WO2016178900A1 - Ocular implant for delivery of pyridinecarboxamide derivative - Google Patents

Abstract

The present invention generally relates to local therapies for the eye and, more particularly, to shaped controlled-release ocular implant devices, including methods for making and using such devices, for delivery of 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4 -(trifluoromethoxy)phenyl]-3-pyridinecarboxamide (referred to as Formula I) or a salt thereof, to the eye. This implant is for placement in the sub-Tenon's space of the eye and provides sustained release of the compound for the treatment or prevention of a disorder of the eye.

Description

OCULAR IMPLANT FOR DELIVERY OF P YRIDINEC ARB OXAMIDE DERIVATIVE CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62/155,632, entitled Ocular Implant for Delivery of a Pyridinecarboxamide Derivative, filed May 1, 2015, the contents of which are herein incorporated by reference in their entirety.

FIELD OF THE INVENTION

[0002] The present invention generally relates to local therapies for the eye and, more particularly, to curved controlled-release ocular implant devices, including methods for making and using such devices, for delivery of 2-[[[2-[(hydroxyacetyl)amino]-4- pyridinyl]methyl]thio]-N-[4 -(trifluoromethoxy)phenyl]-3-pyridinecarboxamide or a pharmaceutically acceptable salt thereof to the eye.

BACKGROUND OF THE INVENTION

[0003] Ocular angiogenesis, the formation of new blood vessels from the existing vascular tree, is an important cause for severe loss of vision. It can occur in a spectrum of ocular disorders such as age-related macular degeneration (AMD), diabetic retinopathy, retinal artery or vein occlusion, and retinopathy of prematurity (ROP). One of the underlying causes of vision loss in proliferative retinal diseases is the increased vascular permeability leading to retinal edema, vascular fragility resulting in hemorrhage, or fibrovascular proliferation with tractional and rhegmatogenous retinal detachment. Pro- and antiangiogenic factors regulate an "angiogenic switch," which when turned on, leads to the pathogenesis of the above ocular diseases. Abnormal retinal vascular permeability such as hyperpermeability causing edema in the area of the macula is the leading cause of vision loss in diseases such as diabetic retinopathy, exudative macular degeneration, retinal vascular occlusions, and inflammatory and neoplastic conditions.

[0004] Age-related macular degeneration (AMD) is a common disease associated with aging that gradually impairs sharp, central vision. There are two common forms of AMD: dry AMD and wet AMD. About ninety percent of the cases of AMD are the dry form, caused by degeneration and thinning of the tissues of the macula; a region in the center of the retina that allows people to see straight ahead and to discern fine details. Although only about ten percent of people with AMD have the wet form, it poses a much greater threat to vision. With the wet form of the disease, rapidly growing abnormal blood vessels known as choroidal neovascular membranes (CNVM) develop beneath the macula. These vessels leak fluid and blood that destroy light sensing cells, thereby producing blinding scar tissue, with resultant severe loss of central vision. Wet AMD is the leading cause of legal blindness in the United States for people aged sixty-five or more with approximately 25,000 new cases diagnosed each year in the United States. Ideally, treatments of the indication would include inducing an inhibitory effect on the choroidal neovascularization (CNV) associated with AMD. The macula is located at the back of the eye and therefore treatment of CNVM by topical delivery of pharmacological agents to the tissues of the macula tissues is not possible. Intravitreal injections of anti-angiogenic agents, laser photocoagulation, photodynamic therapy, and surgical removal are currently used to treat CNVM. Unfortunately, the recurrence rate using such methods exceeds 50 - 90% in some cases. In most cases indefinite treatment is required.

[0005] 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4 - (trifluoromethoxy)phenyl]-3-pyridinecarboxamide is a small molecule represented by the following structural formula:

[0006]

Formula I

[0007] Formula I is described in US Patent 7,544,703, the entire contents of which are incorporated herein by reference in their entirety. Formula I is shown to exhibit a cell proliferation inhibiting effect in a test system using a VEGF-induced HUVEC proliferation reaction evaluation system and exhibit a choroidal neovascularization inhibiting effect in a test system using a rat choroidal neovascularization model. Formula I is useful as a pharmaceutical, prophylactic or therapeutic agent for diseases such as age-related macular degeneration, diabetic retinopathy, diabetic macular edema and the like.

[0008] In the treatment of many diseases and disorders of the eye, and especially in the case of degenerative or persistent conditions, implantable sustained-release delivery devices have been desired that would continuously administer a therapeutic agent to the eye for a prolonged period of time. [0009] Local ocular implants of a wide variety of constructions and placements have been proposed heretofore for dispensing a therapeutic drug to the eye. Local ocular implants avoid the shortcomings and complications that can arise from systemic therapies of eye disorders. For instance, oral therapies for the eye fail to provide sustained-release of the drug into the eye. Instead, oral therapies often only result in negligible actual absorption of the drug in the ocular tissues due to low bioavailability of the drug. Ocular drug levels following systemic administration of drugs is usually limited by various blood/ocular barriers (i.e., tight junctions between the endothelial cells of the capillaries). These barriers limit the amounts of drugs entering the eye via systemic circulation. In addition, variable gastrointestinal drug absorption and/or liver metabolism of the medications can lead to dosage-dependent and inter-individual variations in vitreous drug levels. Moreover, adverse side effects have been associated with systemic administration of certain drugs to the eyes.

[0010] For instance, systemic treatments of the eye using the immune response modifier cyclosporine A (CsA) have the potential to cause nephrotoxicity or increase the risk of opportunistic infections, among other concerns. This is unfortunate since CsA is a recognized effective active agent for treatment of a wide variety of eye diseases and indications, such as endogenous or anterior uveitis, corneal transplantation, Behcet's disease, vernal or ligneous keratoconjunctivitis, dry eye syndrome, and the like. In addition, rejection of corneal allografts and stem cell grafts occurs in up to 90% of patients when associated with risk factors such as corneal neovascularization. CsA has been identified as a possibly useful drug for reducing the failure rate of such surgical procedures for those patients. Thus, other feasible delivery routes for such drugs that can avoid such drawbacks associated with systemic delivery are in demand.

[0011] Apart from implant therapies, other local administration routes for the eye have included topical delivery. Such therapies include ophthalmic drops and topical ointments containing the medicament. Tight junctions between corneal epithelial cells limit the intraocular penetration of eye drops and ointments. Topical delivery to the eye surface via solutions or ointments can in certain cases achieve limited, variable penetration of the anterior chamber of the eye. However, therapeutic levels of the drug are not achieved and sustained in the middle or back portions of the eye. This is a major drawback, as the back (posterior) chamber of the eye is a frequent site of inflammation or otherwise the site of action where, ideally, ocular drug therapy should be targeted for many indications. As an approach for circumventing the barriers encountered by local topical delivery, one local therapy route for the eye has involved direct intravitreal injection of a treatment drug through the sclera (i.e., the spherical, collagen-rich outer covering of the eye). However, the intravitreal injection delivery route tends to result in a short half-life and rapid clearance without sustained release capability being attained. Consequently, weekly to monthly injections are frequently required to maintain therapeutic ocular drug levels. This is not practical for many patients.

[0012] Given these drawbacks, the use of implant devices placed in or adjacent to the eye tissues to deliver therapeutic drugs thereto should offer a great many advantages and opportunities over the rival therapy routes. Despite the variety of ocular implant devices which have been described and used in the past, the full potential of the therapy route has not been realized. Among other things, prior ocular implant devices deliver the drug to the eye tissues via a single mode of administration for a given treatment, such as via slow constant rate infusion at low dosage. However, in many different clinical situations, such as with CNVM in AMD, this mode of drug administration might be a sub-optimal ocular therapy regimen.

[0013] Another problem exists with previous ocular implants, from a construction standpoint, insofar as preparation techniques thereof have relied on covering the drug pellet or core with a permeable polymer by multi-wet coating and drying approaches. Such wet coating approaches can raise product quality control issues such as an increased risk of delamination of the thinly applied coatings during subsequent dippings, as well as thickness variability of the polymer around the drug pellets obtained during hardening. Additionally, increased production costs and time from higher rejection rates and labor and an increased potential for device contamination from additional handling are known problems with present implant technology.

Therefore there is a need for new ocular implants which avoid the shortcomings of the commercially available implants.

SUMMARY OF THE INVENTION

[0014] The present invention provides a shaped ocular implant for delivery of 2-[[[2- [(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4 -(trifluoromethoxy)phenyl]-3- pyridinecarboxamide or a salt thereof (hereinafter also referred to as "Formula I") to the eye for treatment of diseases and disorders of the eye.

[0015] Accordingly, certain aspects of the present invention provide local treatment of a variety of eye diseases. Other aspects of the present invention also provide a method for the delivery of Formula I to the eye to effectively treat eye disease, while reducing or eliminating any systemic side effects. Certain aspects of the present invention also provide shaped sustained-release ocular implants for administration of Formula I to the eye for prolonged periods of time. Additionally, certain aspects of the present invention provide approaches to alter the areas of the eye that are affected by diffusion of Formula I from sustained-release ocular implants. Certain aspects of the present invention also provide methods for making shaped ocular implants with reduced product variability.

[0016] Other aspects of the present invention also provide methods for making shaped ocular implants well-suited for ocular treatment trials using animal models. Other advantages and benefits of aspects of the present invention will be apparent from consideration of the present specification.

[0017] In one aspect of the present invention, there is provided a method for forming a molded single-layer ocular implant, the implant comprising Formula I for treatment or prevention of a disorder of the eye, the method comprising: a) dispensing a silicone adhesive comprising Formula I dispersed therein on a mold body to form a silicone layer having a curved external surface in contact with the bottom of the curved depression and further comprising an exposed upper surface; b) generating a curvature in the exposed upper surface of the silicone layer, thereby forming a curved silicone layer interface surface; c) curing the silicone layer, thereby providing the molded single-layer ocular implant.

[0018] In one aspect of the present invention, there is provided a method for forming a molded two-layer ocular implant, the implant comprising Formula I for treatment or prevention of a disorder of the eye, the method comprising: a) dispensing a polymer into a curved depression on a mold body to form a polymer layer having a curved external surface in contact with the bottom of the curved depression and further comprising an exposed upper surface; b) generating a curvature in the exposed upper surface of the polymer layer, thereby forming a curved polymer layer interface surface; c) curing the polymer layer, thereby providing a cured polymer curved polymer layer interface surface; d) dispensing a silicone adhesive comprising Formula I dispersed therein onto the hardened interface surface to provide a silicone layer with an exposed surface; e) generating a curvature in the exposed surface of the silicone layer thereby forming a curved eye-contacting surface; and f) curing the silicone layer such that the first layer and second layer are fixed to each other, thereby forming the molded two-layer ocular implant.

[0019] In one embodiment the invention is a single-layer ocular implant comprising Formula I for treatment or prevention of a disorder of the eye, the implant comprising: a layer comprising silicone and Formula I. [0020] In one embodiment the invention is a two-layer ocular implant comprising Formula I for treatment or prevention of a disorder of the eye, the implant comprising: a first layer comprising a polymer; and a second layer comprising silicone and Formula I.

[0021] Another aspect of the invention is a single- or two-layer implant formed by the methods described herein. The implants of certain embodiments may be used for

implantation into the sub-Tenon's space of a human. The implant of other embodiments may be used for implantation into the sub-Tenon's space of a rodent.

[0022] In one embodiment the invention is a method of treating a disease or disorder in a subject in need thereof, comprising placing an implant comprising: a layer comprising silicone and therapeutically effective amount of Formula I; in an ocular region.

[0023] In one embodiment the invention is a method of treating a disease or disorder in a subject in need thereof, comprising placing an implant comprising: a first layer comprising a polymer; and a second layer comprising silicone and therapeutically effective amount of Formula I; in an ocular region.

[0024] In one embodiment the disease or disorder is age-related macular degeneration (AMD), wet age related macular degeneration, choroidal neovascularization, diabetic macular edema (DME), retinal vein occlusion, diabetic retinopathy, proliferative diabetic retinopathy, polypoidal chorioretinopathy, uveitis, retinopathy of prematurity in newborns, choroidal melanoma, chorodial metastasis, retinal capillary hemangioma, retinal artery occlusion, polypoidal choroidal vasculopathy, retinal angiomatous proliferation, myopic choroidal neovascularization, eye tumor, radiation retinopathy, rubeosis iridis, rubeotic glaucoma, and proliferative vitreoretinopathy.

[0025] Another aspect of the invention is a molded two-layer ocular implant comprising Formula I for treatment or prevention of a disorder of the eye, the implant comprising: a first hardened layer comprising a polymer, the first hardened layer comprising curvature at both the upper and lower surfaces (see FIG. 3); and a second hardened layer comprising a silicone adhesive and Formula I, the second hardened layer comprising curvature at both the upper and lower surfaces (see FIG. 3).

[0026] In these and other ways described below, the inventive implants offer a myriad of advantages, improvements, benefits, and therapeutic opportunities. The inventive implants are highly versatile and can be tailored to enhance the delivery regimen. The implants of this invention permit continuous release of Formula I into the eye over a specified period of time, which can be weeks, months, or even years as desired. As another advantage, the inventive implant systems of this invention require intervention only for initiation and termination of the therapy (i.e., removal of the implant). Patient compliance issues during a regimen are eliminated. The time-dependent delivery of one or more drugs to the eye by this invention makes it possible to maximize the pharmacological and physiological effects of the eye treatment. The inventive implants have human and veterinary applicability.

BRIEF DESCRIPTION OF THE FIGURES

[0027] FIG. 1 is a perspective view of an implant according to one embodiment of the invention with curved lines 12 and 14 showing the curvature of the upper surface of the implant. FIG. 1 is reproduced from US Patent publication US2016/0081920.

[0028] FIG. 2 is a top view of the implant of FIG. 1. FIG. 2 is reproduced from US Patent publication US2016/0081920.

[0029] FIG. 3 is a cross sectional side view of the implant of FIG. 1 and FIG. 2 taken along line 3'-3' of FIG. 2 (along dotted line 14) showing the lower layer 16 and upper layer 18 of the implant with drug particles 20 dispersed in the lower layer 16. Features of the implant are omitted for clarity. FIG. 3 is reproduced from US Patent publication

US2016/0081920.

[0030] FIG. 4 is a schematic side slice view showing selected anatomy of an eye E with the placement of a perspective view of the implant of FIG. 1-3 in the sub-Tenon's space E0. Other structures of the eye E are shown for context. FIG. 4 is reproduced from US Patent publication US2016/0081920.

[0031] FIG. 5 is a magnified view of the rectangular inset 5' of FIG. 4 showing a perspective view of the implant embodiment of FIG. 1-4. Also shown are additional layers of structures and tissues within the eye and diffusion of a drug 20 to the sclera E3 and the choroid E4. FIG. 5 is reproduced from US Patent publication US2016/0081920.

[0032] FIG. 6 is a plot showing the kinetics of release of the drug Formula I from a 2.5 mm implant containing 30% by weight of Formula I into phosphate buffered saline (PBS). The drug is released to its solubility limit within about 6 hours.

[0033] FIG. 7 is a plot showing the rate of release of Formula I into PBS from the same 2.5 mm implant described for FIG. 6 over a period of 12 days.

[0034] FIG. 8 is a plot showing the retinal concentration of Formula I in albino and pigmented rats which were subjected to the implant described in Example 3 over a period of 4 weeks.

[0035] FIG. 9 is a plot showing the rate of release of Formula I in vitro from the implant described in Example 4 over a period of 6 weeks. [0036] FIG. 10 is a plot showing the cumulative release of Formula I in vitro from the implant described in Example 4 over a period of 6 weeks.

[0037] FIG. 11 is a plot showing the percent of cumulative release of Formula I in vitro from the implant described in Example 4 over a period of 6 weeks.

[0038] FIG. 12 is a plot showing the rate of release of Formula I in vitro from the implant described in Example 5 over a period of 6 weeks.

[0039] FIG. 13 is a plot showing the cumulative release of Formula I in vitro from the implant described in Example 5 over a period of 6 weeks.

[0040] FIG. 14 is a plot showing the percent of cumulative release of Formula I in vitro from the implant described in Example 5 over a period of 6 weeks.

DETAILED DESCRIPTION OF THE INVENTION

Overview

[0041] The present invention provides a molded composite ocular implant comprising Formula I for treatment or prevention of a disorder of the eye. Also provided are methods of making the silicone composite ocular implant and using the implant for treatment of various diseases or disorders of the eye, including tests of the implant with experimental animals such as rodents. This implant provides sustained release of Formula I during the treatment or prevention of the disorder of the eye. This implant configuration is particularly well-suited for placement in the sub-Tenon's space (also known as the bulbar sheath), but is not limited thereto and could be installed on or in other eye regions where convenient and useful.

General Definitions

[0042] The following general definitions are supplied in order to facilitate the understanding of the present invention.

[0043] As used herein, the term "depression" refers to a region of a surface which is lower with respect to the majority of the surface. More specifically, the present specification describes a depression in a mold body which represents a region with a lower surface than the remainder of the contact surface of the mold body.

[0044] As used herein, the term "excipient" includes, but is not limited to, any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, and the like, as suited to the particular dosage form desired. Various excipients for formulating pharmaceutical compositions and techniques for preparing the composition are known in the art (see Remington: The Science and Practice of Pharmacy, 21^st Edition, A. R. Gennaro, Lippincott, Williams & Wilkins, Baltimore, MD, 2006; incorporated herein by reference in its entirety). The use of a conventional excipient medium may be contemplated within the scope of the present disclosure, except insofar as any conventional excipient medium may be incompatible with a substance or its derivatives, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other

component(s) of the therapeutic agent. As used herein, the term "impression body" refers to a body used to alter a surface of another body by pressure. The impression body may have one or more features that produce an impression having a specific shape such as a curvature for example.

[0045] As used herein, the terms "hardened layer", "hardened polymer", "cured layer" and "cured polymer" can be used interchangeably and mean a polymer fluid which has been cured to form a substantially solid polymer.

[0046] As used herein the term "ophthalmic permeation agent" (also known as "transport facilitator") refers to a compound that increases the permeability of a therapeutic agent into the tissues of the eye. Methylsulfonylmethane is a non-limiting example of an ophthalmic permeation agent.

[0047] As used herein, the term "permeation agent" refers to a molecule that increases the permeability of a therapeutic agent. An ophthalmic permeation agent increases the permeability of a therapeutic agent with respect to tissues of the eye.

[0048] As used herein, the term "pharmaceutically acceptable excipient," as used herein, refers to any ingredient other than active agents (e.g., as described herein) present in pharmaceutical compositions and having the properties of being substantially nontoxic and non-inflammatory in subj ects. In some embodiments, pharmaceutically acceptable excipients are vehicles capable of suspending and/or dissolving active agents. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, and waters of hydration. Excipients include, but are not limited to: butylated hydroxy toluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine,

methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0049] As used herein the term "radius of curvature" refers to the radius of a circle that best fits the curved surface at a given point.

[0050] As used herein, the term "subject" or "patient" refers to any organism to which a composition in accordance with the invention may be administered, e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes. Typical subjects include animals (e.g. , mammals such as mice, rats, rabbits, non-human primates, and humans).

[0051] As used herein, the term "substantially" refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result. The term "substantially" is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.

[0052] An individual who is "suffering from" a disease, disorder, and/or condition has been diagnosed with or displays one or more symptoms of a disease, disorder, and/or condition.

[0053] An individual who is "susceptible to" a disease, disorder, and/or condition has not been diagnosed with and/or may not exhibit symptoms of the disease, disorder, and/or condition but harbors a propensity to develop a disease or its symptoms. In some

embodiments, an individual who is susceptible to a disease, disorder, and/or condition (for example, cancer) may be characterized by one or more of the following: (1) a genetic mutation associated with development of the disease, disorder, and/or condition; (2) a genetic polymorphism associated with development of the disease, disorder, and/or condition; (3) increased and/or decreased expression and/or activity of a protein and/or nucleic acid associated with the disease, disorder, and/or condition; (4) habits and/or lifestyles associated with development of the disease, disorder, and/or condition; (5) a family history of the disease, disorder, and/or condition; and (6) exposure to and/or infection with a microbe associated with development of the disease, disorder, and/or condition. In some

embodiments, an individual who is susceptible to a disease, disorder, and/or condition will develop the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition will not develop the disease, disorder, and/or condition. [0054] The term "therapeutic agent" refers to any agent that, when administered to a subject has a therapeutic, diagnostic, and/or prophylactic effect and/or elicits a desired biological and/or pharmacological effect.

[0055] As used herein, the term "therapeutically effective amount" means an amount of an agent to be delivered (e.g. , nucleic acid, drug, therapeutic agent, diagnostic agent, prophylactic agent, etc.) that is sufficient, when administered to a subject suffering from or susceptible to an infection, disease, disorder, and/or condition, to treat, improve symptoms of, diagnose, prevent, and/or delay the onset of the infection, disease, disorder, and/or condition. In some embodiments, a therapeutically effective amount is provided in a single dose. In some embodiments, a therapeutically effective amount is administered in a dosage regimen comprising a plurality of doses. Those skilled in the art will appreciate that in some embodiments, a unit dosage form may be considered to comprise a therapeutically effective amount of a particular agent or entity if it comprises an amount that is effective when administered as part of such a dosage regimen.

[0056] As used herein, the term "treating" refers to partially or completely alleviating, ameliorating, improving, relieving, delaying onset of, inhibiting progression of, reducing severity of, and/or reducing incidence of one or more symptoms or features of a particular infection, disease, disorder, and/or condition. For example, "treating" cancer may refer to inhibiting survival, growth, and/or spread of a tumor. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition and/or to a subject who exhibits only early signs of a disease, disorder, and/or condition for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and/or condition as well as to a subject who is exhibiting signs of a disease, disorder and/or condition.

[0057] As used herein, the terms "salt" or" pharmaceutically acceptable salt" of 2-[[[2- [(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4 -(trifluoromethoxy)phenyl]-3- pyridinecarboxamide refers to any pharmaceutically acceptable salt, and examples thereof include salts with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid or phosphoric acid; salts with an organic acid such as acetic acid, fumalic acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, lactic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzensulfonic acid or p- toluenesulfonic acid; salts with an alkali metal such as lithium, sodium or potassium; salts with an alkaline earth metal such as calcium or magnesium; and quaternary salts with ammonia, methyl iodide and the like. A single-layer ocular implant for treatment of eye disorders

[0058] In one embodiment the ocular implants of the present invention contain between about 5 to about 80%, between about 5 to about 70%, between about 5 to about 60%, between about 5 to about 50%, between about 10 to about 60%, between about 10 to about 50%, between about 20 to about 40%, between about 25 to about 45%, and about 30% by weight Formula I.

[0059] Another aspect of the present invention is a method for forming a molded single- layer ocular implant, the implant comprising Formula I for treatment or prevention of a disorder of the eye, the method comprising: a) dispensing a silicone adhesive comprising Formula I dispersed therein into a curved depression on a first mold body to form silicone layer with a curved silicone layer interface surface in contact with the bottom of the curved depression and further comprising an exposed upper silicone surface; b) generating a curvature in the exposed silicone surface, thereby forming a curved eye-contacting surface; c) curing the silicone layer to produce a hardened silicone layer.

[0060] In certain embodiments, the implant is circular or oval-shaped.

[0061] In certain embodiments, step b) is performed using an impression body with a curved protrusion for generating the curvature in the exposed surface of the exposed surface of the silicone layer.

[0062] In certain embodiments, the silicone layer is about a thickness ranging from about 1 mm to about 3 mm, or from about 1 mm to about 2 mm.

[0063] In certain embodiments, the silicone layer further comprise an agent that blocks lymphatic absorption of Formula I. In certain embodiments agents the block lymoathic absorption include, but are not limited to, nystatin, amiloride, and N-ethymaleimide.

[0064] In certain embodiments, the silicone layer further comprises an ophthalmic permeation agent that increases ocular permeability of Formula I into the eye.In certain embodiments, the ophthalmic permeation agent is, for example, methylsulfonylmethane, dimethyl sulfoxide, dimethylformamide, azone, N-methyl-2- pyrolidone glycols (diethylene glycol and tetraethylene glycol), fatty acids (lauric acid, myristic acid and capric acid), nonic surfactant (polyoxyethylene-2-oleyl ether, polyoxy ethylene-2-stearly ether), oxazolidinones such as 4-decyloxazolidin-2-one or urea.

[0065] In certain embodiments, the radius of curvature of the curved eye-contacting surface of the silicone layer ranges from between about 5 mm to about 15 mm, from about 7 to about 14 mm, or from about 9 mm to about 12 mm. In certain embodiments, the radius of curvature of the silicone layer of the implant of the present invention ranges from between about 5 mm to about 15 mm, from about 7 to about 14 mm, or from about 9 mm to about 12 mm.

[0066] In certain embodiments, the implant of the present invention is circular with a diameter ranging between about 1 mm and about 14 mm, about 1 mm and about 10 mm, or about 1 mm and about 6 mm.

[0067] In certain embodiments, the implant of the present invention is circular with a diameter ranging between about 8 mm and about 14 mm.

[0068] In certain embodiments, the implant of the present invention is circular with a diameter ranging between about 6 mm and about 10 mm.

[0069] In certain embodiments, the implant of the present invention is circular with a diameter ranging between about 1 mm and about 3 mm.

[0070] In certain embodiments, the silicone layer further comprises an excipient that improves the release of Formula I.

[0071] In certain embodiments, the excipient is selected from one or more of isopropyl myristate, levomenthol, propylene and tetraglycol.

A two-layer ocular implant for treatment of eye disorders

[0072] In one embodiment the ocular implants of the present invention contain between about 5 to about 80%, between about 5 to about 70%, between about 5 to about 60%, between about 5 to about 50%, between about 10 to about 60%, between about 10 to about 50%, between about 20 to about 40%, between about 25 to about 45%, and about 30% by weight Formula I.

[0073] Another aspect of the present invention is a method for forming a molded two- layer ocular implant, the implant comprising Formula I for treatment or prevention of a disorder of the eye, the method comprising: a) dispensing a polymer into a curved depression on a first mold body to form a polymer layer having a curved external surface in contact with the bottom of the curved depression and further comprising an exposed upper polymer surface; b) generating a curvature in the exposed upper surface of the polymer layer, thereby forming a curved polymer layer interface surface; c) curing the polymer layer to produce a hardened polymer layer, d) dispensing a silicone adhesive comprising Formula I dispersed therein into second curved depression on a second mold body to provide a silicone layer with a curved silicone layer interface surface in contact with the bottom of the curved depression and further comprising an exposed upper silicone surface; e) generating a curvature in the exposed silicone surface, thereby forming a curved eye-contacting surface; f) curing the silicone layer to produce a hardened silicone layer; and g) joining the hardened polymer layer to the hardened silicone layer by attachment of the polymer layer interface surface to the silicone layer interface surface with biocompatible adhesive.

[0074] In certain embodiments, the implant is circular or oval-shaped.

[0075] In certain embodiments, steps b) and e) are performed using an impression body with a curved protrusion for generating the curvature in the exposed surface of the polymer layer and the exposed surface of the silicone layer.

[0076] In certain embodiments, step b) is performed using a first impression body comprising a first curved protrusion for generating the curvature in the exposed surface of the polymer layer and step e) is performed using a second impression body comprising a second curved protrusion for generating the curvature in the exposed surface of the silicone layer, wherein the curvature dimensions of the first and second curved protrusions are different.

[0077] In certain embodiments, the polymer layer is resistant to diffusion of Formula I from the silicone layer.

[0078] In certain embodiments, the polymer layer is substantially impermeable to diffusion of Formula I from the silicone layer.

[0079] In certain embodiments, the polymer is polyvinyl acetate, cross-linked polyvinyl alcohol, cross-linked polyvinyl butyrate, ethylene ethylacrylate co-polymer, polyethyl hexylacrylate, polyvinyl chloride, polyvinyl acetals, plasiticized ethylene vinylacetate copolymer, polyvinyl alcohol, polyvinyl acetate, ethylene vinylchloride copolymer, polyvinyl esters, polyvinylbutyrate, polyvinylformal, polyamides, polymethylmethacrylate, polybutylmethacrylate, plasticized polyvinyl chloride, plasticized nylon, plasticized soft nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, polytetrafluoroethylene, polyvinylidene chloride,

polyacrylonitrile, cross-linked polyvinylpyrrolidone, polytrifluorochloroethylene, chlorinated polyethylene, poly(l,4'-isopropylidene diphenylene carbonate), vinylidene chloride, acrylonitrile copolymer, vinyl chloride-diethyl fumarate copolymer, silicone rubbers, medical grade polydimethylsiloxanes, ethylene-propylene rubber, silicone-carbonate copolymers, vinylidene chloride-vinyl chloride copolymer, vinyl chloride-acrylonitrile copolymer or vinylidene chloride-acrylonitride copolymer.

[0080] In certain embodiments, the polymer layer and the silicone layer are each about a thickness ranging from about 1 mm to about 3 mm, or from about 1 mm to about 2 mm. [0081] In certain embodiments, the polymer layer and/or the silicone layer further comprise an agent that blocks lymphatic absorption of Formula I. In certain embodiments agents the block lymoathic absorption include, but are not limited to, nystatin, amiloride, and N-ethymaleimide.

[0082] In certain embodiments, the silicone layer further comprises an ophthalmic permeation agent that increases ocular permeability of Formula I into the eye. In certain embodiments, the ophthalmic permeation agent is, for example, methylsulfonylmethane, dimethyl sulfoxide, dimethylformamide, azone, N-methyl-2- pyrolidone glycols (diethylene glycol and tetraethylene glycol), fatty acids (lauric acid, myristic acid and capric acid), nonic surfactant (polyoxyethylene-2-oleyl ether, polyoxy ethylene-2-stearly ether), oxazolidinones such as 4-decyloxazolidin-2-one or urea.

[0083] In certain embodiments, the radius of curvature of the curved eye-contacting surface of the silicone layer ranges from between about 5 mm to about 15 mm, from about 7 to about 14 mm, or from about 9 mm to about 12 mm. In certain embodiments, the radius of curvature of the silicone layer of the implant of the present invention ranges from between about 5 mm to about 15 mm, from about 7 to about 14 mm, or from about 9 mm to about 12 mm.

[0084] In certain embodiments, the implant of the present invention is circular with a diameter ranging between about 1 mm and about 14 mm, about 1 mm and about 10 mm, or about 1 mm and about 6 mm.

[0085] In certain embodiments, the implant of the present invention is circular with a diameter ranging between about 8 mm and about 14 mm.

[0086] In certain embodiments, the implant of the present invention is circular with a diameter ranging between about 6 mm and about 10 mm.

[0087] In certain embodiments, the implant of the present invention is circular with a diameter ranging between about 1 mm and about 3 mm.

[0088] In certain embodiments, the silicone layer further comprises an excipient that improves the release of Formula I.

[0089] In certain embodiments, the excipient is selected from one or more of isopropyl myristate, levomenthol, propylene and tetraglycol.

[0090] An example embodiment of the ocular implant of the present invention will now be described with reference to FIG. 1 to 5. Skilled artisans will appreciate that elements in the figures are illustrated for simplicity and clarity and have not necessarily been drawn to scale. For example, the dimensions of some of the features shown in the figures may be enlarged relative to other elements to better illustrate and/or facilitate the discussion herein of the embodiments of the invention. Features in the various figures identified with the same reference numerals represent like features, unless indicated otherwise. Altemative features of alternative embodiments will also be discussed in context of the features of this example embodiment.

[0091] One embodiment of the present invention is a curved two-layer composite ocular implant comprising Formula I. The curved shape of the implant 10 is indicated by dotted lines 12 and 14 in FIG. 1 and FIG. 2. This shape may be formed by using a molding process which will be described in WO2014/179568.

[0092] The ocular implant is formed of two curved layers, a lower layer 16 and an upper layer 18 as can be seen in the cross-sectional view of FIG. 3 which is taken along line 3'-3' of FIG. 2. In this particular embodiment, the lower layer 16 is formed of a silicone adhesive which contains a therapeutic agent 20. The two layers are demarcated by line 26 (FIG. 3). The lower layer 16 has a lower surface 24 which makes contact with the sclera E3 when the implant is in use.

[0093] The upper layer 18 is formed of a polymer which may be a silicone polymer or another polymer. Examples of polymers suitable for forming the upper layer 18 include, but are not limited to, polyvinyl acetate, cross-linked polyvinyl alcohol, cross-linked polyvinyl butyrate, ethylene ethylacrylate co-polymer, polyethyl hexylacrylate, polyvinyl chloride, polyvinyl acetals, plasiticized ethylene vinylacetate copolymer, polyvinyl alcohol, polyvinyl acetate, ethylene vinylchloride copolymer, polyvinyl esters, polyvinylbutyrate,

polyvinylformal, polyamides, polymethylmethacrylate, polybutylmethacrylate, plasticized polyvinyl chloride, plasticized nylon, plasticized soft nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, polytetrafluoroethylene, polyvinylidene chloride, polyacrylonitrile, cross-linked

polyvinylpyrrolidone, polytrifluorochloroethylene, chlorinated polyethylene, poly(l,4'- isopropylidene diphenylene carbonate), vinylidene chloride, acrylonitrile copolymer, vinyl chloride-diethyl fumarate copolymer, silicone rubbers, medical grade polydimethylsiloxanes, ethylene-propylene rubber, silicone-carbonate copolymers, vinylidene chloride-vinyl chloride copolymer, vinyl chloride-acrylonitrile copolymer or vinylidene chloride-acrylonitride copolymer or any suitable equivalent of these polymers or combinations thereof. In certain alternative embodiments, the polymer is a silicone adhesive which may be the same as the silicone adhesive used to form the lower layer 16. [0094] As noted above, the lower layer 16 is formed of a medical grade silicone adhesive, generally is a polydimethylsiloxane (PDMS)-based compound. The silicone adhesive is biologically (physiologically) inert and is well tolerated by body tissues. Suitable silicones for use in the practice of this embodiment include MED-6810 silicone, MED 1-4213, MED2- 4213 silicone, which can be obtained from NuSil Technology LLC (Carpinteria, CA, USA). Other biocompatible silicone adhesives may be used and can be adapted for use in preparation of implants according to certain alternative embodiments of the present invention. The time and temperature needed to cure the silicone will depend on the silicone used and the drug release profile desired. These silicones, if left to cure at room temperature (e.g., 20-30 °C) will require about 24 hours or more to cure. The cure rate will increase with increasing cure temperatures. For instance, MED2-4213 silicone will cure in about 30 minutes at about 100 °C. As will be discussed in more detail below, the more quickly the silicone is cured, the less opportunity for therapeutic agent, Formula I, to leach out of the layer. In some cases, a catalyst such as platinum may be used to induce curing.

[0095] Dimensions of the ocular implant may vary. However, in this particular embodiment, the implant 10 has a diameter of 7 mm and a thickness of 2 mm. In this particular embodiment, each of the two layers 16 and 18 is 1 mm thick. In this particular embodiment, the upper surface 22 of the upper layer 18 has a radius of curvature of 5 - 15 mm for generally conforming to the radius of curvature of the surface of Tenon's capsule El of an average human eye (as indicated in FIG. 5). Likewise, the lower layer 16 is also curved with a similar radius of curvature configured to generally conform to the radius of curvature of the sclera E3 of an average human eye. These dimensions provide the implant 10 with characteristics appropriate for implantation with scleral contact in the sub-Tenon's space E0 of a human. It will be understood by the skilled person that these dimensions should be modified appropriately for an implant designed for use in an experimental animal such as a rat, mouse or rabbit for example. Armed with the knowledge of average dimensions of the eye and radii of curvature of Tenon's capsule and sclera of the chose experimental animal, the dimensions of an ocular implant according to may be selected by the skilled person and appropriate molding tools may be constructed without undue experimentation.

[0096] It is advantageous to provide the ocular implant with an upper layer 18 which is generally resistant to diffusion of the therapeutic agent 20 which is dispersed in the lower layer 16. In certain embodiments, the upper layer 18 is impermeable to the therapeutic agent 20. In other embodiments, the therapeutic agent 20 has a rate of diffusion within the upper layer 18 which is significantly less than the rate of diffusion of the therapeutic agent 20 out of the lower layer 16 and into the sclera. In this context, the term "significantly less" means 30%, 40%, 50%, 60%, 70%, 80%, 90% or 99% less than the rate of diffusion of the therapeutic agent 20 out of the lower layer 16 and into the sclera E3. The reduced diffusion characteristics of the therapeutic agent 20 in the upper layer 18 relative to the lower layer 16 provide the advantage of preventing loss of the therapeutic agent 20 to tissues where it is not needed. The reduced rate of diffusion of the therapeutic agent 20 through the upper layer 18 thereby encourages unidirectional diffusion of the therapeutic agent 20 from the lower layer 16 into the sclera E3 and choroid E4 for transfer to the macula E6 where its desired mechanism of action will be effected. A further advantage provided by the reduced diffusion characteristics of the therapeutic agent 20 in the upper layer 18 relative to the lower layer 16 is gained in preventing the therapeutic agent 20 from entering the lymphatic system via Tenon's capsule El and the conjunctiva E2 for transfer to other tissues where it may cause undesirable side-effects. Thus, in certain alternative embodiments of the present invention, the upper layer 18 or lower layer 16 further includes an agent that blocks lymphatic absorption.

[0097] In this particular embodiment, the thickness of the implant is 2 mm with the two layers 16 and 18 each being 1 mm in thick. The skilled person will appreciate that the thickness of each layer may be modified according to various embodiments of the invention, which may include variations with respect to the composition of silicone adhesive of the lower layer, the polymer of the upper layer, or the properties of drugs and/or formulations thereof used in the implant. The dimensional thickness may be modified appropriately by the skilled person without undue experimentation.

[0098] Positioning of the implant 10 with respect to the anatomical structures of an eye E is indicated in FIG. 4 and FIG. 5. In FIG. 4, the features of the implant 10 are omitted for clarity. For convenient reference, the anatomical structures shown in FIG. 4 and FIG. 5 include the sub-Tenon's space E0, Tenon's capsule El (also known as the bulbar sheath), the sclera E3, the choroid E4 (shown in FIG. 5 only), the optic nerve E5, the macula E6, the vitreous humor E7 and the upper and lower eyelids E8 and E9.

[0099] Referring now to FIG. 5 (which represents a magnification of the inset labeled 5' in FIG. 4) there is provided additional detail regarding the placement of the implant 10. The implant 10 is located in the sub-Tenon's space E0 with its lower surface 24 resting upon the surface of the sclera E3. It is also seen that the upper surface 22 of the implant 10 has a curvature which generally conforms to the curvature of the surface of Tenon's capsule El. This feature provides the advantage of minimizing discomfort to the eye as a result of contact of Tenon's capsule El with upper edges of the implant 10. The curved upper surface 22 is smooth and does not have sharp edges which would otherwise cause irritations and/or damage to the tissues of Tenon's capsule and possibly also the conjunctiva E2 in the event that a sharp edge of an alternative implant were to completely puncture Tenon's capsule El and penetrate the conjunctiva E2.

[0100] Drug particles 20 will be released downward to the sclera E3 as indicated by the arrows in FIG. 5, because they are concentrated in the lower layer 16 and because the upper layer 18 is generally resistant to diffusion of the therapeutic agent 20 as described above. In FIG. 5, it is shown that three drug particles 20B have diffused from the lower layer 16 through the sclera E3 to the choroid E4 and one drug particle 20A has diffused from the lower layer 16 to the sclera E3. These drug particles 20A and 20B are expected to be transferred by either diffusion or an active physiological mechanism, or a combination thereof, to the macula E6 where the desired pharmaceutical effect will be obtained. Notably, FIG. 5 does not include arrows indicating diffusion of the therapeutic agent 20 into the upper layer 18 and to upper tissues in Tenon's capsule El and the conjunctiva E2. This is due to resistance of the upper layer 18 to diffusion of the therapeutic agent 20.

[0101] In certain embodiments, the implant 10 is provided with a suture platform (not shown) which can be formed as part of the implant to facilitate attachment of the implant 10 to the sclera E3. An implant having a suture platform with a mesh contained therein to hold sutures in place is described in U.S. Patent 7,658,364, the contents of which are incorporated herein by reference in entirety. The implant described herein can be modified without undue experimentation to include such a suture platform by modification of the molding processes which will be described in detail herein below. Alternatively the implant of the invention may also be fixed to a suture stub as described also in U.S. Patent 7,658,364, the entire contents of which is incorporated herein by reference.

[0102] In accordance with further aspects of the present invention, the implants used herein may be made using a mold assembly and molding process for forming a two-layer ocular implant as described in WO 1024/179568.

[0103] Another aspect of the invention is a two-layer implant formed by the methods described herein. The implants of certain embodiments may be used for implantation into the sub-Tenon's space of a human. The implant of other embodiments may be used for implantation into the sub-Tenon's space of a rodent.

[0104] Another aspect of the invention is a molded two-layer ocular implant comprising Formula I for treatment or prevention of a disorder of the eye, the implant comprising: a first hardened layer comprising a polymer, the first hardened layer comprising curvature at both the upper and lower surfaces (see FIG. 3); and a second hardened layer comprising a silicone adhesive and Formula I, the second hardened layer and comprising curvature at both the upper and lower surfaces (see FIG. 3).

[0105] In certain embodiments, the curvature of one surface of the first hardened layer and the curvature of one surface of the second layer are both formed using an impression body with a curved protrusion.

[0106] In certain embodiments, the first and second hardened layers are formed as follows: the curvature of a first surface of the first hardened layer is formed by dispensing the polymer into a mold body; the curvature of a second surface of the first hardened layer is formed by a first curved protrusion on a first impression body; the curvature of a first surface of the second hardened layer is formed by dispensing the silicone adhesive onto the curvature of the second surface of the first hardened layer; and the curvature of a second surface of the second hardened layer is formed by a second curved protrusion on a second impression body.

[0107] In certain embodiments, the first hardened layer is resistant to diffusion of Formula I from the second hardened layer.

[0108] In certain embodiments, the first hardened layer is substantially impermeable to diffusion of Formula I from the second hardened layer.

[0109] In certain embodiments the implants used herein are formed in a mold assembly described in WO2014/179568 the entire contents of which are incorporated herein by reference.

Kit for production of single-layer ocular implants

[0110] Another aspect of the present invention is a kit for preparing a molded single-layer composite ocular implant comprising Formula I for treatment or prevention of a disorder of the eye, the kit comprising: a) a mold assembly for molding the implant; b) a silicone adhesive comprising Formula I for forming a first layer.

[0111] In certain embodiments, the mold assembly of the kit is the mold assembly described herein which includes a single impression body. In other embodiments, the mold assembly of the kit is the mold assembly which includes two impression bodies.

[0112] In certain embodiments, the kit further comprises instructions for making a molded single-layer silicon composite ocular implant.

[0113] The present invention also contemplates a kit for production of single-layer ocular implants. The kit may include any or all of the components and features thereof which are described above. In a very basic embodiment, the kit includes a) a mold body with a depression on its contact surface; and b) an impression body with a protrusion on its contact surface configured to form a silicone-drug (Formula I) layer with curved upper and lower surfaces. This particular embodiment will yield a resilient cured layer that is resistant to damage by pressure of the upper mold body part.

[0114] An alternative embodiment of the kit further includes c) a second impression body with a protrusion on its contact surface which is configured to form the sclera-contacting surface of the silicone-drug (Formula I) layer.

[0115] An alternative embodiment of the kit further includes d) silicone materials for forming the layers of the single-layer ocular implant.

[0116] In some embodiments of the kit, the mold assembly body parts are cylindrical and the kit further includes e) centrifuge tubes for conducting degassing procedures.

[0117] In a further embodiment, the kit further includes a means for trimming the excess silicone from the contact surface of the mold body. In certain embodiments, this means for trimming is provided by a punching device dimensioned to consistently cut the perimeter of a two layer implant to specific dimensions.

[0118] In some embodiments, the kit includes instructions for using the components of the kit in a molding process for molding a two-layer ocular implant.

Kit for production of two-layer ocular implants

[0119] Another aspect of the present invention is a kit for preparing a molded two-layer composite ocular implant comprising Formula I for treatment or prevention of a disorder of the eye, the kit comprising: a) a mold assembly for molding the implant; b) a silicone adhesive comprising Formula I for forming a first layer; and c) a polymer for forming a second layer.

[0120] In certain embodiments, the mold assembly of the kit is the mold assembly described herein which includes a single impression body. In other embodiments, the mold assembly of the kit is the mold assembly which includes two impression bodies.

[0121] In certain embodiments, the kit further comprises instructions for making a molded two-layer silicon composite ocular implant by sequential layering of the polymer and the silicone adhesive comprising Formula I.

[0122] The present invention also contemplates a kit for production of two-layer ocular implants. The kit may include any or all of the components and features thereof which are described above. In a very basic embodiment, the kit includes a) a mold body with a depression on its contact surface; and b) an impression body with a protrusion on its contact surface configured to form a polymer layer with curved upper and lower surfaces and to also form a silicone-drug (Formula I) layer with curved upper and lower surfaces. This particular embodiment is used in conjunction with polymer and silicone adhesive materials provided separately which yield resilient cured layers that are resistant to damage by pressure of the upper mold body part against both layers.

[0123] An alternative embodiment of the kit further includes c) a second impression body with a protrusion on its contact surface which is configured to form the sclera-contacting surface of the silicone-drug (Formula I) layer.

[0124] An alternative embodiment of the kit further includes d) polymer and silicone materials for forming the layers of the two-layer ocular implant.

[0125] In some embodiments of the kit, the mold assembly body parts are cylindrical and the kit further includes e) centrifuge tubes for conducting degassing procedures.

[0126] In a further embodiment, the kit further includes a means for trimming the excess polymer and silicone from the contact surface of the mold body. In certain embodiments, this means for trimming is provided by a punching device dimensioned to consistently cut the perimeter of a two layer implant to specific dimensions.

[0127] In some embodiments, the kit includes instructions for using the components of the kit in a molding process for molding a two-layer ocular implant.

Administration of the ocular implant

[0128] To administer the implants of the present invention, the subconjunctival matrix implant preferably is placed behind the surface epithelium within the sub-Tenon's space. This is done by a surgical procedure that can be performed in an out-patient setting. A lid speculum is placed and a conjunctival radial incision is made through the conjunctiva over the area where the implant is to be placed. Wescott scissors are used to dissect posterior to Tenon's fascia and the implant is inserted. The conjunctiva is reapproximated using a running 10-0 vicryl suture. The eye has many barriers that do not permit easy penetration of drugs. These include the surface epithelium on the front (cornea) of the eye and the blood/retinal barrier either within the retinal blood vessels or between the retinal pigment epithelium that both have tight junctions. These implants are generally about 1 -3 mm in diameter for small rodent (i.e., mouse and rat) eyes, 6-10 mm in diameter for rabbit and human eyes and 6-14 mm in diameter for equine eyes. [0129] In certain embodiments, an applicator device is used to inject the implant into the sub-Tenon's space. Such devices are known in the art and have been used for intraocular injections into the vitreous humor of the eye, particularly in intraocular lens implantation after cataract surgery. In certain embodiments, the device is provided with a retractor that engages the conjunctiva and the surface of Tenon's capsule to produce an opening into the sub-Tenon's space. The device is also provided with a means for pushing the implant into the sub-Tenon's space such that withdrawal of the device allows the surrounding tissues to collapse back into place while holding the implant at the desired location.

[0130] Additionally, when the implant is placed near the limbus (i.e., the area where the conjunctiva attaches anteriorly on the eye) to encourage the drug diffusion to enter the cornea, it may be preferable to fixate the matrix implant with one or two absorbable sutures (e.g., 10-0 absorbable vicryl sutures). This is done by making holes with a 30 gauge needle in the peripheral portion of the implant, approximately 250-500 μιτι away from the peripheral edge of the implant. The holes are made 180 degrees from each other. This is done because subconjunctival matrix implants of this invention, when placed near the cornea, are at higher risk to extrude because of the action of the upper eye lid when blinking. When

subconjunctival matrix implants of this invention are placed about 4 mm or more away from the limbus, the sutures are optional.

[0131] Additionally the implants can be placed anywhere in the eye where treatment in needed, such as, on the sclera, on the choroid, on the retina, on the conjunctiva, or in the vitreous body. The implant can in certain embodiments be placed in the eye by intravitreal injection. As used therein the terms "on the sclera", "on the choroid", "on the retina", and "on the conjunctiva" include placement of the implant on the inner surface, on the outer surface and anywhere inside these tissues.

[0132] This matrix implant can deliver therapeutic levels of different pharmaceuticals agents to the eye to treat a variety of diseases. Using a rabbit model, drug released from the implant placed in the eye produces negligible levels of the drug in the blood. This significantly reduces the chances of systemic drug side-effects. This implant design of this invention is prepared by unique methodologies and selections of materials leading to and imparting the unique pharmacological performance properties present in the finished devices.

Methods of Treatment [0133] In some embodiments the present invention is a method of treating a disease or disorder in a subject in need thereof, wherein the disease or disorder is caused by

angiogenesis or vascular hyperpermeability.

[0134] The implants of this invention can be used to treat a number of eye diseases and indications including, for example, age-related macular degeneration (AMD), wet age-related macular degeneration, choroidal neovascularization, diabetic macular edema (DME), retinal vein occlusion, diabetic retinopathy, proliferative diabetic retinopathy, polypoidal chorioretinopathy, uveitis, retinopathy of prematurity in newborns, choroidal melanoma, chorodial metastasis, retinal capillary hemangioma, retinal artery occlusion, polypoidal choroidal vasculopathy, retinal angiomatous proliferation, myopic choroidal

neovascularization, eye tumor, radiation retinopathy, rubeosis iridis, rubeotic glaucoma, and proliferative vitreoretinopathy.

Diagnostic Methods

[0135] Another aspect of the present invention is a method for determining the effectiveness of the implant as described herein for treatment or prevention of wet macular degeneration in a rodent, rabbit or non-human primate model, the method comprising: a) placing the implant as described herein in the sub-Tenon's space of the eye of the animal, wherein the animal is, for example, exposed to laser to induce choroidal neovascularization or exposed to exogenous excess vascular endothelial growth factor to produce vascular leakage and b) monitoring the release of the Formula I over time by examining the eye of the animal with histology, electroretinography, direct measurement of tissues levels of Formula I or changes in gene expression in various retinal tissues, thereby indicating the effectiveness of the implant against macular degeneration.

[0136] Another aspect of the present invention is a method for evaluating the effectiveness of the implant as described herein for treatment or prevention of macular degeneration in a human, the method comprising: a) placing the implant as described herein into the sub-Tenon's space of the eye of the human; and b) examining the eye of the human using a technique selected from the group consisting of: optical coherence tomography, fluorescein angiography, indocyanine green angiography, best corrected visual acuity, fundus photography or fundus autofluorescence. In one aspect the macular degeneration is age- related macular degeneration.

Examples [0137] The foregoing description will be more fully understood with reference to the following examples. These examples, are, however, exemplary of methods of making and using certain aspects of the present invention and are not intended to impose limits on the scope of the invention as defined by the appended claims.

Example 1 : Release Kinetics of the drug Formula I from a silicone ocular implant

[0138] An experimental ocular implant 2.5 mm in diameter and 1 mm thickness was prepared which contains 30% by weight of Formula I. To create this implant Formula I was solubilized in silicone oil into which it is highly soluble, a platinum crosslinker catalyst was added, the solution was mixed, poured into a Teflon mold of predetermined size and the implants were placed at 100 degree C for 30 minutes. In a first experiment, the rate of release of Formula I from the implant into a solution of phosphate-buffered saline (PBS) was measured over a period of about 24 hours. The results are shown in FIG. 6 where it is seen that the drug is eluted from the implant to its solubility limit of 1.10 ng/μΕ within about 6 hours and remains at approximately the same level for the rest of the 24-hour experiment.

[0139] In a related experiment, release of the drug from the same implant was monitored over a period of 12 days with measurements of the total amount of drug released ^g) from the implant being obtained once each day. The graph shown in FIG. 7 indicates that Formula I elutes consistently from the implant at a constant rate of about 1 μg per day.

Example 2: Measurement of concentration of Formula I in ocular tissues after implantation of Formula I silicone implant on rat episclera and comparison with direct episcleral injection of Formula I alone.

[0140] In this series of experiments, concentration of Formula I in ocular tissues after implantation of the same 2.5 mm ocular implant described in Example 1 on rat episclera was and compared with direct episcleral inj ection of similar doses of Formula I. In animals treated with the ocular implant, a 4 mm punch of tissue comprising sclera, conjunctiva and choroid (SCC) was obtained daily for five days. The amount of drug in the retinal tissue was determined separately. Concentrations of Formula I (ng/mL) were determined and are shown in Table 1 below. The error data shown is the standard deviation.

Table 1 : Concentrations of Formula I (ng/mL) in Ocular Tissues after implantation of a

Formula I silicone ocular implant on rat episclera

2 2.49 ± 0.39 7.2 ± 2.7

3 2.54 ± 0.71 9.5 ± 2.9

4 3.26 ± 0.60 7.6 ± 2.0

5 3.23 ± 0.46 7.1 ± 0.4

[0141] The data shown in Table 1 provide an indication that the maximal concentration of Formula I in retina is obtained after about three days after implantation and that the maximal concentration of Formula I in SCC is obtained after about 2 days after implantation. The concentrations of Formula I in the ocular tissues are in a ratio of approximately 2.5: 1 (episclera:retina). In contrast, measurement of Formula I levels in similarly processed tissues of rats subj ected to direct episcleral injections of similar doses of Formula I after three days indicated that the concentration of Formula I in SCC tissues was 5.4 ± 1.3 ng/mL and undetectable in the retinal tissue (the lower limit of detection is 0.4 ng/mL).

[0142] These results provide an indication that higher concentrations of the drug Formula I can be obtained in SCC and retinal tissues using an implant of the present invention than can be obtained by direct episcleral injection. Without being bound by any particular theory, it is believed that certain drugs, particularly highly lipophilic drugs, recrystallize or otherwise morph into a different crystal form within the matrix of the silicone implant and that this change produces improved ocular penetration relative to direct injections of the "naked" drug.

[0143] These results provide an indication that the implant of the invention functions as intended. The determination that higher concentrations of a lipophilic ocular drug in ocular tissues can be obtained from the implant relative to direct episcleral injections provides a basis for the prediction that other lipophilic drugs can be used in the implant and will function in a similar manner. It is further predicted on this basis that the implant of the present invention is useful for treatment of the ocular disorders described hereinabove.

Example 3 : Concentration of Formula I in retina after implantation of Formula I silicone implant on epiclera of albino and pigmented rat.

[0144] In a related experiment, release of Formula I from an ocular implant in albino and pigmented rats was monitored over a period of 4 weeks following episcleral implantation. The implant was 2.5 mm in diameter and 1 mm thickness and contained 30% by weight of Formula I. To create this implant Formula I was solubilized in silicone oil into which it is highly soluble in which a platinum crosslinker catalyst was added, the solution was mixed, poured into a Teflon mold of predetermined size and the implants were placed at 100 degree C for 30 minutes. The graph shown in FIG. 8 shows the concentration of Formula I in the retina in ng/mg over the four week period. The error data shown is the standard deviation.

[0145] In animals treated with the ocular implant, the amount of drug in the retina was determined by drug extraction and subsequent high pressure liquid chromatography (HPLC). The data shown in FIG. 8 indicate that the maximal concentration Formula I in retina is obtained after about five days in albino rats. The concentration in retina continued to increase up to week four in pigmented rats.

Example 4: In vitro release of Formula I from an episcleral Formula I silicone implant designed for rat.

[0146] An implant of 2.5 mm in diameter and 1 mm thickness containing 30% by weight of Formula I was created by solubilizing Formula I in silicone oil and adding a platinum crosslinker catalyst, the solution was mixed, poured into a Teflon mold of predetermined size and the implants were placed at 100 degree C for 30 minutes. The graph shown in FIG. 9 to 11 show the release of Formula I in-vitro over the six week period. The error data shown is the standard deviation.

[0147] The data shown in FIG. 9 shows that there was an initial higher dose released followed by a leveling off of release rate, which remained stable over the next five weeks.

[0148] Example 5: In vitro release of Formula I from an episcleral Formula I silicone implant designed for rabbit

[0149] An implant of 5 mm in diameter and 1 mm thickness containing 30% by weight of Formula I was created by solubilizing Formula I in silicone oil into which it is highly soluble and adding a platinum crosslinker catalyst, the solution was mixed, poured into a Teflon mold of predetermined size and the implants were placed at 100 degree C for 30 minutes. The graph shown in FIG. 12 to 14 show the release of Formula I in-vitro over the six week period. The error data shown is the standard deviation.

[0150] The data shown in FIG. 12 show that there was an initial higher dose released followed by a leveling off of release rate, which remained stable over the next five weeks.

Concluding Statements

[0151] The person skilled in the art will appreciate that the invention described herein may be varied and/or modified by features other than those specifically described. It is to be understood that the invention as defined by the appended claims includes all such variations and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of the steps or features. The present disclosure is therefore to be considered as in all aspects illustrated and not restrictive, the scope of the invention being indicated by the appended claims, and all changes which come within the meaning and range of equivalency are intended to be embraced therein.

[0152] Various references are cited throughout this specification. Each of these references is incorporated herein by reference in entirety.

Claims

CLAIMS What is claimed is:

1. An ocular implant comprising a compound of formula I:

Formula I

or a pharmaceutically acceptable salt thereof.

2. The ocular implant of claim 1 comprising a silicone layer comprising the compound of Formula I.

3. The ocular implant of claim 2 further comprising a polymer layer.

4. The ocular implant of claim 2 wherein the silicone layer comprises curvature at two surfaces.

5. The ocular implant of claim 3 wherein the silicone layer comprises curvature at two surfaces; and the polymer layer comprises curvature at two surfaces.

6. The ocular implant of claim 2 or 3 wherein the implant is circular or oval shaped.

7. The ocular implant of claim 3 wherein the polymer layer is resistant to diffusion of the compound of Formula I from the silicone layer.

8. The ocular implant of claim 3 wherein the polymer layer is substantially impermeable to diffusion of the compound of Formula I from the silicone layer.

9. The ocular implant of claim 3 wherein the polymer is polyvinyl acetate, cross-linked polyvinyl alcohol, cross-linked polyvinyl butyrate, ethylene ethylacrylate co-polymer, polyethyl hexylacrylate, polyvinyl chloride, polyvinyl acetals, plasiticized ethylene vinylacetate copolymer, polyvinyl alcohol, polyvinyl acetate, ethylene vinylchloride copolymer, polyvinyl esters, polyvinylbutyrate, polyvinylformal, polyamides,

polymethylmethacrylate, polybutylmethacrylate, plasticized polyvinyl chloride, plasticized nylon, plasticized soft nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, polytetrafluoroethylene, polyvinylidene chloride, polyacrylonitrile, cross-linked polyvinylpyrrolidone,

polytrifluorochloroethylene, chlorinated polyethylene, poly(l,4'-isopropylidene diphenylene carbonate), vinylidene chloride, acrylonitrile copolymer, vinyl chloride-diethyl fumarate copolymer, silicone rubbers, medical grade polydimethylsiloxanes, ethylene-propylene rubber, silicone-carbonate copolymers, vinylidene chloride-vinyl chloride copolymer, vinyl chloride-acrylonitrile copolymer or vinylidene chloride-acrylonitride copolymer.

10. The ocular implant of claim 3 wherein the polymer layer and the silicone layer are each about 1 mm thick.

11. The ocular implant of claim 3 wherein the polymer layer and/or the silicone layer further comprise an agent that blocks lymphatic absorption of the compound of Formula I.

12. The ocular implant of claim 2 or 3 wherein the silicone layer further comprises an agent that enhances permeability of the compound of Formula I into the eye.

13. The ocular implant of claim 2 or 3 wherein the radius of curvature of the lower surface of the silicone layer ranges from between about 5 mm to about 15 mm.

14. The ocular implant of claim 6 which is circular with a diameter ranging between about 1 mm and about 14 mm.

15. The ocular implant of claim 14 with a diameter ranging between about 6 mm and about 10 mm.

16. The ocular implant of claim 2 or 3 wherein the silicone layer comprises an excipient that improves the release of the compound of Formula I.

17. The ocular implant of claim 16 wherein the excipient is isopropyl myristate, levomenthol, propylene or tetraglycol.

18. The ocular implant of claim 2 or 3, comprising between about 5% to about 80% by weight of the compound of Formula I.

19. The ocular implant of claim 18, comprising between about 20% to about 40% by weight of the compound of Formula I.

20. The ocular implant of claim 19, comprising about 30% by weight of the compound of Formula I.

21. A method of treating a disease or disorder in a subject in need thereof, comprising placing an implant comprising a therapeutically effective amount of the compound of Formula I or pharmaceutically acceptable salt thereof in an ocular region of said subject.

22. The method of claim 21 wherein the implant comprises a silicone layer comprising a therapeutically effective amount of the compound of Formula I.

23. The method of claim 22 wherein the implant further comprises a polymer layer.

24. The method of claim 23 wherein the polymer layer comprises a curvature at two surfaces; and the silicone layer comprise curvature at two surfaces.

25. The method of claim 21, wherein the ocular region is on the sclera, on the choroid, on the retina, on the conjunctiva, or in the vitreous body.

26. The method of claim 21, wherein the ocular region is in the sub-Tenon space.

27. The method of claim 21, wherein the disease or disorder is caused by angiogenesis or vascular hyperpermeability.

28. The method of claim 21 , wherein the disease or disorder is age-related macular degeneration (AMD), choroidal neovascularization, diabetic macular edema (DME), retinal vein occlusion, diabetic retinopathy, proliferative diabetic retinopathy, polypoidal chorioretinopathy, uveitis, retinopathy of prematurity in newborns, choroidal melanoma, chorodial metastasis, retinal capillary hemangioma, retinal artery occlusion, polypoidal choroidal vasculopathy, retinal angiomatous proliferation, myopic choroidal

neovascularization, eye tumor, radiation retinopathy, rubeosis iridis, rubeotic glaucoma, and proliferative vitreoretinopathy.

29. The method of claim 28, wherein the disease or disorder is age-related macular degeneration.

30. The method of claim 29, wherein the disease or disorder is wet age-related macular degeneration.