane M，et al.Treatment for glaucoma：adherenceby the elderly.Am J Public Health.1993；83(5)：711-716.

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

19.Higginbotham EJ，Gordon MO，Beiser JA，et al.The Ocular HypertensionTreatment Study：topical medication delays or prevents primary open-angle glaucoma inAfrican American individuals.Arch Ophthalmol.2004；122(6)：813-820.

20.Javitt JC，Metrick S，Wang F：Costs of glaucoma in the United States.InvestOphthalmol Vis Sci 1995；36：S429.

21.Kass MA，Gordon MO，Kymes SM.Incorporating the results of the OcularHypertension Treatment Study into clinical practice.Arch Ophthalmol.2005；123(7)：1021-1022.

22.Kass MA，Heuer DK，Higginbotham EJ，et al.The Ocular HypertensionTreatment Study：a randomized trial determines that topical ocular hypotensive medicationdelays or prevents the onset of primary open-angle glaucoma.Arch Ophthalmol 2002；120(6)：701-713.

23.Kim BM，Osmanovic SS，Edward DP.Pyogenic granulomas after siliconepunctal plugs：a clinical and histopathologic study.Am J Ophthalmol.2005；139(4)：678-684.

24.Kobelt-Nguyen G，Gerdtham UG，Alm A：Costs of treating primary open-angleglaucoma and ocular hypertension：a retrospective，observational two-year chart review ofnewly diagnosed patients in Sweden and the United States.J Glaucoma 1998；7：95.

25.Leibowitz HM，Krueger DE，Maunder LR，et al.The Framingham Eye Studymonograph：An ophthalmological and epidemiological study of cataract，glaucoma，diabeticretinopathy，macular degeneration，and visual acuity in a general population of 2631 adults，1973-1975.Surv Ophthalmol.1980；24(Suppl)：335-610.

26.Leonard R.Statistics on Vision Impairment：A Resource Manual(5th E dition).New York：Arlene R.Gordon Research Institute of Lighthouse International；2002.

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

28.Lichter PR，Musch DC，Gillespie BW，et al，and the CIGTS Study Group.Interim clinical outcomes in the Collaborative Initial Glaucoma Treatment Studycomparing initial treatment randomized to medications or surgery.Ophthalmology.2001；108(11)：1943-1953.

29.Liu JHK，Krpike DF，Twa MD，et al.Twenty-four-hour pattern of intraocularpressure in the aging population.Invest Ophthalmol Vis Sci.1999；40(12)：2912-2917.

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

31.Mindel JS.Pharmacokinetics.In：Tasman W，Jaeger EA，eds.Duane′sFoundations of Clinical Ophthalmology.Vol.3：Lippincott Williams & Wilkins，1995：1-17.

32.Musch DC，Lichter PR，Guire KE，Standardi CL，The CIGTS Study Group.The Collaborative Initial Glaucoma Treatment Study Design，Methods，and BaselineCharacteristics of Enrolled Patients.Ophthalmology 1999；106：653-662.

33.Nordstrom BL，Friedman DS，Mozaffari E，Quigley HA，Walker AM.Persistece and adherence with topical glaucoma therapy.Am J Ophthalmol.2005；140(4)：598-606.

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

35.O′Donoghue EP，and the UK and Ireland Latanoprost Study Group.Acomparison of latanoprost and dorzolamide in patients with glaucoma and ocularhypertension：a 3 month，randomised study.Br J Ophthalmol.2000；84：579-582.

36.Parrish RK，Palmberg P，Sheu WP，XLT Study Group.A comparison oflatanoprost，bimatoprost，and travoprost in patients with elevated intraocular pressure：a12-week，randomized，masked-evaluator multicenter study.Am J Ophthalmol.2003；135(5)：688-703.

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

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

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

40.Reardon G，Schwartz GF，Mozaffari E.Patient persistency withpharmacotherapy in the management of glaucoma.Eur J Ophthalmol.2003；13(suppl4)：S44-S52.

41.Regnier，et al.Ocular Effects of Topical 0.03％ Latanoprost Solution inNormotensive Feline Eyes.Vet Ophthalmol 2006；9(1)：39-43.

42.Rouland JF，Berdeaux G，Lafuma A.The economic burden of glaucoma andocular hypertension：implications for patient management：a review.Drugs Aging 2005；22(4)：315-321.

43.Sakamoto A，Kitagawa K，Tatami A.Efficacy and retention rate of two types ofsilicone punctal plugs in patients with and withoutSyndrome.Cornea.2004；23(3)：249-254.

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

45.Shaya FT，Mullins CD，Wong W，Cho J.Discontinuation rates of topicalglaucoma medications in a managed care population.Am J Manag Care.2002；8(suppl10)：S271-S277.

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

47.Spooner JJ，Bullano MF，Ikeda LI，et al.Rates of discontinuation and changeof glaucoma therapy in a managed care setting.Am J Manag Care.2002；8(suppl10)：S262-S270.

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

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

50.Thylefors B，Negrel A-D，Pararajasegaram R，Dadzie KY：Global data onblindness.Bull World Health Org 1995；73：115-121.

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

52.Waldock A，Snape J，Graham CM.Effects of glaucoma medications on thecardiorespiratory and intraocular pressure status of newly diagnosed glaucoma patients.BrJ Ophthalmol.2000；84(7)：710-713.

53.Whitcup SM，et al.A randomized，doube masked，multicenter clinical trialcomparing latanoprost and timolol for the treatment of glaucoma and acular hypertension.Br J Ophthalmol 2003；87：57-62.

54.Winfield AJ，et al.A study of the causes of non-compliance by patientsprescribed eyedrops.Br J Ophthalmol.1990 Aug；74(8)：477-80.

55.Woodward DF，et al.Pharmalogical Characterization of a Novel AntiglaucomaAgent，(AGN 192024).J Pharmacology and Experimental Therapeutics 2003；305(2)：772-785.

56.(latanoprost ophthalmic solution)0.005％(50μg/mL)prescribinginformation.Division of Pfizer Inc.New York，NY：Pharmacia & Upjohn Company；2007.http://www.xalatan.com/consumer/prescribinginfo.asp.Accessed October 1，2007.

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.

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.

The concentrations, amounts, percentages, time periods, etc. of the various components of the invention (including but not limited to the drug core, IOP lowering indications and treatment periods), or the uses or effects of the various components, are often shown in this patent document in the form of ranges or baseline thresholds. The description in the form of a range or baseline threshold is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Thus, the description of a range or baseline threshold should be considered to have specifically disclosed all possible subranges as well as individual numerical values within that range or exceeding the baseline threshold. For example, a description of a drug core having a concentration range of 3.5 micrograms to 135 micrograms of drug or other medicament should be considered to have specifically disclosed sub-ranges, such as 5 micrograms to 134 micrograms, 6 micrograms to 135 micrograms, 40 micrograms to 100 micrograms, 44 micrograms to 46 micrograms, etc., as well as individual numbers within that range, such as 41 micrograms, 42 micrograms, 43 micrograms, 44 micrograms, 45 micrograms, 46 micrograms, 47 micrograms, 48 micrograms, etc. This structure applies to all aspects of this description regardless of the width of the range or baseline threshold.

Claims (54)

1. A method of reducing intraocular pressure in an eye of a patient in need thereof, the method comprising administering to the eye of the patient a sustained release topical formulation comprising an intraocular pressure-reducing therapeutic agent, wherein the intraocular pressure-reducing therapeutic agent is capable of being continuously released over time to the eye, and wherein the intraocular pressure is reduced at least 10% from baseline.

2. The method of claim 1, wherein the intraocular pressure is reduced from baseline by an amount selected from the group consisting of: at least 15%, at least 20% and at least 25%.

3. The method of claim 1, wherein the intraocular pressure-reducing therapeutic agent is released for a period of time selected from the group consisting of: at least about 30 days, at least about 60 days, and at least about 90 days.

4. The method of claim 1 wherein the intraocular pressure-reducing therapeutic agent is an anti-glaucoma drug.

5. The method of claim 4, wherein the anti-glaucoma drug is selected from the group consisting of: adrenergic agonists, adrenergic antagonists, beta-blockers, carbonic anhydrase inhibitors, parasympathomimetics, prostaglandin analogs, hypotensive lipids, neuroprotective agents, and combinations thereof.

6. The method of claim 5, wherein the anti-glaucoma drug is latanoprost.

7. The method of claim 1, wherein the formulation is disposed in and eluted from an ocular implant.

8. The method of claim 7, wherein the ocular implant comprises a punctal implant.

9. The method of claim 8, wherein the formulation is impregnated within the punctal implant such that at least one surface of the implant is coated with the formulation.

10. The method of claim 8, wherein the formulation is contained within a sustained release core disposed within the punctal implant.

11. The method of claim 8, wherein the punctal implant contains an intraocular pressure-reducing therapeutic agent in an amount of about 3.5 micrograms, about 14 micrograms, about 21 micrograms, or about 44 micrograms.

12. The method of claim 8, wherein the punctal implant is inserted into one punctum of each of both eyes of the patient.

13. The method of claim 1, wherein the formulation is administered approximately every 90 days, and wherein the intraocular pressure-reducing therapeutic agent is continuously released to the eye for a period of time 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, and about 900 days.

14. The method of claim 1, wherein between about 25 ng/day and about 250 ng/day of the intraocular pressure-reducing therapeutic agent is released.

15. The method of claim 1, wherein the intraocular pressure is at least about 20mm Hg prior to administration of the intraocular pressure-reducing therapeutic agent.

16. The method of claim 1, wherein 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 56 days, up to about 84 days, and up to about 105 days.

17. The method of claim 1 wherein patient noncompliance is significantly reduced as compared to eye drops of intraocular pressure-reducing therapeutic agents.

18. The method of claim 1 wherein the intraocular pressure is associated with ocular hypertension.

19. The method of claim 1 wherein the intraocular pressure is associated with glaucoma.

20. A method of reducing intraocular pressure in an eye of a patient in need thereof, the method comprising inserting an implant into at least one punctum of the eye, wherein the implant comprises a sustained release core comprising an intraocular pressure-reducing agent, wherein the intraocular pressure-reducing therapeutic agent is capable of being continuously released over time to the eye, and wherein the intraocular pressure is reduced at least about 10% from baseline.

21. The method of claim 20, wherein the intraocular pressure is reduced from baseline by an amount selected from the group consisting of: at least 15%, at least 20% and at least 25%.

22. The method of claim 20, wherein the intraocular pressure-reducing therapeutic agent is released for a period of time selected from the group consisting of: at least about 30 days, at least about 60 days, and at least about 90 days.

23. The method of claim 20, wherein the sustained release core is disposed in the implant body.

24. The method of claim 20, wherein the patient is suffering from glaucoma.

25. The method of claim 20, wherein at least one of the implant or the sustained release core is at least partially coated with an impermeable coating.

26. The method of claim 25, wherein the impermeable coating comprises parylene.

27. The method of claim 20, wherein the intraocular pressure-reducing therapeutic agent comprises latanoprost.

28. Use of an intraocular pressure-reducing therapeutic agent in the manufacture of a medicament for reducing intraocular pressure in an eye of a patient in need thereof, wherein the medicament is a sustained release topical formulation, wherein the intraocular pressure-reducing therapeutic agent is capable of continuous release to the eye over time, and wherein the intraocular pressure of the patient is reduced at least about 10% from baseline.

29. The use of claim 28, wherein the intraocular pressure is reduced from baseline by an amount selected from the group consisting of: at least 15%, at least 20% and at least 25%.

30. The use of claim 28, wherein the intraocular pressure-reducing therapeutic agent is released for a period of time selected from the group consisting of: at least about 30 days, at least about 60 days, and at least about 90 days.

31. The use of claim 28, wherein the intraocular pressure-reducing therapeutic agent is an anti-glaucoma drug.

32. The use of claim 31, wherein the anti-glaucoma agent is selected from the group consisting of: adrenergic agonists, adrenergic antagonists, beta-blockers, carbonic anhydrase inhibitors, parasympathomimetics, prostaglandin analogs, hypotensive lipids, neuroprotective agents, and combinations thereof.

33. The use of claim 32, wherein the anti-glaucoma drug is latanoprost.

34. The use of claim 28, wherein the formulation is disposed in and eluted from an ocular implant.

35. The use of claim 34, wherein the ocular implant comprises a punctal implant.

36. The use of claim 35, wherein the formulation is impregnated within the punctal implant such that at least one surface of the implant is coated with the formulation.

37. The use of claim 35, wherein the formulation is contained within a sustained release core disposed within the punctal implant.

38. The use of claim 35, wherein the punctal implant contains an intraocular pressure-reducing therapeutic agent in an amount of about 3.5 micrograms, about 14 micrograms, about 21 micrograms, or about 44 micrograms.

39. The use of claim 35, wherein the punctal implant is inserted into one punctum of each of both eyes of the patient.

40. The use of claim 28, wherein the formulation is administered approximately once every 90 days, and wherein the intraocular pressure-reducing therapeutic agent is continuously released to the eye for a period of time 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, and about 900 days.

41. The use of claim 28, wherein about 25 ng/day to about 250 ng/day of the intraocular pressure-reducing therapeutic agent is released.

42. The use of claim 28, wherein the intraocular pressure is at least about 20mm Hg prior to administration of the intraocular pressure-reducing therapeutic agent.

43. The use of claim 28, wherein the reduction in intraocular pressure is maintained for the following consecutive period of time: up to about 7 days, up to about 14 days, up to about 21 days, up to about 28 days, up to about 56 days, up to about 84 days, and up to about 105 days.

44. The use of claim 28 wherein patient noncompliance is significantly reduced as compared to eye drops of intraocular pressure-reducing therapeutic agents.

45. The use of claim 28, wherein the intraocular pressure is associated with ocular hypertension.

46. The use of claim 28, wherein the intraocular pressure is associated with glaucoma.

47. Use of an intraocular pressure-reducing agent in the manufacture of a medicament for reducing intraocular pressure in an eye of a patient in need thereof, wherein the medicament is adapted for use in an implant inserted into at least one punctum of the eye, wherein the implant comprises a sustained release core comprising the intraocular pressure-reducing agent, wherein the intraocular pressure-reducing therapeutic agent is capable of being continuously released over time to the eye, and wherein the intraocular pressure is reduced at least about 10% from baseline.

48. The use of claim 47, wherein the intraocular pressure is reduced from baseline by an amount selected from the group consisting of: at least 15%, at least 20% and at least 25%.

49. The use of claim 47, wherein the intraocular pressure-reducing therapeutic agent is released for a period of time selected from the group consisting of: at least about 30 days, at least about 60 days, and at least about 90 days.

50. The use of claim 47, wherein the sustained release core is disposed in an implant body.

51. The use of claim 47, wherein the patient is suffering from glaucoma.

52. The use of claim 47, wherein at least one of the implant or the sustained release core is at least partially coated with an impermeable coating.

53. The use of claim 52, wherein the impermeable coating comprises parylene.

54. The use of claim 47, wherein the intraocular pressure-reducing therapeutic agent comprises latanoprost.