Ocular device and methods

Abstract

New ocular implant devices are provided. In one aspect, devices are provided that can administer one or more therapeutic agents are desired release rates. In a further aspect, devices are provided that comprise a therapeutic agent with one or more in vivo-labile amide or ester moieties, or one or more therapeutic agents formulated as nanoparticles.

Description

[0001] Docket No. 348619.00402

[0002] OCULAR DEVICE AND METHODS

[0003] The present application claims the benefit of U.S. provisional application no. 63 / 764,366 filed February 27, 2025, which is incorporated herein by reference in its entirety.

[0004] FIELD

[0005] The present disclosure generally relates to local therapies for the eye and, such as ocular implant devices, that have specified release rates of one or more therapeutic agents. Also provided are therapeutic agents that comprise one or more functional groups that can provide stability

[0006] BACKGROUND

[0007] Relative to drug delivery to the other parts of the body, the delivery of a drug to the eye segments is met with numerous difficulties.

[0008] Thus, effective ocular penetration of topically-applied drugs remains a pharmaceutical challenge. Conventional topical ophthalmic formulations typically present limited bioavailability because of the occurrence of lacrimation, tear dilution and conjunctival absorption. Limited bioavailability associated topical delivery also can result due to the transient residence time and impermeability of corneal epithelium.

[0009] Intraocular injections of drug agents also can be problematic, as the injections are invasive, carry a risk of infection and typically less acceptable to patients than other methods of drug delivery.

[0010] It would be desirable to have devices and methods for ocular drug delivery.

[0011] SUMMARY

[0012] We now provide new ocular implant devices and methods for effective and sustained administration of therapeutic agents to ocular tissue.

[0013] The present devices and methods have demonstrated effective drug release in long-term in vivo studies, including 30-day rabbit studies.

[0014] 182716999.1The present devices and methods have shown in long-term in vivo protocols to effectively administer drug agents to the back of a subject’s eye, including into subjects’ RPE / choroid and retina. No ocular toxicities associated with use of a present implant device were observed in these long-term in vivo treatments.

[0015] The devices and methods also have demonstrated substantial advances over prior approaches, including topical delivery. We have found that the present devices and methods can achieve sustained ocular drug levels that are 4 to 10 times greater than provided by chronic topical administration of the same drug agent. The preferred devices and methods also are needle-free avoiding problems associated with intraocular injections.

[0016] In one aspect, ocular implant devices are provided that have specified release rates of one or more therapeutic agents.

[0017] Preferred ocular implant devices may reside for extended periods within a subject’s eye, e.g. multiple days, weeks or months. In certain aspects, the implant device is adapted for residence in the sub-Tenon’s space of a patient’s eye.

[0018] Preferred ocular implants have been demonstrated to provide effective in vivo drug release.

[0019] In one aspect, the drug release rate may also be controlled through one or more materials incorporated into the device, for example one or more coating layers that can modulate as desired delivery or administration from the device one or more therapeutic agents that have been loaded in the device.

[0020] For example, in one system, a drug agent will be formulated with a polymer as disclosed herein and incorporated into the device. A material that degrades in vivo may be coated onto the device element over the therapeutic agent that will enable a desired release rate of the drug agent coupled with the degradation of the overcoating material. Alternatively, a material that provides diffusion of therapeutic agent(s) loaded on the device may be coated onto the device element over the therapeutic agent(s) to thereby provide a desired release rate.

[0021] In preferred devices, an active therapeutic agent may be administered (released) from the device at an average rate of at least or up to 10 μg / hour, or 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400 or 500 μg / hour or more.

[0022] 2

[0023] 182716999.1In additional preferred devices, an active therapeutic agent may be administered (released) from the device at an average rate of at least or up to 50 μg / day, or 60, 70,80, 90, 100, 120, 140, 160, 180, 200, 240, 280, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 mg / day.

[0024] Optimal release rates (either per day or per day) can vary with the therapeutic agent being administered, as well as patient characteristics which may include patient age, disorder being treated, ocular pigmentation, size of the eye, thickness of the sclera, thickness of the choroid and choriocapillaris, and other factors.

[0025] In preferred systems, a device does not administer (release) in significant excess of a targeted release rate of drug, for example the device will not release in excess of 10, 20, 30 or 40 weight percent above a targeted drug release rate.

[0026] While not be being bound by theory, it is believed that ocular tissue can absorb a maximum amount of drug over a specified time period. Administration of drug that exceeds such tissue adsorption amounts may not provide any added therapeutic benefit while increasing patient drug exposure.

[0027] As used herein, a drug “release rate” refers to the quantity of drug released from a dosage form per unit time, e.g., micrograms or milligrams of drug released per hour (μg / hr or mg / hr). Drug release rates are suitably calculated under in vitro dosage form dissolution testing conditions known in the art. As used herein, a drug release rate obtained at a specified time “following administration” refers to the in vitro drug release rate obtained at the specified time following implementation of an appropriate dissolution assay.

[0028] In a further aspect, the ocular implant is provided that contains a prodrug of a therapeutic agent for ocular delivery. The prodrug may be for example have an ester or amide moiety incorporated into a recognized ocular therapeutic agent.

[0029] In another aspect, the ocular implant is provided that contains a therapeutic agent comprises one or more ester or amide groups that contain provide enhanced lipophilicity or otherwise facilitate delivery of the agent to targeted tissue. In certain aspects, the amide or ester moi eties of the therapeutic agent may be hydrolyzed or otherwise cleaved from the agent in vivo.

[0030] 3

[0031] 182716999.1In certain preferred aspects, an administered therapeutic agent comprises one or more amide groups. Such amidation can facilitate uptake of the agent into desired ocular tissue, for example by increasing lipophilicity of the drug agent and / or rendering the agent more resistant to degradation upon administration. In certain aspects, subsequent hydrolysis of the amide group (an in v / vo-labile amide moiety) can provide a parent drug compound.

[0032] Amidation or esterification of a therapeutic agent can be carried out by recognized synthetic methods, such as amidation or esterification of hydroxyl, amino or carboxyl acid moieties of the formed therapeutic agent, or incorporation of an amide moiety in a total synthesis of a drug agent.

[0033] In certain preferred aspects, an amidated agent is substantially enzymatically stable upon release from the device, for example within the sub-Tenon’s space of a patient’s eye and then can readily degrade (de-amidate to function as in vivo-labile amide moiety) to the parent compound upon reaching various targeted ocular tissues.

[0034] In other aspects, a therapeutic agent of an implant may be formulated as nanoparticles, for example in a polymer matrix system and particle size range of 1 to 1000 nm.

[0035] In one aspect, an implant device contains one or more non-steroidal anti-inflammatory drugs (NSAIDs) that contain one or more amide groups that can be removed (e.g. hydrolyzed) in vivo to provide the parent compound such as bromfenac; diclofenac; indomethacin; nepafenac; metformin; flurbiprofen; suprofen; and / or ketorolac, or a pharmaceutically acceptable salt thereof. Amidated derivatives of bromfenac; diclofenac; indomethacin; nepafenac; metformin; flurbiprofen; suprofen; and / or ketorolac can be preferred agents. See Example 5 which follows for preferred syntheses and amidated agents.

[0036] In one aspect, an implant device contains one or more non-steroidal anti-inflammatory drugs (NSAIDs) that contain one or more ester groups that can be removed (e.g. hydrolyzed) in vivo to provide the parent compound such as bromfenac; diclofenac; indomethacin; nepafenac; metformin; flurbiprofen; suprofen; and / or ketorolac, or a pharmaceutically acceptable salt thereof. Ester derivatives of bromfenac; diclofenac; indomethacin; nepafenac; metformin; flurbiprofen; suprofen; and / or ketorolac can be preferred agents. See Example 6 which follows for preferred syntheses and ester agents.

[0037] 4

[0038] 182716999.1In a further aspect, an implant device contains one or more prostaglandins such as latanoprost that contain one or more amide groups that can be removed (e.g. hydrolyzed) in vivo to provide the parent compound.

[0039] In an additional aspect, an implant device contains one or more prostaglandins such as latanoprost that contain one or more ester groups that can be removed (e.g. hydrolyzed) in vivo to provide the parent compound.

[0040] In a yet further aspect, an implant device contains one or more coticosteriod agents such as one or more of: cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone; and / or hydrocortisone, or a pharmaceutically acceptable salts thereof, that contain one or more amide groups that can be removed (e.g. hydrolyzed) in vivo to provide the parent compound.

[0041] In a yet further aspect, an implant device contains one or more coticosteriod agents such as one or more of: cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone; and / or hydrocortisone, or a pharmaceutically acceptable salts thereof, that contain one or more ester groups that can be removed (e.g. hydrolyzed) in vivo to provide the parent compound.

[0042] Preferred ocular implant devices are disclosed in U. S. Patent 10,881,609. Particularly preferred ocular implant devices are disclosed in PCT / US2022 / 075538.

[0043] In one embodiment, an ocular implant device is provided and comprises:

[0044] a) a first layer comprising a polymer; and

[0045] b) a second layer 1) distinct from the first layer and 2) comprising a therapeutically effective amount of one or more therapeutic agents as disclosed herein. In this embodiment, the one or more therapeutic agents and the device may be formulated and / or configured to provide a desired release rate of the therapeutic agents. In addition or alternatively, the one or more therapeutic agents may comprise an amide or ester group that can be hydrolyzed or otherwise removed in vivo (i.e. an in vivo-labile amide moiety). In addition or alternatively, the one or more therapeutic agents may be formulated as nanoparticles. While the ocular implant suitably may have a variety of configurations, in one suitable system, the implant has a curved surface, particularly configured as lens type element.

[0046] 5

[0047] 182716999.1In a further embodiment, an ocular implant device is provided and comprises:

[0048] a) a first layer comprising a polymer;

[0049] b) a second layer 1) distinct from the first layer and 2) comprising a therapeutically effective amount of one or more therapeutic agents as disclosed herein; and

[0050] c) a third layer. In this embodiment, the one or more therapeutic agents and the device may be formulated and / or configured to provide a desired release rate of the therapeutic agents. In addition or alternatively, the one or more therapeutic agents may comprise an amide or ester group that can be hydrolyzed or otherwise removed in vivo (i.e. an in vivo-labile amide moiety). In addition or alternatively, the one or more therapeutic agents may be formulated as nanoparticles. While the ocular implant suitably may have a variety of configuration, in one suitable system, the implant has a curved surface, particularly configured as a lens type element.

[0051] Suitably, the third layer is distinct from the first and second layers. In preferred systems, the third layer comprises one or more rate-controlling agents (which may include one or more polymers) as well as one or more therapeutic agents whereby the administration rate and duration of the one or more therapeutic agents can be extended for prolonged periods, including 0.5, 1, 2, 3, 4, 5, 6 or more days, or 1, 2, 3, 4 or more weeks.

[0052] In certain preferred systems, the third layer is interposed between the first layer and second layer. In the preferred systems, the third layer is an outermost layer of the implant.

[0053] The distinct layers of an implant may have a variety of configurations. For instance, suitably, the cross-sectional thickness of the third layer is less than the cross-sectional thickness of the first layer and / or the cross-sectional thickness of the third layer is less than the cross-sectional thickness of the second layer.

[0054] Suitably, the third layer comprises a polymer such as a polyimide or other material. In certain embodiments, the first layer does not contain a therapeutic agent. In certain embodiments, the second layer comprises a Si-material. Suitably, the second layer comprises a polymer distinct from the first layer polymer.

[0055] In certain preferred configurations, the first layer of an implant device extends circumferentially beyond the second layer such that the surface of the circumferential extension 6

[0056] 182716999.1of the first hardened layer is capable of making contact with the sclera of the eye. Preferably, at least one surface of the second layer is capable of making contact with the sclera of a subject’s eye.

[0057] In certain preferred systems, an implant may comprise a fourth layer distinct from each of the first, second or third layer.

[0058] In certain other preferred systems, an implant comprises a fourth layer distinct from an adjacent layer.

[0059] In certain configurations, the fourth layer is an outer layer of the implant. In other suitably configurations, the fourth layer is interposed between two other implant layers.

[0060] In additional certain preferred systems, an implant may comprise a fifth layer distinct from each of the first, second, third or fourth layer.

[0061] In additional preferred systems, the implant comprises a fifth layer distinct from an adjacent layer.

[0062] In certain configurations, the fifth layer is an outer layer of the implant. In other suitably configurations, the fifth layer is interposed between two other implant layers.

[0063] In certain aspects, a single layer of a multiple layer implant will contain one or more therapeutic agents that are administered to a patient via the implant. The other layers would not contain administered therapeutic agents, but may contain one or more materials such as a sustained release formulation that facilitate administration of the therapeutic agents(s) though the layer and to the patient.

[0064] In other aspects, two or more implant layers may comprise a therapeutic agent.

[0065] As referred to herein, a layer (e.g. first layer) of the implant device will be considered distinct from another layer (e.g. second layer) where the composition of the first layer differs from at least 5, 10, 20, 25 or 30 weight percent (based on total weight of the layer) from the composition of the second layer. The composition of the first layer differs from at least 40, 50, 60, 70, 80, 90 or 100 weight percent (based on total weight of the layer) from the composition of the second layer. Separate layers of an implant also may be fabricated in separate steps during production of an implant device. For instance, a device substrate may have a first layer

[0066] 7

[0067] 182716999.1composition applied such as by coating and in a separate and subsequent step a second layer composition may be applied such as by coating over the first layer or other material that has been applied over the first layer.

[0068] Thickness of each layer suitably may vary widely. Typical layer thickness may range from about 30 pm to 5 mm, more typically 30 pm to 0.5, 0.6, 0.7, 0.8, 0.9 or 1 or 2 mm or more. In certain aspects, a layer that comprises a therapeutic agent may have a comparatively greater thickness than an adjoining layer that does not contain a therapeutic agent. In certain aspects, the one or more layers of an implant are each about 2 mm or less thick, such as 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3 or 0.2 mm or less thick.

[0069] As discussed, the present implant devices preferably have a curved surface. In preferred configurations, the implant is circular or oval shape. In additional preferred configurations, the implant has a configuration that enhances anchoring upon implanting to a patient.

[0070] In the present implant devices, preferably at least one layer is substantially impermeable to diffusion of therapeutic agent. For instance, the at least one impermeable layer suitably may comprise one or more polymers of 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(1,4'-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.

[0071] Suitably, at least one implant layer may comprise one or more of polyvinyl acetate, cross-linked polyvinyl alcohol, cross-linked polyvinyl butyrate, ethylene ethylacrylate co- 8

[0072] 182716999.1polymer, polyethyl hexyl acrylate, 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(1,4'-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.

[0073] In certain aspects, suitably, at least one implant layer comprises an ophthalmic permeation agent that increases ocular permeability of the therapeutic agent into the eye.

[0074] In certain aspects, suitably, an implant layer comprises a therapeutic agent admixed with a controlled release composition. Suitable controlled release compositions may comprise one or more polymers, such as one or more biodegradable polymers, where the one or more biodegradable polymers may degrade over extended time in a patient eye to thereby administer the one or more therapeutic agents to the patient. Exemplary biodegradable polymers that may be incorporated into an implant layer comprise for example poly(lactic-co-glycolide), polylactic-polyglycolic acid block copolymers (PLGA), hydroxypropyl methyl cellulose, hydroxyl methyl cellulose, polyglycolide-polyvinyl alcohol, croscarmellose sodium, hydroxypropylcellulose, sodium carboxymethylcellulose, polyglycolic acid-polyvinyl alcohol block copolymers (PGA / PVA), hydroxypropylmethylcellulose (HPMC), and / or polycaprolactonepolyethylene glycol block copolymers.

[0075] In further aspects, methods are provided for delivery of a therapeutic agent to a patient’s eye that comprise: (a) providing an implant device as disclosed herein wherein the device comprises one or more therapeutic agents; and (b) inserting the device into a patient’s eye.

[0076] Preferably, the implant device is placed into the sub-Tenon’s space and in contact with the sclera of the eye.

[0077] 182716999.1In certain aspects a bioadhesive material may be utilized as an integral outer coating or material of an implant or a material applied to an implant prior to administration of the implant in a patient’s eye. The bioadhesive material can further secure the implant in a desired position in a patient’s eye. A variety of bioadhesive materials may be suitably used, including for example a bioadhesive polymer as polyvinyl carboxylic acid type polymers or

[0078] bioadhesive polysaccharides.

[0079] The patient may be treated for a variety of disorders and diseases including macular degeneration and in particular age-related macular degeneration (AMD).

[0080] Treatment kits also are provided and may comprise (a) an implant device as disclosed herein and (b) instructions for use of the implant to treat an eye disorder.

[0081] Further provided are methods 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: 2 color (blue, red) microperimetry, low luminance visual acuity, multi-focal electroretinography, dynamic perimetry, color vision assessment, photo-stress testing and static perimetry, thereby evaluating the effectiveness of the implant against macular degeneration.

[0082] Other aspects of the invention are disclosed infra.

[0083] BRIEF DESCRIPTION OF DRAWINGS FIG. 1 depicts schematically a preferred multilayer implant device.

[0084] FIG. 2 depicts schematically a further preferred multilayer implant device.

[0085] FIG. 3 is a photograph of an implant of Example 2 which follows.

[0086] FIGS. 4A-4B show NACA-loaded disks that have three layers. FIG. 4A shows a disk including the NACA coating of 25 pm thickness, and FIG. 4B shows a disk including NACA coating of 100 pm.

[0087] FIG. 5 depicts poly(glycerol sebacate urethane) (PGSU) bioerodible implants that include coated surface with NACA in comparison to uncoated surface.

[0088] 10

[0089] 182716999.1FIG. 6 shows a photograph of the coated unidirectional PGSU bioerodible. The depicted implant shows PGSU layer overcoating an interior drug (N-acetylcysteine amide (NACA)) portion or layer.

[0090] FIG. 7A shows a graph measuring the amount of released NACA from the coated surface (disk) during the time course (50 days following implantation into rabbit’s eye) and FIG. 7B shows a table with measured mass, thickness, and diameter of the coated NACA released after day 50 following eye implant. FIG. 7C shows photographs of NACA-coated and uncoated surfaces of the disc and its cross section.

[0091] FIGS. 8-9 showNAC / NACA tissue analysis from 48-hour pigmented rabbit pK study. FIGS. 10 (includes FIGS. 10A-10B) and FIG. 11 show N-acetylcysteine (NAC) plasma concentration in subjects following sub-Tenon’s administration.

[0092] FIGS. 12 and 13 shows results of 30-day in vivo residence of the present ocular implant loaded with nepafenac and amfenac.

[0093] FIGS. 14A-14C show results of 30-day in vivo residence of the present ocular implants loaded with nepafenac and amfenac with posterior punch analysis demonstrating effective localized administration of drug agent.

[0094] FIG. 15 shows further show results of 30-day in vivo residence of the present ocular implants loaded with nepafenac and amfenac.

[0095] DETAILED DESCRIPTION

[0096] Definition

[0097] The following general definitions are supplied in order to facilitate the understanding of the present disclosure.

[0098] 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.

[0099] As used herein, an “intraocular implant” refers to a device or element that is structured, sized, or otherwise configured to be placed in an eye. Intraocular implants are generally

[0100] 11

[0101] 182716999.1biocompatible with physiological conditions of an eye and do not cause adverse side effects. Intraocular implants may be placed in an eye without disrupting vision of the eye.

[0102] As used herein, an “ocular region” or “ocular site” refers generally to any area of the eyeball, including the anterior and posterior segment of the eye, and which generally includes, but is not limited to, any functional (e.g., for vision) or structural tissues found in the eyeball, or tissues or cellular layers that partly or completely line the interior or exterior of the eyeball. Specific examples of areas of the eyeball in an ocular region include the anterior chamber, the posterior chamber, the vitreous cavity, the choroid, the suprachoroidal space, the conjunctiva, the subconjunctival space, the episcleral space, the intracorneal space, the epicorneal space, the sclera, the pars plana, surgically-induced avascular regions, the macula, and the retina.

[0103] As used herein, an “ocular condition” is a disease, ailment or condition which affects or involves the eye or one of the parts or regions of the eye. Broadly speaking the eye includes the eyeball and the tissues and fluids which constitute the eyeball, the periocular muscles (such as the oblique and rectus muscles) and the portion of the optic nerve which is within or adjacent to the eyeball.

[0104] An “anterior ocular condition” is a disease, ailment or condition which affects or which involves an anterior (i.e. front of the eye) ocular region or site, such as a periocular muscle, an eye lid or an eye ball tissue or fluid which is located anterior to the posterior wall of the lens capsule or ciliary muscles. Thus, an anterior ocular condition primarily affects or involves the conjunctiva, the cornea, the anterior chamber, the iris, the posterior chamber (behind the retina but in front of the posterior wall of the lens capsule), the lens or the lens capsule and blood vessels and nerve which vascularize or innervate an anterior ocular region or site. Thus, an anterior ocular condition can include a disease, ailment or condition, such as for example, aphakia; pseudophakia; astigmatism; blepharospasm; cataract; conjunctival diseases; conjunctivitis; corneal diseases; corneal ulcer; dry eye syndromes; eyelid diseases; lacrimal apparatus diseases; lacrimal duct obstruction; myopia; presbyopia; pupil disorders; refractive disorders and strabismus. Glaucoma can also be considered to be an anterior ocular condition because a clinical goal of glaucoma treatment can be to reduce a hypertension of aqueous fluid in the anterior chamber of the eye (i.e. reduce intraocular pressure).

[0105] 12

[0106] 182716999.1A “posterior ocular condition” is a disease, ailment or condition which primarily affects or involves a posterior ocular region or site such as choroid or sclera (in a position posterior to a plane through the posterior wall of the lens capsule), vitreous, vitreous chamber, retina, optic nerve (i.e. the optic disc), and blood vessels and nerves which vascularize or innervate a posterior ocular region or site. Thus, a posterior ocular condition can include a disease, ailment or condition, such as for example, acute macular neuroretinopathy; Behcet’s disease; choroidal neovascularization; diabetic uveitis; histoplasmosis; infections, such as fungal or viral-caused infections; macular degeneration, such as acute macular degeneration, non-exudative age related macular degeneration and exudative age related macular degeneration; edema, such as macular edema, cystoid macular edema and diabetic macular edema; multifocal choroiditis; ocular trauma which affects a posterior ocular site or location; ocular tumors; retinal disorders, such as central retinal vein occlusion, diabetic retinopathy (including proliferative diabetic retinopathy), proliferative vitreoretinopathy (PVR), retinal arterial occlusive disease, retinal detachment, uveitic retinal disease; sympathetic opthalmia; Vogt Koyanagi -Harada (VKH) syndrome; uveal diffusion; a posterior ocular condition caused by or influenced by an ocular laser treatment; posterior ocular conditions caused by or influenced by a photodynamic therapy, photocoagulation, radiation retinopathy, epiretinal membrane disorders, branch retinal vein occlusion, anterior ischemic optic neuropathy, non-retinopathy diabetic retinal dysfunction, retinitis pigmentosa, and glaucoma. Glaucoma can be considered a posterior ocular condition because the therapeutic goal is to prevent the loss of or reduce the occurrence of loss of vision due to damage to or loss of retinal cells or optic nerve cells (i.e. neuroprotection).

[0107] The term “biodegradable polymer” refers to a polymer or polymers which degrade in vivo, and wherein degradation of the polymer or polymers over time occurs concurrent with or subsequent to release of the therapeutic agent. Specifically, hydrogels such as methylcellulose which act to release drug through polymer swelling are specifically excluded from the term “biodegradable polymer”. The terms “biodegradable” and “bioerodible” are equivalent and are used interchangeably herein. A biodegradable polymer may be a homopolymer, a copolymer, or a polymer comprising more than two different polymeric units.

[0108] 13

[0109] 182716999.1The term “treat”, “treating”, or “treatment” as used herein, refers to reduction or resolution or prevention of an ocular condition, ocular injury or damage, or to promote healing of injured or damaged ocular tissue.

[0110] The term “therapeutically effective amount” as used herein, refers to the level or amount of agent needed to treat an ocular condition, or reduce or prevent ocular injury or damage without causing significant negative or adverse side effects to the eye or a region of the eye.

[0111] An “immediate-release” dose of a drug refers to a dose that is substantially completely released within a time period of about 1 hour or less and, preferably, about 30 minutes or less. An immediate-release dose of drug applied as a coating on the surface of a dosage form, as used herein, refers to a dose of a drug prepared in a suitable pharmaceutically acceptable carrier to form a coating solution that will dissolve rapidly upon administration to thereby provide an immediate-release dose of drug. As is known in the art, such immediate-release drug overcoats may contain the same or a different drug or drugs as is contained within the underlying dosage form.

[0112] A “periodic release rate” refers to the quantity of drug released from a dosage form during a specified periodic interval as determined at the end of that specified periodic interval, i.e., at each periodic interval when a determination is made, the quantity of drug released represents the periodic release rate during that periodic interval. For example, the quantity of drug released as determined at t=1 h represents the periodic release rate from the dosage form during the first hour following administration and the quantity of drug released as determined at t=2 h represents the periodic release rate during the second hour following administration, etc.

[0113] An “ascending release rate” refers to a periodic release rate that is increased over the immediately-preceding periodic release rate, where the periodic intervals are the same. For example, when the quantity of drug released from a dosage form is measured at hourly intervals and the quantity of drug released during the fifth hour following administration (determined at t=5 hours) is greater than the quantity of drug released from the dosage form during the fourth hour following administration (determined at t=4 hours), an ascending release rate from the fourth hour to the fifth hour has occurred.

[0114] 14

[0115] 182716999.1It will be appreciated that the first periodic release rate measured, e.g., the periodic release rate at t=l hour (unless equal to 0), will always be greater than the release rate during the preceding period, e.g., the hour before the dosage form was administered, and, thus, the first periodic release rate always constitutes an occurrence of an ascending release rate.

[0116] A drug “release rate” as used herein refers to the quantity of drug released from a dosage form or pharmaceutical composition per unit time, e.g., micrograms or milligrams

[0117] of drug released per hour (pg / hr or mg / hr). Drug release rates for drug dosage forms are typically measured as an in vitro rate of dissolution, i.e., a quantity of drug released from the dosage form or pharmaceutical composition per unit time measured under appropriate conditions and in a suitable fluid.

[0118] Unless otherwise specified, a drug release rate obtained at a specified time refers to the in vitro drug release rate obtained at the specified time following implementation of an appropriate dissolution test. The time at which a specified percentage of the drug within a dosage form has been released may be referenced as the “Tx” value, where “x” is the percent of drug that has been released. For example, a commonly used reference measurement for

[0119] evaluating drug release from dosage forms or pharmaceutical compositions is the time at which 90% of drug within the dosage form or pharmaceutical composition has been released. This measurement is referred to as the “T90” for the dosage form.

[0120] Unless specifically designated as a “single dose” or at “steady-state”, the pharmacokinetic parameters disclosed and claimed herein encompass both single dose and steady state conditions.

[0121] As used herein, the phrase “a single rate controlling mechanism” refers to one or more pharmaceutically acceptable rate controlling materials, such as, but not limited to, one or more polymers, one or more excipients or other materials, that are incorporated in a composition (such as, but not limited to, a dosage form) to modify the rate of release of an opioid analgesic, a nonopioid analgesic or both an opioid analgesic and a nonopioid analgesic from said composition. For example, the one or more pharmaceutically acceptable rate controlling materials can be a hydrophobic rate controlling material, a hydrophilic rate controlling material, a polymeric rate controlling material, a pharmaceutically acceptable non-polymer rate controlling material or any combinations thereof. Sustained release pharmaceutical compositions 15

[0122] 182716999.1are sometimes classified as “matrix”, “reservoir”, or “osmotic” mechanisms (or systems), depending on the type or principle type of rate controlling mechanism employed by the formulation.

[0123] Therapeutic Agents

[0124] As discussed, in one aspect, ocular implants are provided that comprise one or more of the following therapeutic agents, or amidated forms as well as ester forms of these compounds, for example where an amine or carboxylic acid moiety is functionalized to the corresponding amide or ester moiety. Preferred amidated or ester forms of these compounds will have an in vzTo-labile amide or ester moiety, i.e. where the amide or ester group will hydrolyze or other be removed in vivo to provide the parent amine or carboxylic acid moiety:

[0125] (Bromfenac),

[0126] (Indomethacin),

[0127] (Nepafenac),

[0128]

[0129] NH NH (Metformin),

[0130] 16

[0131] 182716999.1> o

[0132] HS'' (N-acetylcysteine amide or “NACA”),

[0133]

[0134] 0

[0135]

[0136] CH3(Suprofen), or pharmaceutically acceptable salts thereof.

[0137] In another aspect, ocular implants are provided that comprise one or more of the following therapeutic agents, or amidated or esterified forms of these compounds, for example where an amine or carboxylic acid moiety is functionalized to the corresponding amide or ester moiety. Preferred amidated or ester forms of these compounds will have an in vzvo-labile amide or ester moiety, i.e. where the amide or ester group will hydrolyze or other be removed in vivo to provide the parent amine or carboxylic acid moiety:

[0138]

[0139] (Cortisone)

[0140] 17

[0141] 182716999.1OH

[0142] (Prednisone),

[0143]

[0144] OH

[0145] HO OH

[0146] (Dexamethasone),

[0147] HO

[0148] o

[0149] HO,

[0150] (Betamethasone),

[0151]

[0152] (Hydrocortisone), or pharmaceutically acceptable salts thereof.

[0153] 18

[0154] 182716999.1In another aspect, a present implant device may comprise vabysmo (faricimab-svoa) for administration to a subject, e.g. for to treat wet age-related macular degeneration (AMD) or diabetic macular edema (DME).

[0155] In another aspect, a present implant device may comprise bevacizamab, ranibizumab, and / or aflibercept.

[0156] Prodrugs as disclosed herein may be readily prepared.

[0157] For example, as discussed, amidation or esterification of a therapeutic agent can be carried out by recognized synthetic methods, such as amidation or esterification of hydroxyl, amino or carboxyl acid moieties of the formed therapeutic agent, or incorporation of an amide moiety in a total synthesis of a drug agent. Preferred synthetic methods to produce amide and ester agents are set forth in Examples 5 and 6 below.

[0158] In certain preferred aspects, an amidated agent is substantially enzymatically stable upon release from the device, for example within the sub-Tenon’s space of a patient’s eye and then can readily degrade (de-amidate to function as in vivo-labile amide moiety) to the parent compound upon reaching various targeted ocular tissues.

[0159] Nanaparticles also can be readily prepared. In certain preferred compositions, a drug agent may be substantially encapsulated within a polymer matrix. Suitable nanoparticle sizes can vary, for example in certain compositions a particle size range of 1 to 1000 nm can be suitable.

[0160] A variety of nanoparticles and materials can be used to encapsulate a drug agent including chitosan nanoparticles; Human Serum Albumin nanoparticles; biodegradable materials such as poly(alkylcynoacrylates), e.g., polybutylcyanoacrylate, polyhexylcyanoacrylate, polyethylcyanoacrylate (PECA), PEGylated core-shell nanoparticles; biodegradable PLGA (poly(D, L-lactide-co-glycolide)) particles; PLA (poly lactic acid),; liposomes; and gelatin nanoparticles.

[0161] 19

[0162] 182716999.1Organic nanocarriers can be preferred and comprises liposome, niosomes, dendrimers, solid lipids, polymers and protein / peptide-based nanoparticles and may be fabricated from proteins, lipids, carbohydrates or other organic compounds.

[0163] In certain aspects, polymeric nanoparticles are spherical-shaped solid colloidal particles composed of biocompatible and biodegradable polymers in a size range from 10 nm to 1000 nm.

[0164] Some polymeric nanoparticles obtained from natural polymers include chitosan, alginate, albumin, gelatin, and dextran, while some are obtained from synthetic sources such as polylactic acid (PLA), polyglycolide (PGA), poly(L-lysine), polyaspartic acid, poly-alkyl cyanoacrylate, and polyethyleneimine (PEI) which are biodegradable synthetic polymers.

[0165] Suitable nanoparticle systems and methods for preparation also are disclosed in Khiev et al., Nanomaterials 2021, 11, 173 Omerovic et al., Heath and Technology (2020) 10:61-78; and U. S. Patent 8273366.

[0166] As further discussed, in various aspects, a composite ocular implant is provided comprising a therapeutic agent for treatment or prevention of a disorder of the eye. In preferred systems, implant provides sustained release of the therapeutic agent 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.

[0167] The present implants can be used to treat a number of eye diseases and indications including, for example, age-related macular degeneration, wet macular wet age-related macular degeneration (AMD) or diabetic macular edema (DME), glaucoma, diabetic retinopathy, uveitis, retinopathy of prematurity in newborns, choroidal melanoma, chorodial metastasis, and retinal capillary hemangioma.

[0168] Multiple-Layer Ocular Implants

[0169] Referring now to the drawings, FIG. 1 shows schematically a preferred ocular implant 10 which includes multiple layers 12, 14, 16 and 18. The implant also suitably may contain additional layers.

[0170] 20

[0171] 182716999.1Suitably, one or more layers comprises one or more therapeutic agents such as a nonsteroidal anti-inflammatory drugs (NSAIDs) and / or a coticosteriod agent as discussed above, or other agent including those therapeutic agents disclosed below.

[0172] In certain systems, an outermost layer such as layer 12 or 18 depicted in FIG. 1 may comprise a therapeutic agent.

[0173] In other preferred systems, an encased or inner layer such as layer 14 and / or 16 depicted in FIG. 1 may comprise one or more therapeutic agents and one or more outmost layers such as layer 12 or 18 depicted in FIG. 1 will not contain a therapeutic agent. In such configurations, the outer layers 12 and / 18 depicted in FIG. 1 suitably can function to control drug administration such as by modulating release of a therapeutic agent from layer 14 or 16 to a subject. For instance, layer 12 and / or 18 may comprise one or more bioerodable or biodegradable materials that provide for release therapeutic agent(s) from the implant over extended time such as 1, 2, 3, 4, 5, 6, or 7 days or more, or periods such as 2, 3,4, 5, 6, 7, or 8 weeks or more.

[0174] The various implant layers such as 12, 14, 16, 18 depicted in FIG. 1 may comprise one or more polymers such as 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(1,4'-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.

[0175] 21

[0176] 182716999.1In certain systems, a vinyl acetate or ethylene-vinyl acetate (EVA) copolymer material is a preferred material for one or more implant layers. Suitable materials are commercially available including Celanese, Aldrich and others.

[0177] Dimensions of an implant device may vary. However, in this particular embodiment, the implant device 10 has a diameter (shown as dimension b in FIG. 1) of 7 mm and a thickness (shown as dimension a in FIG. 1) 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 of deice 10 (top surface of layer 12) suitably has a radius of curvature of 5 mm for generally conforming to the radius of curvature of the surface of Tenon’s capsule El of an average human eye. Likewise, the lower layer 18 of FIG. 1 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.

[0178] In one preferred system, the implant upper layer 12 is generally resistant to diffusion of the implant’s one or more therapeutic agents such as may be loaded in encased layer 16 of FIG.

[0179] 1. In certain embodiments, the upper layer 12 is effectively impermeable to one or more therapeutic agents present in the implant such as layer 16. In other embodiments, the one or more therapeutic agents of the implant 10 has a rate of diffusion within the upper layer 12 which is significantly less than the rate of diffusion of the one or more therapeutic agents out of the lower layer 18 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 one or more therapeutic agents out of the lower layer 18 and into the sclera of a subject eye. The reduced diffusion characteristics of the one or more therapeutic agents in the upper layer 12 relative to the lower layer 18 provide the advantage of preventing loss of the therapeutic agent(s) to tissues where it is not needed. The reduced rate of diffusion of the therapeutic agent(s) through the upper layer 12

[0180] 22

[0181] 182716999.1thereby encourages unidirectional diffusion of the therapeutic agent(s) from the lower layer 16 into the subject’s sclera and choroid for transfer to the macula. A potential further advantage provided by the reduced diffusion characteristics of the therapeutic agent(s) in the upper layer 12 relative to the lower layer 18 is gained in preventing the therapeutic agent(s) from entering the lymphatic system via Tenon’s capsule and the conjunctiva for transfer to other tissues where it may cause undesirable side-effects. Thus, in certain alternative embodiments of the present disclosure, the upper layer 12 or lower layer 18 further includes an agent that blocks lymphatic absorption.

[0182] In one aspect, one or more therapeutic agents that may be administered to a patient with a present implant device include, but are not limited to: antibiotic agents such as fumagillin analogs, minocycline, fluoroquinolone, cephalosporin antibiotics, herbimycon A, tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, oxytetracy cline, chloramphenicol, gentamicin and erythromycin; antibacterial agents such as sulfonamides, sulfacetamide, sulfamethizole, sulfoxazole, nitrofurazone, and / or sodium propionate.

[0183] In another aspect, one or more therapeutic agents that may be administered to a patient with a present implant device include antiviral agents such as idoxuridine, famvir, trisodium phosphonoformate, trifluorothymidine, acyclovir, ganciclovir, DDI and AZT, protease and / or integrase inhibitors.

[0184] In another aspect, one or more therapeutic agents that may be administered to a patient with a present implant device include anti-glaucoma agents such as beta blockers (timolol, betaxolol, atenolol), prostaglandin analogues, hypotensive lipids, and / or carbonic anhydrase inhibitors.

[0185] In another aspect, one or more therapeutic agents that may be administered to a patient with a present implant device include antiallergenic agents such as antazoline, methapyriline, chlorpheniramine, pyrilamine and / or prophenpyridamine.

[0186] In another aspect, one or more therapeutic agents that may be administered to a patient with a present implant device include anti-inflammatory agents such as hydrocortisone, leflunomide, dexamethasone phosphate, fluocinolone acetonide, medrysone, methylprednisolone, prednisolone phosphate, prednisolone acetate, fluoromethalone,

[0187] 23

[0188] 182716999.1betamethasone, triamcinolone acetonide, adrenalcortical steroids and their synthetic analogues, and / or 6-mannose phosphate.

[0189] In another aspect, one or more therapeutic agents that may be administered to a patient with a present implant device include antifungal agents such as fluconazole, amphotericin B, liposomal amphotericin B, voriconazole, imidazole-based antifungals, tiazole antifungals, echinocandin-like lipopeptide antibiotics, lipid formulations of antifungals; polycations and polyanions such as suramine and / or protamine.

[0190] In another aspect, one or more therapeutic agents that may be administered to a patient with a present implant device include decongestants such as phenylephrine, naphazoline, and / or tetrahydrazoline.

[0191] In another aspect, one or more therapeutic agents that may be administered to a patient with a present implant device include anti-angiogenesis compounds including those that can be potential anti-choroidal neovascularization agents such as 2-methoxyestradiol and its analogues (e.g., 2-propynl-estradiol, 2-propenyl-estradiol, 2-ethoxy-6-oxime-estradiol, 2-hydroxyestrone, 4-methoxyestradiol), VEGF antagonists such as VEGF antibodies and VEGF antisense, angiostatic steroids (e.g., anecortave acetate and its analogues, 17-ethynylestradiol, norethynodrel, medroxyprogesterone, mestranol, androgens with angiostatic activity such as ethisterone), thymidine kinase inhibitors.

[0192] In another aspect, one or more therapeutic agents that may be administered to a patient with a present implant device include adrenocortical steroids and their synthetic analogues including fluocinolone acetonide and triamcinolone acetonide and all angiostatic steroids.

[0193] In another aspect, one or more therapeutic agents that may be administered to a patient with a present implant device include immunological response modifying agents such as cyclosporine A, Prograf (tacrolimus), macrolide immunosuppressants, mycophenolate mofetil, rapamycin, and muramyl dipeptide.

[0194] In another aspect, one or more therapeutic agents that may be administered to a patient with a present implant device include one or more vaccine.

[0195] In another aspect, one or more therapeutic agents that may be administered to a patient with a present implant device include one or more anti-cancer agents such as 5-fluorouracil,

[0196] 24

[0197] 182716999.1platinum coordination complexes such as cisplatin and carboplatin, adriamycin, antimetabolites such as methotrexate, anthracycline antibiotics, antimitotic drugs such as paclitaxel and docetaxel, epipdophylltoxins such as etoposide, nitrosoureas including carmustine, alkylating agents including cyclophosphamide; arsenic trioxide; anastrozole; tamoxifen citrate; triptorelin pamoate; gemtuzumab ozogamicin; irinotecan hydrochloride; leuprolide acetate; bexarotene; exemestrane; epirubicin hydrochloride; ondansetron; temozolomide; topotecan hydrochloride; tamoxifen citrate; irinotecan hydrochloride; trastuzumab; valrubicin; gemcitabine HCL; goserelin acetate; capecitabine; aldesleukin; rituximab; oprelvekin; interferon alfa-2a; letrozole; toremifene citrate; mitoxantrone hydrochloride; irinotecan HCl; topotecan HCL; etoposide phosphate; gemcitabine HCL; and amifostine; antisense agents; antimycotic agents; miotic and anticholinesterase agents such as pilocarpine, eserine salicylate, carbachol, diisopropyl fluorophosphate, phospholine iodine, and demecarium bromide; mydriatic agents such as atropine sulfate, cyclopentane, homatropine, scopolamine, tropicamide, eucatropine, and hydroxyamphetamine; differentiation modulator agents; sympathomimetic agents such as epinephrine; anesthetic agents such as lidocaine and benzodiazepam; vasoconstrictive agents; vasodilatory agents; polypeptides and protein agents such as angiostatin, endostatin, matrix metalloproteinase inhibitors, platelet factor 4, interferon-gamma, insulin, growth hormones, insulin related growth factor, heat shock proteins, humanized antiIL2 receptor mAb (Daclizumab), etanercept, mono and polyclonal antibodies, cytokines, antibody to cytokines.

[0198] In another aspect, one or more therapeutic agents that may be administered to a patient with a present implant device include neuroprotective agents such as calcium channel antagonists including nimodipine and diltiazem, neuroimmunophilin ligands, neurotropins, memantine and other NMDA antagonists.

[0199] In another aspect, one or more therapeutic agents that may be administered to a patient with a present implant device include acetylcholinesterase inhibitors, estradiol and analogues, vitamin B 12 analogues, alpha-tocopherol, NOS inhibitors, antioxidants (e.g. glutathione, superoxide dismutase), metals like cobalt and copper, neurotrophic receptors (Akt kinase), growth factors, nicotinamide (vitamin B3), alpha-tocopherol (vitamin E), succinic acid, dihydroxylipoic acid, fusidic acid; cell transport / mobility impending agents such as colchicine, vincristine, cytochalasin B; carbonic anhydrase inhibitor agents; integrin antagonists; lipophilic 25

[0200] 182716999.1agents such as Idebenone, rapamycin, 2-cyano-3,12 dioxooleana-1,9 dien-28-imidazolide (CDDO-Im), 2-cyano-3,12-dioxooleana-l,9(ll)-dien-28-oic acid - ethyl amide (CDDO-ethyl amide), and 2-cyano-3,12-dioxooleana-l,9(ll)-dien-28-oic acid trifluoroethyl amide (CDDO-TFEA); and lubricating agents.

[0201] Any pharmaceutically acceptable form of the agents can be used, such as the free base form or a pharmaceutically acceptable salt or ester thereof. In one aspect, a dosage of one or more therapeutic agents of an implant may be in the range of 1 to 100 mg.

[0202] Administration of the ocular implant

[0203] To administer the implant, the mutli-layer implant is suitably placed behind the surface epithelium within the sub-Tenon’s space. This may be 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 1-2 mm in diameter for small rodent (i.e., mouse and rat) eyes, 3-4 mm in diameter for rabbit and human eyes and 6-8 mm in diameter for equine eyes.

[0204] In certain embodiments, an applicator device is used to inject the implant into the subTenon’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.

[0205] 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

[0206] 26

[0207] 182716999.1may be preferable to fixate the matrix implant with one or two absorbable sutures (e g., 10-0 absorbable vicryl sutures). This may be done by making holes with a 30 gauge needle in the peripheral portion of the implant, approximately 250-500 pm away from the peripheral edge of the implant.

[0208] The holes are made 180 degrees from each other. This is done because subconjunctival matrix implants of this disclosure, 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 disclosure are placed about 4 mm or more away from the limbus, the sutures are optional.

[0209] Lipophilic Agents

[0210] In one aspect, an implant device may comprise one or more lipophilic agents, including in one or more device layers that comprise a therapeutic agent. Such lipophilic agents may be small molecules. Lipophilic agents may be released from the implant by diffusion, erosion, dissolution or osmosis. Exemplary lipophilic agents are disclosed in US20140031408.

[0211] In another aspect, the implant may comprise one or more therapeutic agents that comprise a lipophilic agent.

[0212] In preferred systems, the present implants provide a sustained or controlled delivery of therapeutic agents at a maintained level despite the rapid elimination of the lipophilic agents from the eye. For example, in certain aspects, preferred implants may be capable of delivering therapeutic amounts of a lipophilic agent for a period of at least about 10, 20, or 3-0 or more days, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months or more.

[0213] The present implants may be placed in an ocular region to treat a variety of ocular conditions, such as treating, preventing, or reducing at least one symptom associated with nonexudative age related macular degeneration, exudative age related macular degeneration, choroidal neovascularization, acute macular neuroretinopathy, cystoid macular edema, diabetic macular edema, Behcet’s disease, diabetic retinopathy, retinal arterial occlusive disease, central retinal vein occlusion, uveitic retinal disease, retinal detachment, trauma, conditions caused by laser treatment, conditions caused by photodynamic therapy, photocoagulation, radiation retinopathy, epiretinal membranes, proliferative diabetic retinopathy, branch retinal vein

[0214] 27

[0215] 182716999.1occlusion, anterior ischemic optic neuropathy, non-retinopathy diabetic retinal dysfunction, retinitis pigmentosa, ocular tumors, ocular neoplasms, and the like.

[0216] Kits in accordance with the present disclosure may comprise one or more of the present implants, and instructions for using the implants. For example, the instructions may explain how to administer the implants to a patient, and types of conditions that may be treated with the implants.

[0217] EXAMPLES

[0218] The following non-limiting examples are illustrative.

[0219] Example 1: Implant fabrication

[0220] A preferred implant as generally depicted in FIG. 1 is prepared as follows.

[0221] A drug layer composition is prepared by admixing a drug compound (nepafenac or other therapeutic agent) with ethylene-vinyl acetate (EVA). The admixture is heated at 70°C for approximately 30 minutes.

[0222] The EVA-therapeutic agent composition then is placed in a mold that can apply heat and pressure and establish the implant shape. The EVA-therapeutic agent composition layer in the configuration of the implant device is then removed from the mold and cooled. A vinyl acetate film is placed on opposing sides of the EVA-therapeutic agent layer. An interposing adhesive material optionally may be used to secure the layers. A silicone adhesive (e.g. BIO-PSA 7-4302, DOW CORNING) is one suitable material.

[0223] The resulting multi-layer implant suitably is 7, 8 or 9 to 10 mm in diameter or longest dimension (dimension b is FIG. 1) and has an overall thickness of 1.8 to 2.0 mm (dimension a in FIG. 1). The implant suitably has an outer layer that is a 0.065 mm EVA film which is bonded to a LDPE barrier layer 0.050 mm thick. The nepafenac or other therapeutic agent is contained in the core EVA layer 1.3 mm thick which is covered by a 0.45 mm EVA film.

[0224] Example 2: Additional implant fabrication

[0225] A further preferred multi layer implant device was prepared by the procedures of Example 1 above. A photograph of the implant device cross-section is shown in FIG. 3. As depicted in FIG. 3, the implant has an inner layer of vinyl acetate polymer with 40 weight 28

[0226] 182716999.1percent of therapeutic agent. A 450 pm vinyl acetate layer adjoins one surface of the implant layer and a low-density polyethylene (LDPE) layer abuts the opposing inner layer surface. An outer 450 pm vinyl acetate layer overcoats the LDPE layer.

[0227] Example 3: Administration of a multiple layer ocular implant containing nepafenac in a mouse model of dry AMD

[0228] Hydroquinone is known as an oxidant component of cigarette smoke. It has been found that mice treated with hydroquinone may be used as a model of dry AMD (Espinosa-Heidmann et al., Invest. Ophthal. Vis. Sci., 2006, 47-729). Aged male mice (>60 weeks, n = 4) are fed a high fat diet (TD 88051; Harlan Teklad) supplemented with 0.8% hydroquinone for a minimum of 8 weeks. Alternatively, hydroquinone can be injected subconjunctivally for up 4 weeks as an alternate model. Other models of macular degeneration including the Y402H CFH transgenic under the control of the ApoE promoter, the Ccl2- / - Cx3crl- / - mice, the Sodl- / - mice, the OXY rats as well other animal models may also be used.

[0229] A three-layer ocular implant as described in Example 1 above is administered to the treated mice. The implants are circular, 2.0 mm in diameter and 1 mm thick and contain nepafenac at doses of 10 mg and 30 mg.

[0230] It has been disclosed that placement of test implants in the sub-Tenon’s space of rodents leads to episcleral clearance of the test substance (Chan, Pridgen and Csaky, 2010, Exp. Eye Res.

[0231] 90, 501). Therefore, surgical placement of the implants is performed by incising the conjunctiva and Tenon’s fascia prior to placement of the implants in the sub-Tenon’s space as far posteriorly as possible.

[0232] The mice are then monitored to determine the release of the drug over time by examining the eye using histology, electroretinography or changes in gene expression in the retinal pigment epithelium or photoreceptors. Confirmation of morphological changes in cells indicating the presence of the drug indicates the effectiveness of the implant in transfer of the administered therapeutic agent from the implant to the surrounding tissues in the process of treating macular degeneration.

[0233] Example 4: Treatment of patient with macular degeneration

[0234] A patient is diagnosed as suffering from age-related macular degeneration.

[0235] 29

[0236] 182716999.1A three-layer ocular implant is provided as described in Example 1 above (circular, 2.0 mm in diameter, 1.0 mm thick) and containing N-acetylcysteine amide (NACA) at a dose of 25 mg. The implant is placed behind the surface epithelium within the sub-Tenon’s space. 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.

[0237] Example 5: Admidating reaction for pro-drugs

[0238] Scheme 1

[0239]

[0240] Bromfenac

[0241] In Scheme 1, each Rnand R'2is independently hydrogen or alkyl.

[0242] 1 mmol of Bromfenac is added to 1 mmol of amine (NR’dRi) and 3 mmol of amine (e.g., EtsN) in dichloromethane, then 1 mmol of SOCI2 is added at room temperature. The mixture is stirred for 5-20 minutes at room temperature. The recovery of the reaction product is performed by evaporating the solvent under reduced pressure. The resulting residue is taken up in di chloromethane and washed first with 1 N HCl and then with 1 N NaOH. The organic phase was dried and evaporated to dryness to afford the corresponding carboxylic amide.

[0243] Scheme 2

[0244] SO3Py

[0245]

[0246] Diclofenac

[0247] 30

[0248] 182716999.1In Scheme 2, each R11and R12is independently hydrogen or alkyl. Amidation reaction of Diclofenac including carboxylic acid with formamide derivative (NR11R12C(O)H) using SO3·pyridine. 0.1 mmol of Diclofenac, 0.5 mL of formamide derivative (e.g., R1and R2are methyl or hydrogen), and 05 mL of DMF are added to a reaction vessel, and SO3·pyridine in 4 equivalent of Diclofenac is added to the reaction vessel. 1,2-Dichlorobenzene (DCB) can be used as a co-solvent, for example, the formamide is added in DCB at a ratio of DCB to formamide 3:2 and the combined volume thereof is 0.5 mL. The reaction is performed at a temperature of about 150 to 160 ° for 1 to 3 days.

[0249] Scheme 3

[0250]

[0251] flurbiprofen

[0252] In Scheme 3, each R11and R12is independently hydrogen or alkyl. Flurbiprofen can readily react with sulfuryl chloridefluoride in the presence of triethylamine. The resulting intermediate acylfluorosulfonates, the mixed anhydrides of the flurbiprofen and fluorosulfuric acid, without separating them, are then reacted with a primary amine at room temperature to yield the amide prodrug from of flurbiprofen. The reaction is generally carried out in dichloromethane solution.

[0253] Example 6: Esterifying reaction to produce prodrug

[0254] Scheme 1

[0255]

[0256] Bromfenac

[0257] As shown in Scheme 1,1 mmol of Bromfenac is added to 1 mmol (molar equivalent) of alkyl alcohol (X here X is OH-R where R is C1-15alkyl) in the presence of HCl in

[0258] 31

[0259] 182716999.1dichloromethane at room temperature followed by heating as required. The mixture is stirred for 5-20 minutes at room temperature. The recovery of the reaction product is performed by evaporating the solvent under reduced pressure. The resulting residue is taken up in

[0260] dichloromethane and washed first with 1 N HCl and then with 1 N NaOH. The organic phase was dried and evaporated to dryness to afford the corresponding ester shown above.

[0261] Scheme 2

[0262]

[0263] Diclofenac

[0264] As shown in Scheme 2, 1 mmol of diclofenac is added to 1 mmol (molar equivalent) of alkyl alcohol (X here Xis OH-R where R is Cnisalkyl) in the presence of HC1 in

[0265] di chloromethane at room temperature followed by heating as required. The mixture is stirred for 5-20 minutes at room temperature. The recovery of the reaction product is performed by evaporating the solvent under reduced pressure. The resulting residue is taken up in

[0266] di chloromethane and washed first with 1 N HCl and then with 1 N NaOH. The organic phase was dried and evaporated to dryness to afford the corresponding ester shown above.

[0267] Scheme 3

[0268]

[0269] flurbiprofen

[0270] As shown in Scheme 3, 1 mmol of flurbioprofen is added to 1 mmol (molar equivalent) of alkyl alcohol (X here X is OH-R where R is C1-15alkyl) in the presence of HCl in dichloromethane at room temperature followed by heating as requirede. The mixture is stirred for 5-20 minutes at room temperature. The recovery of the reaction product is performed by

[0271] 32

[0272] 182716999.1evaporating the solvent under reduced pressure. The resulting residue is taken up in dichloromethane and washed first with 1 N HC1 and then with 1 N NaOH. The organic phase was dried and evaporated to dryness to afford the corresponding ester shown above.

[0273] Example 7: Fabrication of PGSU implant with N-Acetyl-Cysteine-Amide (NACA) derivative Modified NAC-derivative delivered via an episcleral sustained-release delivery system is provided. In order to prevention of progression to advanced forms of dry AMD (e.g., complete retinal pigment epithelium (RPE) and outer retinal atrophy (cRORA)) and improvement in low luminance deficits, an optical implant device can be fabricated with N-Acetyl-Cysteine-Amide (NACA) derivatives. This implant device can be used as the first in class treatment for dry AMD and aims sustained delivery for >3 months (single episcleral implant q >3 months). It has been reported adverse event profile similar or better than an intravitreal injections.

[0274] FIG. 3 depicts poly(glycerol sebacate urethane) (PGSU) bioerodible implants that include coated surface with NACA in comparison to uncoated surface. FIGS. 4 A and 4B shows photographs of the coated unidirectional PGSU bioerodible implants.

[0275] The amount of released NACA from the coated surface (disk) during the time course (50 days) was measured and shown in FIG. 7A-7B. Coated NACA released from day 1 but the amount of the released NACA was plateaued after day 7, and overall about 79.6 ± 2.4% NACA was released (FIG. 7C).

[0276] Sensitive and specific assay were performed by utilizing NAC-d3 as calibrator and homocysteine-d4 as the internal standard to reduce impact of variation due to variance in endogenous levels. Sensitivity was 1 ng / mL for total NAC-d3 ( = 1 ng / mL NAC) and 5 ng / mL total NACA and endogenous levels in the blank matrix was about 10 ng / mL total NAC.

[0277] NACA loaded disk was produced by reaction injection molding and following spray coating. API-loaded disks was prepared by mixing API and pre-polymer components (e.g., silicone) and injection-molded using a dual-barrel syringe. The, using a spray coater, for example, nozzle tilted at 45°, NACA was coated on the surface of the disks.

[0278] 33

[0279] 182716999.1FIGS. 4A and 4B show photographs of coating layer on the disks. In FIG. 4A, a coating layer having 25 pm thickness is shown and in FIG. 4B, a coating layer having 100 pm thickness is shown.

[0280] Example 8: In vivo studies

[0281] A first device corresponding to the implant of Example 1 loaded with acetylcysteine amide (NACA) was administered to Sub-Tenon regions of eyes of rabbit subjects. A second device corresponding to the implant of Example 1 loaded with N-acetylcysteine (NAC) was administered to Sub-Tenon regions of eyes of rabbit subjects.

[0282] Results are set forth in FIGS. 8, 9, 10A, 10B and 11 which show NAC and NACA plasma concentration in rabbits following sub-Tenon’s administration of an implant over a 2-day period.

[0283] Example 9: Additional in vivo studies - 30 days

[0284] A first device corresponding to the implant of Example 1 loaded with nepafenac was administered to Sub-Tenon regions of eyes of rabbit subjects. A second device corresponding to the implant of Example 1 loaded with amfenac was administered to Sub-Tenon regions of eyes of rabbit subjects. Drug residence in the specified ocular tissue was evaluated at specified days following initial administration of the implants in the rabbit eyes.

[0285] Results are set forth in FIGS. 12, 13, 14A-14C and 15. FIGS. 14A and 14B are results of a punch test which indicate substantial localized residence of drug administrated from the implant in the specified ocular tissue.

[0286] In these long-term studies, preclinical data in pigmented rabbits has demonstrated penetration of both nepafenac and n-acetyl-cysteine-amide into RPE / choroid and retina.

[0287] In these long-term studies, preclinical data in rabbits showed no evidence of any implant-related ocular toxi cities over a period of 30 days.

[0288] Example 10: Drug administration levels

[0289] It was found that the present implant devices achieved sustained ocular drug levels 4 to 10 times greater than provided by chronic topical administration of the same drug agent.

[0290] 34

[0291] 182716999.1The following nepafenac and amfenac levels were observed in rabbit eyes following administration 1) using an implant device of Example 1 and 2) a chronic topical (eye drop) protocol.

[0292] Implant device Topical

[0293] Nepafenac (nM) Amfenac (nM) Nepafenac (nM) Amfenac (nM) Sclera 2840 1563 55 43 RPE / Choroid 982 1355 4 3

[0294] Retina 254 236 88 25

[0295] These data show that drug tissue levels in the ocular posterior pole were 4 to 10 times greater using a present implant device relative to standard chronic topical administration.

[0296] Example 11: Administration protocol

[0297] On Day 1, prior to test device administration, a subject’s eye is be dilated with 1% tropicamide HC1 and each subject receives buprenorphine (approximately 0.03 mg / kg SQ). The subject may be sedated for the injections using 20-50 mg / kg ketamine and 4-10 mg / kg xylazine IM, and the eyes can be aseptically prepared using topical 5% betadine solution, followed by rinsing with sterile eye wash. One drop of 0.5% proparacaine HC1 then is applied. The superior conjunctiva is gently grasped with colibri forceps, and a 5-mm conjunctival incision is made 2-3 mm posterior and parallel to the limbus. Using Wescott scissors, the subtenon’s space is opened and undermined superiorly. The implant is then be placed into the subtenon’s space and the tenon and conjunctiva is closed with 8-0 or 9-0 nylon without tension. The implant of Example 1 can be used that include dimethyl amide bromfenac of Example 5 (R11and R12each methyl) for administration. The process can be repeated on the contralateral eye. Following the surgical procedure, digital photographs of implants may be taken and 1 drop of neomycin polymyxin B sulfates gramicidin ophthalmic solution or ofloxacin applied topically to the ocular surface. Example 12: Treatment of patient with macular degeneration.

[0298] A patient is diagnosed as suffering from age-related macular degeneration.

[0299] 35

[0300] 182716999.1A four-layer ocular implant device is provided as described in Example 1 above (circular, 2.0 mm in diameter, 1.0 mm thick) and containing include dimethyl amide dimethyl bromfenac of Example 5 (R11andR12each methyl) at a dose of 3 mg. The implant device is placed behind the surface epithelium within the sub-Tenon’s space. A lid speculum is placed and a conjunctival radial incision is made through the conjunctiva over the area where the implant device is to be placed. Wescott scissors are used to dissect posterior to Tenon’s fascia and the implant device is inserted. The conjunctiva is reapproximated using a running 10-0 vicryl suture.

[0301] Equivalents and Scope

[0302] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments in accordance with the disclosure described herein. The scope of the present disclosure is not intended to be limited to the above Description, but rather is as set forth in the appended claims.

[0303] All cited sources, for example, references, publications, databases, database entries, and art cited herein, are incorporated into this application by reference, even if not expressly stated in the citation. In case of conflicting statements of a cited source and the instant application, the statement in the instant application shall control.

[0304] 36

[0305] 182716999.1

Claims

WHAT IS CLAIMED IS:

1. An ocular implant device comprising:a first layer comprising a polymer; anda second layer 1) distinct from the first layer and 2) comprising one or more therapeutic agents,wherein the device is configured to provide a release rate of the one or more therapeutic agents of at least 50 mg / day.

2. An ocular implant device comprising:a first layer comprising a polymer; anda second layer 1) distinct from the first layer and 2) comprising one or more therapeutic agents,wherein the one or more one or more therapeutic agents comprise one or more amide or ester moieties that are liable in vivo.

3. An ocular implant device comprising:a first layer comprising a polymer; anda second layer 1) distinct from the first layer and 2) comprising one or more prodrug agents.

4. The device of claim 3 wherein the prodrug comprises one or more amide groups.

5. The device of claim 3 or 4 wherein the prodrug comprises one or more amide groups.

6. The device of any one or more claims 3 through 5 wherein the prodrug is formulated as a nanoparticle.37182716999.

17. The device of any one of claims 1 through 6 wherein the device is configured to provide a release rate of the one or more therapeutic agents of at least 50 mg / day8. The device of any one of claims 1 through 6 wherein the device is configured to provide a release rate of the one or more therapeutic agents of at least 100 mg / day.

9. The device of any one of claims 1 through 6 wherein the device is configured to provide a release rate of the one or more therapeutic agents of up to at least 200 mg / day.

10. The device of any one of claims 1 through 9 further comprising a third layer.

11. The device of any one of claims 1 through 10 further comprising a fourth layer.

12. The device of any one of claims 1 through 11 wherein one or more of the device layers comprises one or more release rate-controlling agents.

13. The device of any one of claims 1 through 12 wherein the device comprises one or more of bromfenac, diclofenac, indomethacin, nepafenac, metformin, N-acetylcysteine amide (NAC amide); flurbiprofen; suprofen, and / or ketorolac, or a pharmaceutically acceptable salt thereof.

14. The device of any one of claims 1 through 13 wherein the device comprises one or more NS AID agents.

15. The device of any one of claims 1 through 14 wherein the device comprises one or more of cortisone; prednisone; prednisolone; methylprednisolone; dexamethasone; betamethasone; and hydrocortisone, or a pharmaceutically acceptable salt thereof.

16. The device of any one of claims 1 through 15 wherein the implant comprises one or more coticosteriod agents.38182716999.

117. The device of any one of claims 1 through 16 wherein the implant is circular or oval shape.

18. The device of any one of claims 1 thought 17 wherein the device comprises one or more biodegradable polymers.

19. The device of claim 18 wherein the one or more biodegradable polymers degrade over extended time in a patient eye to thereby administer the one or more therapeutic agents to the patient.

20. The implant of claim 18 or 19 wherein the one or more biodegradable polymers comprise poly(lactic-co-glycolide), polylactic-polyglycolic acid block copolymers (PLGA), hydroxypropyl methyl cellulose, hydroxyl methyl cellulose, polyglycolide-polyvinyl alcohol, croscarmellose sodium, hydroxypropylcellulose, sodium carboxymethylcellulose, polyglycolic acid-polyvinyl alcohol block copolymers (PGA / PVA), hydroxypropylmethylcellulose (HPMC), and / or polycaprolactonepolyethylene glycol block copolymers.

21. A method for delivery of a therapeutic agent to a patient’s eye comprising:(a) providing an implant device of any one of claims 1 through 20 wherein the device comprises one or more therapeutic agents; and(b) inserting the device into a patient’s eye.

22. The method of claim 21 wherein the implant device is placed into the sub-Tenon’s space and in contact with the sclera of the eye.

23. The method of claim 21 or 22 wherein the one or more therapeutic agents have a delivery duration of about two weeks to about 6 weeks.39182716999.

124. The method of any one of claims 21 through 23 wherein the patient is suffering from macular degeneration.

25. The method of any one of claims 21 through 24 wherein the patient is suffering from age-related macular degeneration.

26. The method of any one of claims 21 through 25 wherein the patient is suffering from cystoid macular edema.

27. The method of any one of claims 21 through 26 wherein the patient is suffering from diabetic macular edema.

28. The method of any one of claims 21 through 27 wherein the implant is placed in the posterior of the eye near the macula of the eye.

29. The method of any one of claims 21 through 28 wherein an applicator device is used to place the ocular implant into the sub-Tenon’s space the eye.

30. A method for treating a subject suffering from or susceptible to macular degeneration, comprising:(a) providing an implant device of any one of claims 1 through 20 wherein the device comprises one or more therapeutic agents; and(b) inserting the device into the subject’s eye.

30. The method of claim 30 wherein the subject is suffering from age-related macular degeneration.

32. A method for treating a subject suffering from or susceptible to cystoid macular edema, comprising:(a) providing an implant device of any one of claims 1 through 20 wherein the device comprises one or more therapeutic agents; and40182716999.1(b) inserting the device into the subj ect’ s eye.

33. A method for treating a subject suffering from or susceptible to diabetic macular edema, comprising:(a) providing an implant device of any one of claims 1 through 20 wherein the device comprises one or more therapeutic agents; and(b) inserting the device into the subject’s eye.

34. A kit comprising:(a) an implant of any one of claims 1 through 20; and(b) instructions for use of the implant to treat an eye disorder.41182716999.1

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