Ophthalmic Devices and Methods

Abstract

A novel multi-layered ocular implant device is provided. In some embodiments, the device is adapted to reside in the sub-Tenon space of the patient's eye. In some systems, the separate layers of the implant device will contain separate therapeutic agents, for example, two or more different agents that can deliver a desired pharmacological effect. In some preferred systems, the separate therapeutic agents in the separate device layers may provide a coordinated pharmacological effect, for example, a first layer may contain a primary therapeutic agent, and a second layer may contain a therapeutic agent that provides a supportive benefit to the primary therapeutic agent, such as reducing side effects or enhancing patient uptake of the primary therapeutic agent, or other delivery enhancement.

Description

[Technical field]

[0001] This application claims priority to 1) U.S. Provisional Application No. 63 / 397,202, filed August 11, 2022, and 2) U.S. Provisional Application No. 63 / 260,621, filed August 26, 2021, which applications are incorporated by reference herein in their entireties.

[0002] The present disclosure relates generally to localized therapies for the eye, and more particularly to an ocular implant device. In some aspects, the implant device is adapted to reside within the sub-Tenon's space of a patient's eye. [Background technology]

[0003] In the treatment of many diseases and disorders of the eye, particularly in the case of degenerative or persistent conditions, implantable sustained release delivery devices are desirable. See Gote et al, Journal of Pharmacology and Experimental Therapeutics, September 2019, 370(3) 602-624.

[0004] Certain ocular implants and configurations have been reported for administering therapeutic agents to the eye. A particularly useful system is disclosed in U.S. Patent No. 10,881,609.

[0005] It would be desirable to have new ocular implant devices and drug delivery systems. Summary of the Invention [Means for solving the problem]

[0006] Provided herein is a novel ocular implant device useful for administering a therapeutic agent to the eye of a patient.

[0007] In one embodiment, the ocular implant device comprises three or more layers, each layer being different from the adjacent layer.

[0008] It has been discovered that such multi-layered implant devices can provide significant advantages, including enhanced delivery of a therapeutic agent. For example, the multiple layers can allow for a desired delivery rate of a therapeutic agent to a patient.

[0009] In a preferred embodiment, the ocular implant device comprises three or more layers, and one or more therapeutic agents are present in at least one layer of the device.

[0010] In certain preferred embodiments, the ocular implant device comprises three or more layers, and one or more therapeutic agents are present in at least two or three layers of the device. The therapeutic agents present in the different layers may suitably be the same or different.

[0011] In some systems, the separate layers of the implant device will contain separate therapeutic agents, for example, two or more different agents capable of delivering a desired pharmacological effect. In some preferred systems, the different therapeutic agents in the separate device layers may provide a coordinated pharmacological effect, for example, a first layer may contain a primary therapeutic agent, and a second layer may contain a therapeutic agent that provides a supportive benefit to the primary therapeutic agent, such as reducing side effects or enhancing patient uptake of the primary therapeutic agent, or other delivery enhancements.

[0012] In a particularly preferred system, at least one administered therapeutic agent may control or regulate the lymphatic clearance or absorption of a separate primary therapeutic agent being administered by the device. The primary therapeutic agent and the lymphatic absorption modulator may suitably be contained in separate layers of the implant device.

[0013] In further certain preferred systems, at least one administered therapeutic agent may comprise a steroid or other agent (including non-steroidal agents) that controls fibrosis and is administered in combination with another distinct therapeutic agent. The anti-fibrotic agent and the additional distinct therapeutic agent may suitably be contained in separate layers of the implant device.

[0014] In a preferred system, a multi-layer ocular implant device is provided. (a) a first layer comprising a polymer; (b) a second layer that is 1) different from the first layer and 2) comprises one or more therapeutic agents; (c) The third layer and the implant device may preferably have one or more additional layers (eg, four, five or more layers) that are different from at least one other layer.

[0015] In one system, the primary therapeutic agent may be loaded into an inner core layer that is encased within two or more separate implant layers. A first layer abutting or adjacent to the therapeutic agent core layer may be substantially impermeable to the therapeutic agent, providing directional delivery of the therapeutic agent to the opposing implant device side, etc. Suitably, an additional layer adjacent to or in contact with the therapeutic agent core layer on the opposing therapeutic core layer may include one or more materials that provide a long-term, controllable release of the therapeutic agent from the core layer through that second layer for administration to the patient. For example, the additional layer adjacent to the core therapeutic agent may include one or more polymers that may degrade over time or otherwise regulate the release of the therapeutic agent. Such polymers may include any of a variety of biodegradable or bioerodible polymers, such as poly(lactic-co-glycolic acid) (PLGA), poly(caprolactone) (PCL), poly(ethylene glycol) (PEG), polyethylene glycol diacrylate (PEGDA), poly(glycerol sebacate) (PGS) and / or poly(glycerol sebacate urethane) (PGSU).

[0016] In another multi-layered implant device system, one or more therapeutic agents may be included in two or more device layers. For example, a core device layer may contain a primary therapeutic agent, and a second layer adjacent to the core layer may include a second separate therapeutic agent that may support the primary therapeutic agent of the core layer, for example, to treat possible side effects or to provide a desired bioavailability, such as enhanced exposure, of the primary therapeutic agent. Alternatively, an implant device core layer may include a second therapeutic agent, and an outer implant device layer may include the primary therapeutic agent that is administered to the patient.

[0017] In a preferred device, the implant device preferably has a curved surface.

[0018] In a preferred system, the third layer comprises one or more rate controlling agents and / or one or more therapeutic agents, whereby the rate and duration of administration of the one or more therapeutic agents can be extended for an extended period of time, including 1, 2, 3, 4, 5, 6 days or more, or 1, 2, 3, 4 weeks or more, or for a longer period of time, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 18, 21, 24, 27, 30, 33, or 36 months or more.

[0019] In one preferred system, the third layer is interposed between the first and second layers. In a preferred system, the third layer is the outermost layer of the implant device.

[0020] The separate layers of the implant device can have a variety of configurations, for example, the cross-sectional thickness of the third layer is preferably 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.

[0021] Suitably, the third layer comprises a polymer, such as a polyimide, or other material, including one or more other materials capable of inhibiting transport of a therapeutic agent through the third layer.

[0022] In some embodiments, the first layer does not contain a therapeutic agent, including when the first layer is the outermost layer of the implant device. Suitably, the second layer comprises a polymer different from the polymer of the first layer.

[0023] In one preferred configuration, the first layer extends circumferentially beyond the second layer such that a surface of the circumferential extension of the first stiffening layer is capable of contacting the sclera of the eye. Preferably, at least one surface of the second layer is capable of contacting the sclera of the subject's eye.

[0024] In one preferred system, the implant device may include a fourth layer that is different from any of the first, second, or third layers.

[0025] In certain other preferred systems, the implant device includes a fourth layer that is different from the adjacent layers.

[0026] In further certain preferred systems, the implant device may include a fifth layer that is different from any of the first, second, third or fourth layers.

[0027] In a further preferred system, the implant device includes a fifth layer that is different from the adjacent layers.

[0028] In certain preferred embodiments, the implant device contains a single therapeutic agent. That therapeutic agent may suitably be present in a single layer of a multi-layer device. In certain embodiments, each layer of the device may comprise a single type of polymer.

[0029] The multi-layered ocular implant device preferably comprises, for administration to a subject, one or more nonsteroidal anti-inflammatory drugs (NSAIDs), particularly one or more of bromfenac; diclofenac; indomethacin; nepafenac; metformin; flurbiprofen; suprofen; and / or ketorolac, or a pharma- ceutically acceptable salt thereof.

[0030] In another embodiment, the multi-layered ocular implant device preferably comprises N-acetylcysteine ​​amide (NAC amide or NACA) for administration to a subject.

[0031] In another embodiment, the multi-layered ocular implant device preferably includes one or more prostaglandins, such as latanoprost, for administration to a subject.

[0032] The ocular implant devices of the present invention may also include one or more other therapeutic agents.

[0033] In one embodiment, a layer (e.g., a first layer) of an implant device is considered to be different from another layer (e.g., a second layer), and the two layers have different composition and / or function. For example, the first layer may contain one or more therapeutic agents, and the adjacent layer that is at least the same or does not contain any therapeutic agent is a separate layer as referred to herein. In such an exemplary system, the polymer matrix of these two layers may be the same or different.

[0034] The separate layers may also include one or more of the same polymers or other materials, but may differ in at least one material, such as at least one polymer. For example, an outer drug delivery modulating layer may include an additional polymer that modulates the release of a therapeutic agent from the implant device to the patient.

[0035] In other embodiments, the two layers are distinct if they have different functions, such as permeability of a therapeutic agent through the layers.

[0036] A single layer may also suitably not have a uniform composition throughout the layer, for example, a first portion of the cross-sectional thickness of a layer may be relatively similar to an adjacent layer, while a second portion of the layer may have a more significant amount of a component, such as a polymer or therapeutic agent, that is not present in the first portion of the layer.

[0037] Such graded compositional profiles across the layer cross-section can provide more precise device function, such as long-term drug delivery from an implant device.

[0038] Separate device layers may also be manufactured in separate steps during the manufacture of an implant device. For example, a device substrate may have a first layer composition applied thereto, such as by coating, and in a separate subsequent step, a second layer composition may be applied, such as by coating, onto the first layer or another material applied onto the first layer. A single layer may be manufactured in multiple steps, such as multiple polymer deposition steps.

[0039] The thickness of each layer may suitably vary widely. Typical layer thicknesses may range from about 30 μm to 5 or 8 mm, more typically 30 μm to 0.5, 0.6, 0.7, 0.8, 0.9, or 1 or 2 mm or more. In certain embodiments, a layer containing a therapeutic agent may have a relatively greater thickness than an adjacent layer that does not contain a therapeutic agent. In certain embodiments, one or more layers of the implant device are each about 2 mm or less in thickness, e.g., 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 in thickness. For the layer(s) containing a therapeutic agent, the layer thickness may be determined, at least in part, by the solubility of the therapeutic agent and the amount of therapeutic agent required to achieve a target release duration.

[0040] As mentioned above, the implant device of the present invention preferably has a curved surface. In a preferred configuration, the implant device is circular or elliptical. In a further preferred configuration, the implant device has a configuration that enhances fixation when implanted in a patient. For example, the implant device may include features that allow for the attachment of sutures to the device.

[0041] In one aspect, preferably at least one layer of the implant device comprises a biodegradable or bioerodible material, such as a polymeric material that degrades over time in vivo. In certain embodiments, multiple or all layers of the implant device can comprise one or more biodegradable or bioerodible materials.

[0042] In one embodiment, the outer layer (ie, the layer of the implant device having an extended cross-sectional surface exposed to or otherwise in direct contact with the patient's tissue) comprises a biodegradable or bioerodible material.

[0043] Exemplary biodegradable or bioerodible polymers that may be incorporated into the implant device layers include, for example, poly(lactic acid-co-glycolide), polylactic acid-polyglycolic acid polymer (PLGA), hydroxypropyl methylcellulose, hydroxyl methylcellulose, polyglycolide-polyvinyl alcohol, croscarmellose sodium, hydroxypropyl cellulose, carboxymethylcellulose (e.g., sodium carboxymethylcellulose), polyglycolic acid-polyvinyl alcohol copolymer (PGA / PVA), hydroxypropyl methylcellulose (HPMC), poly(glycerol sebacate) (PGS), poly(glycerol sebacate urethane) (PGSU), and / or polycaprolactone polyethylene glycol polymer materials.

[0044] In one embodiment, preferably at least one layer of the implant device comprises a polylactic-polyglycolic acid (PLGA) material.

[0045] In one embodiment, preferably at least one layer of the implant device comprises a polylactic-polyglycolic acid (PLGA) material, and that device layer comprises one or more therapeutic agents.

[0046] In one aspect, preferably at least one layer of the implant device comprises a poly(glycerol sebacate) (PGS) material.

[0047] In one embodiment, preferably at least one layer of the implant device comprises a poly(glycerol sebacate) (PGS) material, which device layer comprises one or more therapeutic agents.

[0048] In one aspect, preferably at least one layer of the implant device comprises a poly(glycerol sebacate urethane) (PGSU) material.

[0049] In one aspect, preferably at least one layer of the implant device comprises a poly(glycerol sebacate urethane) (PGSU) material, which device layer comprises one or more therapeutic agents.

[0050] In the implant device of the present invention, preferably at least one layer is at least substantially impermeable to diffusion of the therapeutic agent. Such a layer can direct the diffusion of the therapeutic agent to the patient. For example, the at least one impermeable layer can be made of polyvinyl acetate, crosslinked polyvinyl alcohol, crosslinked polyvinyl butyrate, ethylene ethyl acrylate copolymer, polyethylhexyl acrylate, polyvinyl chloride, polyvinyl acetal, ethylene vinyl acetate copolymer, polyvinyl alcohol, polyvinyl acetate, ethylene vinyl acetate copolymer, polyvinyl ester, polyvinyl butyrate, polyvinyl formal, polyamide, polymethyl methacrylate, polybutyl methacrylate, plasticized polyvinyl chloride, plasticized nylon, plasticized soft nylon, plasticized polyethylene terephthalate, polyisoprene, polyisobutylene, polybutadiene, polyisobutyl ... The polymer may include one or more polymers of vinylidene chloride, polyethylene, polytetrafluoroethylene, polyvinylidene chloride, polyacrylonitrile, crosslinked polyvinylpyrrolidone, polytrifluorochloroethylene, chlorinated polyethylene, poly(1,4'-isopropylidenediphenylene carbonate), vinylidene chloride, acrylonitrile copolymer, vinyl chloride-diethyl fumarate copolymer, silicone rubber, medical grade polydimethylsiloxane, ethylene-propylene rubber, silicone-carbonate copolymer, vinylidene chloride-vinyl chloride copolymer, vinyl chloride-acrylonitrile copolymer, vinylidene chloride-acrylonitrile copolymer, vinylidene chloride-acrylonitrile copolymer.

[0051] Preferably, at least one implant device layer is made of a material selected from the group consisting of polyvinyl acetate, crosslinked polyvinyl alcohol, crosslinked polyvinyl butyrate, ethylene ethyl acrylate copolymer, polyethylhexyl acrylate, polyvinyl chloride, polyvinyl acetal, plasticized ethylene vinyl acetate copolymer, polyvinyl alcohol, polyvinyl acetate, ethylene vinyl acetate copolymer, polyvinyl ester, polyvinyl butyrate, polyvinyl formal, polyamide, polymethyl methacrylate, polybutyl methacrylate, plasticized polyvinyl chloride, plasticized nylon, plasticized soft nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, The polymeric material may include one or more of polybutadiene, polyethylene, polytetrafluoroethylene, polyvinylidene chloride, polyacrylonitrile, crosslinked polyvinylpyrrolidone, polytrifluorochloroethylene, chlorinated polyethylene, poly(1,4'-isopropylidenediphenylene carbonate), vinylidene chloride, acrylonitrile copolymer, vinyl chloride-diethyl fumarate copolymer, thermoplastic polyurethane (TPU), silicone rubber, medical grade polydimethylsiloxane, ethylene-propylene rubber, silicone-carbonate copolymer, vinylidene chloride-vinyl chloride copolymer, vinyl chloride-acrylonitrile copolymer, vinylidene chloride-acrylonitrile copolymer, vinylidene chloride-acrylonitrile copolymer.

[0052] A preferred material for the outer implantable device layer is polyethylene, including LDPE (low density polyethylene).

[0053] Preferred materials for implant device layers that include one or more therapeutic agents include vinyl acetate and ethylene-vinyl acetate (EVA). It may also be preferred that a bioerodible device layer (e.g., an implant layer that includes poly(glycerol sebacate urethane) (PGSU)) include one or more therapeutic agents.

[0054] In one embodiment, at least one layer of the implant device comprises a permeability enhancer that increases ocular permeability of a therapeutic agent to the eye.

[0055] In one embodiment, the implant device layer may include a therapeutic agent mixed with a controlled release composition. A suitable controlled release composition may include one or more polymers, such as one or more biodegradable polymers, which degrade over time in the patient's eye, thereby administering one or more therapeutic agents to the patient. Exemplary biodegradable polymers that may be incorporated into the implant device layer include, for example, poly(lactic acid-co-glycolide), polylactic acid-polyglycolic acid block copolymer (PLGA), hydroxypropyl methylcellulose, hydroxyl methylcellulose, polyglycolide-polyvinyl alcohol, croscarmellose sodium, hydroxypropyl cellulose, sodium carboxymethylcellulose, polyglycolic acid-polyvinyl alcohol block copolymer (PGA / PVA), hydroxypropyl methylcellulose (HPMC), poly(glycerol sebacate) (PGS), poly(glycerol sebacate urethane) (PGSU), and / or polycaprolactone polyethylene glycol copolymer.

[0056] Bioerodible layers can also be configured to provide a desired release rate, inter alia, by selection of the crosslink density of the polymer matrix of the layer, selection of the layer material and layer thickness. The desired degradation rate of a layer that is intended to erode over a particular period of time can be readily identified empirically by testing implant device layers with various materials, crosslink densities and layer thicknesses, among other characteristics.

[0057] In a further aspect, a method is provided for delivering a therapeutic agent to a patient's eye, comprising: (a) providing an implant device as disclosed herein, the device comprising one or more therapeutic agents; and (b) inserting the device into the patient's eye.

[0058] Preferably, the implant device is placed in the sub-Tenon's space and in contact with the sclera of the eye.

[0059] Patients may be treated for a variety of disorders and diseases, including macular degeneration, particularly age-related macular degeneration (AMD).

[0060] In certain aspects, the patient may be treated for diabetic macular edema (DME). In one embodiment, the patient may be identified as suffering from or susceptible to diabetic macular edema, which may involve the accumulation of excess fluid in the extracellular space within the retina in the macular region, and the identified patient is treated with the implants disclosed herein.

[0061] In certain aspects, the patient may be treated for cystoid macular edema or CME. In one embodiment, the patient may be identified as suffering from or susceptible to cystoid macular edema, and the identified patient is treated with an implant disclosed herein.

[0062] Treatment kits are also provided and may include (a) an implant device as disclosed herein and (b) instructions for use of the implant device to treat an ocular disorder.

[0063] The treatment kit may suitably include other components.

[0064] Further provided is a method for assessing the effectiveness of an implant device described herein for the treatment or prevention of an ocular disease or disorder, such as macular degeneration, in a human, comprising the steps of a) placing an implant device described herein into the sub-Tenon space of the human's eye; and b) examining the human's eye using an appropriate analytical technique, thereby assessing the effectiveness of the implant device for the ocular disease or disorder being evaluated.

[0065] Any of a variety of analytical or investigative procedures may be utilized, for example, two-color (blue, red) microperimetry, low-light visual acuity, multifocal electroretinography, dynamic perimetry, color vision assessment, light stress testing and static perimetry, contrast sensitivity, qCST, BCVA, qVA, OCT / FAF / IR / OCT-A / flavo-protein detection / color fundus photography, etc.

[0066] Other aspects of the invention are disclosed below. [Brief description of the drawings]

[0067] [Figure 1] FIG. 1 illustrates a schematic of a preferred multi-layer implant device. [Diagram 2] FIG. 2 illustrates, in schematic form, a further preferred multi-layer implant device. [Diagram 3] FIG. 3 is a photograph of the implant of Example 2 below. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0068] As described, in various embodiments, a composite ocular implant device is provided that includes a therapeutic agent for the treatment or prevention of an ocular disorder. In a preferred system, the implant device provides sustained release of the therapeutic agent during the treatment or prevention of an ocular disorder. This device configuration is particularly well suited for placement under Tenon's capsule (also known as the bulbar cavity), but is not limited thereto, and may be placed on or in other ocular regions where it is convenient and useful.

[0069] The implant device of the present invention can be used to treat many ocular diseases and indications including, for example, age-related macular degeneration, glaucoma, diabetic retinopathy, uveitis, neonatal retinopathy of prematurity, choroidal melanoma, choroidal metastases, and retinal capillary hemangioma.

[0070] Multi-layered ocular implant device Referring to the drawings, Figure 1 illustrates generally a preferred ocular implant device 10 including multiple layers 12, 14, 16 and 18. The implant device may also suitably include additional layers.

[0071] Preferably, one or more layers contain one or more therapeutic agents, such as a nonsteroidal anti-inflammatory drug (NSAID) or other agent, including those therapeutic agents disclosed below.

[0072] In some systems, an outermost layer, such as layer 12 or 18 shown in Figure 1, may function as a drug release rate limiting membrane. For example, the layer may be a polymer matrix (including a cross-linked matrix) that can regulate the flow of one or more therapeutic agents from the device through the layer to the scleral surface 11.

[0073] In one configuration, layer 14 can include one or more therapeutic agents. The layer preferably includes one or more polymers into which the therapeutic agent is mixed. In some embodiments, it may be preferred that the implant device layer contains a single polymer rather than a blend of two or more different polymers.

[0074] In one configuration, layer 12 may function as a drug diffusion barrier layer. For example, the layer may include a polymer or polymer matrix that substantially prevents a therapeutic agent present in layer 14 from passing through layer 16.

[0075] In one configuration, layer 18 may be an additional polymeric layer. In one embodiment, layer 18 may contain one or more therapeutic agents that may be the same as or different from the one or more therapeutic agents present in layer 14. As noted above, in certain preferred aspects, the one or more therapeutic agents of layer 18 are different from the therapeutic agents present in layer 14. The therapeutic agents of layer 18 may be suitably administered to Tenon's capsule / conjunctival surface 20.

[0076] In other embodiments, layer 18 may not contain a therapeutic agent.

[0077] In other preferred systems, an encased or inner layer, such as layers 14 and / or 16 shown in Figure 1, may include one or more therapeutic agents. In such a configuration, outer layers 12 and / or 18 shown in Figure 1 may function to control drug administration, such as by regulating the release of the therapeutic agent from layers 14 or 16 to the subject. For example, layers 12 and / or 18 may include one or more bioerodible or biodegradable materials that release the therapeutic agent from the implant device over an extended period of time, such as 1, 2, 3, 4, 5, 6, or 7 days or more, or over a period of time, such as 2, 3, 4, 5, 6, 7, or 8 weeks or more, or over a longer period of time, such as discussed above, such as 0.5, 1, 1.5, 2, 2.5, 3, or more years.

[0078] The various layers 12, 14, 16, 18 may be made of any of a variety of materials, including polyvinyl acetate, crosslinked polyvinyl alcohol, crosslinked polyvinyl butyrate, ethylene ethyl acrylate copolymers, polyethylhexyl acrylate, polyvinyl chloride, polyvinyl acetal, plasticized ethylene vinyl acetate copolymers, polyvinyl alcohol, polyvinyl acetate, ethylene vinyl acetate copolymers, polyvinyl esters, polyvinyl butyrate, polyvinyl formal, polyamides, polymethyl methacrylate, polybutyl methacrylate, plasticized polyvinyl chloride, plasticized nylon, plasticized soft nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, polytetrafluoroethylene ... The polymer may include one or more polymers such as ethylene, polyvinylidene chloride, polyacrylonitrile, crosslinked polyvinylpyrrolidone, polytrifluorochloroethylene, chlorinated polyethylene, poly(1,4'-isopropylidenediphenylene carbonate), vinylidene chloride, acrylonitrile copolymers, vinyl chloride-diethyl fumarate copolymers, silicone rubber, medical grade polydimethylsiloxane, ethylene-propylene rubber, silicone-carbonate copolymers, vinylidene chloride-vinyl chloride copolymers, vinyl chloride-acrylonitrile copolymers, vinylidene chloride-acrylonitrile copolymers, any suitable equivalents of these polymers, or any suitable equivalents of these polymers, or combinations thereof.

[0079] In some systems, vinyl acetate or ethylene vinyl acetate (EVA) materials are the preferred materials for one or more of the implant device layers.

[0080] The dimensions of the implant device may vary. However, in this particular embodiment, the implant device 10 has a diameter of 7 mm (shown as dimension b in FIG. 1) and a thickness of 2 mm (shown as dimension a in FIG. 1). In this particular embodiment, each of the two layers 16 and 18 is 1 mm thick. As mentioned above, layers 16 and 18 can be of a wide range of thicknesses, including, for example, 0.5 mm to 25 mm. In this particular example, the outer surface 18' of layer 18 has a radius of curvature of 1 cm or less to approximately match the radius of curvature of the surface of the Tenon's capsule of the average human eye. Similarly, layer 12 is curved with a similar radius of curvature configured to approximately match the radius of curvature of the sclera of the average human eye. These dimensions provide the implant device 10 with characteristics suitable for implantation with scleral contact in the human sub-Tenon's space. It will be understood by those skilled in the art that these dimensions should be appropriately modified for implant devices designed for use in laboratory animals, such as rats, mice, or rabbits. Armed with knowledge of the average eye dimensions of a selected experimental animal and the radius of curvature of the Tenon's capsule and sclera, the dimensions of an ocular implant device according to the present invention can be selected by one of skill in the art and a suitable molding tool can be constructed without undue experimentation.

[0081] In certain systems, it may be advantageous to provide an ocular implant device having upper layers 12 and / or 14 that are generally resistant to diffusion of a therapeutic agent dispersed in layer 16, as shown in FIG. 1. In certain embodiments, layer 12 is impermeable to the therapeutic agent. In other embodiments, the therapeutic agent has a diffusion rate in layer 12 that is greater than the diffusion rate of the therapeutic agent through layer 16. The differential diffusion properties of the therapeutic agent through certain implant device layers provide the advantage of preventing loss of the therapeutic agent to tissues where the therapeutic agent is not needed. For example, a reduction in the diffusion rate of the therapeutic agent through layer 16 promotes unidirectional diffusion of the therapeutic agent to the sclera and choroid for migration to the macula. An additional advantage provided by the reduced diffusion properties of the therapeutic agent in layers 12 and / or 14 relative to layers 16 or 18 (18, if present) is obtained in preventing the therapeutic agent from entering the lymphatic system via Tenon's capsule and conjunctiva for migration to other tissues where it may cause undesirable side effects. Thus, in certain embodiments of the present disclosure, one or more layers of the implant device further include an agent that blocks lymphatic absorption, as discussed above.

[0082] Additionally, as discussed above, separate implant device layers may contain other coordinated multi-drug therapies, for example, as discussed, one layer may contain a steroid or an anti-fibrotic agent such as 5-fluorouracil or mitomycin C, and preferably another layer contains one or more additional different therapeutic agents.

[0083] In certain embodiments, the therapeutic agent administered in layer 14 is a nonsteroidal anti-inflammatory drug (NSAID), such as nepafenac. The drug is released via diffusion through layer 12, shown in FIG.

[0084] In certain preferred embodiments, the implant device 10 is placed in the sub-Tenon space of the patient's eye with the implant device surface resting on the surface of the sclera. Preferably, the opposing upper implant device layer has a curvature that generally matches the curvature of the surface of the Tenon's capsule. Such a configuration can minimize discomfort to the eye as a result of the Tenon's capsule contacting the upper edge of the implant device 10. In one preferred configuration, the curved upper surface of the implant device is smooth and does not have sharp edges that would otherwise cause irritation and / or damage to the tissue of the Tenon's capsule and possibly also the conjunctiva if a sharp edge of an alternative implant were to completely puncture the Tenon's capsule and penetrate the conjunctiva.

[0085] In a preferred system, one or more therapeutic agents contained in the implant device are released into the sclera because the therapeutic agent is concentrated in the implant device layer 14 and the top layer 12 allows for diffusion of the therapeutic agent. In a system, the therapeutic agent administered by the implant device may be transported by either diffusion or active physiological mechanisms, or a combination thereof, to the macula where the desired pharmaceutical effect will be achieved.

[0086] A further preferred implant device 30 is shown in Figure 2, which includes at least five different implant device layers. Thus, the implant device 30 of Figure 2 includes layers 32, 34, 36, 38, and 40. Any of the layers may include one or more therapeutic agents. One or more of the layers may function to control drug administration by regulating the release of the therapeutic agent as described above, for example, via one or more bioerodible or biodegradable materials that release the therapeutic agent.

[0087] In one preferred system, device 30 includes a drug release rate limiting membrane 32 in contact with scleral surface 31. For example, layer 32 may be a polymer matrix (including a cross-linked matrix) capable of regulating the flow of one or more therapeutic agents from the device through the layer to scleral surface 31.

[0088] In one configuration, layer 36 can include one or more therapeutic agents. The layer preferably includes one or more polymers into which the therapeutic agents are mixed. In one configuration, layer 32 or 34 can function as a drug diffusion barrier layer. For example, a layer may include a polymer or polymer matrix that substantially prevents a therapeutic agent present in layer 36 from passing through layer 32.

[0089] In one configuration, layer 38 may be an additional polymeric layer. In one embodiment, layer 38 may contain one or more therapeutic agents that may be the same as or different from the one or more therapeutic agents present in layer 36. As noted above, in certain preferred embodiments, the one or more therapeutic agents in layer 38 are different from the therapeutic agents present in layer 36. The therapeutic agents in layer 38 may be preferably administered to Tenon's capsule / conjunctival surface 42.

[0090] In one configuration, layer 40 is a drug release rate limiting membrane in contact with Tenon's / conjunctival surface 42. Thus, for example, layer 40 may be a polymer matrix (including a cross-linked matrix) that can regulate the flow of one or more therapeutic agents through the layer and out of the device to the scleral surface.

[0091] Therapeutic Agents As discussed above, the implant device can contain and deliver a variety of therapeutic agents to a subject.

[0092] In one embodiment, the one or more therapeutic agents that can be administered to a patient using the implant device of the present invention include, but are not limited to, antibiotics such as fumagillin analogs, minocycline, fluoroquinolones, cephalosporin antibiotics, herbimycon A, tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol, gentamicin, and erythromycin; antibacterial agents such as sulfonamides, sulfacetamide, sulfamethizole, sulfoxazole, nitrofurazone, and / or sodium propionate.

[0093] In another aspect, the one or more therapeutic agents that may be administered to a patient using the implant device of the present invention include N-acetylcysteine ​​(NAC) alkyl-ester analog compounds, including those disclosed in WO2021 / 092470.

[0094] In another embodiment, the one or more therapeutic agents that may be administered to a patient using an implant device of the present invention includes N-acetylcysteine ​​amide (NAC amide or NACA).

[0095] In another embodiment, the one or more therapeutic agents that can be administered to a patient using an implant device of the present invention include one or more prostaglandins, such as latanoprost. The ocular implant device of the present invention also comprises one or more

[0096] In another embodiment, the one or more therapeutic agents that can be administered to a patient using the implant device of the present invention include antiviral agents such as idoxuridine, fanvir, trisodium phosphonoformate, trifluorothymidine, acyclovir, ganciclovir, DDI and AZT, protease and / or integrase inhibitors.

[0097] In another embodiment, the one or more therapeutic agents that can be administered to a patient using the implant device of the present invention include anti-glaucoma agents such as beta-blockers (timolol, betaxolol, atenolol), prostaglandin analogs, antihypertensive lipids, and / or carbonic anhydrase inhibitors.

[0098] In another embodiment, the one or more therapeutic agents that may be administered to a patient using the implant device of the present invention include anti-allergy agents such as antazoline, methapyrilin, chlorpheniramine, pyrilamine and / or profenpyridamine.

[0099] In another embodiment, the one or more therapeutic agents that can be administered to a patient using the implant device of the present invention include anti-inflammatory agents such as hydrocortisone, leflunomide, dexamethasone phosphate, fluocinolone acetonide, medrysone, methylprednisolone, prednisolone phosphate, prednisolone acetate, fluoromethalone, betamethasone, triamcinolone acetonide, corticosteroids and their synthetic analogs, and / or 6-mannose phosphate.

[0100] In another embodiment, the one or more therapeutic agents that can be administered to a patient using the implant device of the present invention include antifungals such as fluconazole, amphotericin B, liposomal amphotericin B, voriconazole, imidazole antifungals, thiazole antifungals, echinocandin-like lipopeptide antibacterial agents, liquid formulations of antifungals; polycations and polyanions such as suramin and / or protamine.

[0101] In another embodiment, the one or more therapeutic agents that can be administered to a patient using the implant device of the present invention include decongestants such as phenylephrine, naphazoline, and / or tetrahydrazoline.

[0102] In another embodiment, one or more therapeutic agents that may be administered to a patient using the implant device of the present invention include VEGF antagonists such as 2-methoxyestradiol and its analogs (e.g., 2-propynyl-estradiol, 2-propenyl-estradiol, 2-ethoxy-6-oxime-estradiol, 2-hydroxyestrone, 4-methoxyestradiol), VEGF antibodies and VEGF antisense, angiogenesis inhibitory steroids (e.g., androgens with angiogenesis inhibitory activity such as anecortave acetate and its analogs, 17-ethynylestradiol, norethynodrel, medroxyprogesterone, mestranol, ethisterone), and thymidine kinase inhibitors, which may be potential antichoroidal neovascularization agents.

[0103] In another embodiment, the one or more therapeutic agents that can be administered to a patient using the implant device of the present invention include corticosteroids and their synthetic analogs, including fluocinolone acetonide and triamcinolone acetonide, as well as all angiogenesis-suppressing steroids.

[0104] In another embodiment, the one or more therapeutic agents that can be administered to a patient using the implant device of the present invention include immunological response modifiers such as cyclosporine A, prograf (tacrolimus), macrolide immunosuppressants, mycophenolate mofetil, rapamycin, and muramyl dipeptide.

[0105] In another embodiment, the one or more therapeutic agents that may be administered to a patient using the implant device of the present invention include one or more of the following anti-cancer agents: platinum coordination complexes such as 5-fluorouracil, cisplatin and carboplatin, antimetabolites such as adriamycin, methotrexate, anthracycline antibodies, antimitotics such as paclitaxel and docetaxel, epidophyltoxins such as etoposide, nitrosoureas including carmustine, alkylating agents including cyclophosphamide; arsenic trioxide; Nastrozole;Tamoxifen citrate;Triptorelin pamoate;Gemtuzumab ozogamicin;Irinotecan hydrochloride;Leuprolide acetate;Bexarotene;Exemestran;Epirubicin hydrochloride;Ondansetron;Temozolomide;Topoatene hydrochloride;Tamoxifen citrate;Irinotecan hydrochloride;Trastuzumab;Valrubicin;Gemcitabine;Goserelin acetate;Capecitabine;Aldesleukin;Riximab;Oprelvekin;Interferon alpha-2a;Letrozole;Toremife citrate; mitoxantrone hydrochloride; irinotecan; topotecan; etoposide phosphate; gemcitabine; and amifostine; antisense agents; antifungal agents; miotics and anticholinesterase agents such as pilocarpine, eserine salicylate, carbachol, diisopropylfluorophosphate, phosphoinositide, and demecarium bromide; mydriatics such as atropine sulfate, cyclopentane, homatropine, scopolamine, tropicamide, eucatropine, and hydroxyamphetamine; differentiation inducer agents; Sympathomimetics such as epinephrine; anesthetic agents such as lidocaine and benzodiazepam; vasoconstrictors; vasodilators; polypeptide and protein agents such as angiostatin, endostatin, matrix metalloproteinase inhibitors, platelet factor 4, interferon gamma, insulin, growth hormone, insulin-related growth factor, heat shock proteins, humanized anti-lL2 receptor mAb (daclizumab), etanercept, mono and polyclonal antibodies, cytokines, antibodies against cytokines.

[0106] In another embodiment, the one or more therapeutic agents that can be administered to a patient using the implant device of the present invention include neuroprotective agents such as calcium channel antagonists, including nimodipine and diltiazem, neuroimmunophilin ligands, neurotropins, memantine, and other NMDA antagonists.

[0107] In another embodiment, the one or more therapeutic agents that may be administered to a patient using the implant device of the present invention include acetylcholinesterase inhibitors, estradiol and analogs, vitamin B12 analogs, alpha-tocopherol, NOS inhibitors, antioxidants (e.g., glutathione, superoxide dismutase), cobalt and copper alloys, neurotrophic receptors (Akt kinase), growth factors, nicotinamide (vitamin B3), alpha-tocopherol (vitamin E), succinic acid, dihydroxylipoic acid, fusidic acid; colchicine, vincristine, cytochalasin. carbonic anhydrase inhibitors; integrin antagonists; lipophilic agents such as idebenone, rapamycin, 2-cyan-3,12-dioxooleana-1,9(11)-dien-28-oic acid-ethylamide (CDDO-ethylamide), and 2-cyan-3,12-dioxooleana-1,9(11)-dien-28-oic acid trifluoroethylamide (CDDO-TFEA); and lubricants.

[0108] In certain embodiments, preferred therapeutic agents administered to a patient's eye using a multi-layered implant device as disclosed include one or more nonsteroidal anti-inflammatory drugs (NSAIDs), such as bromfenac; diclofenac; indomethacin; nepafenac; metformin; N-acetylcysteine ​​amide (NAC amide); flurbiprofen; suprofen; and / or ketorolac, or one or more pharma- ceutically acceptable salts thereof.

[0109] Any pharma- ceutically acceptable form of the agent may be used, such as the free base form or a pharma- ceutically acceptable salt or ester thereof. In this particular embodiment, the dosage of the therapeutic agent provided by the implant device of the present invention ranges from 1 to 100 mg. Administration or Use of Multi-Layer Ocular Implant Devices

[0110] In one preferred embodiment for administering the implant device, the subconjunctival matrix implant device is preferably placed behind the surface epithelium in the sub-Tenon's space. This is done by a surgical procedure that can be performed in an outpatient setting. A lid speculum is placed and a radial incision is made through the conjunctiva over the area where the conjunctival implant device will be placed. Westcott scissors are used to incise the posterior to the Tenon's capsule and the implant device is inserted. The conjunctiva is reapproximated using a continuous 10-0 vicryl suture. The eye has many barriers that do not allow easy penetration of drugs. These include the surface epithelium on the front of the eye (cornea) and the blood / retinal barrier, either within the retinal blood vessels or between the retinal pigment epithelium, both of which have tight junctions. These implant devices 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 horse eyes.

[0111] In certain embodiments, an applicator device is used to inject the implant device into the sub-Tenon's space. Such devices are known in the art and are used for intraocular injections into the vitreous humor of the eye, particularly for intraocular lens implantation after cataract surgery. In certain embodiments, the device includes a retractor that engages the conjunctiva and the surfaces of the Tenon's capsule to create an opening into the sub-Tenon's space. The device also includes a means for pushing the implant device into the sub-Tenon's space such that withdrawal of the device holds the implant device in the desired position while allowing the surrounding tissue to collapse back into place.

[0112] Additionally, to facilitate drug diffusion into the cornea, it may be preferable to secure the matrix implant device with one or two absorbable sutures (e.g., 10-0 absorbable vicryl sutures) when the implant device is placed near the limbus (i.e., the area where the conjunctiva attaches to the front of the eye). This may be done by puncturing the peripheral portion of the implant with a 30-gauge needle approximately 250-500 µm away from the peripheral edge of the implant.

[0113] These holes are at a 180° angle to each other. This is done because certain subconjunctival matrix implant devices of the present disclosure, if placed close to the cornea, are at higher risk of extrusion due to the action of the upper eyelid when blinking. If the subconjunctival matrix implant devices disclosed herein are placed about 4 mm or more away from the limbus, suturing is optional.

[0114] In addition to sutures, other attachment means can be used including, for example, biocompatible adhesives for adhering the implant device to the target site.

[0115] This matrix implant device is capable of delivering different therapeutic levels of pharmaceuticals to the eye to treat a variety of diseases. Using a rabbit model, drugs released from implants placed in the eye produce negligible levels of drug in the blood. This significantly reduces the chance of systemic drug side effects. This implant device design of the present disclosure is prepared by unique methodologies and material selections that result in and impart unique pharmacological performance characteristics present in the finished device.

[0116] Lipophilic drugs According to the present disclosure, the therapeutic agent or component of the implant device may comprise, consist essentially of, or consist of a lipophilic drug. Such lipophilic drugs may be small molecules. The lipophilic drug may be released from the implant device by diffusion, erosion, dissolution, or osmosis. The drug release sustaining component may include one or more biodegradable polymers or one or more non-biodegradable polymers.

[0117] In one embodiment, the intraocular implant device includes a lipophilic drug. Lipophilic or other drugs that may be used in the implant device include those disclosed in U.S. Patent Publication No. 20140031408, the contents of which are incorporated herein by reference in their entirety.

[0118] In another embodiment, the intraocular implant device comprises a therapeutic agent or component that comprises a lipophilic agent.

[0119] In preferred systems, the implant devices of the present invention provide sustained or controlled delivery of a therapeutic agent at sustained levels despite rapid clearance of the lipophilic agent from the eye. The controlled delivery of lipophilic agents from the implant devices of the present invention allows lipophilic agents to be administered to the eye with reduced toxicity or degradation of the blood-aqueous humor and blood-retinal barriers that may be associated with intraocular injection of liquid formulations containing lipophilic agents.

[0120] The implant device of the present invention may be placed in an ocular region to treat various ocular conditions, such as treating, preventing, or alleviating at least one symptom associated with non-exudative age-related macular degeneration, exudative age-related macular degeneration, choroidal neovascularization, acute macular neuroretinal disorders, cystoid macular edema, diabetic macular edema, Behcet's disease, diabetic retinopathy, retinal artery occlusion 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 membrane, proliferative diabetic retinopathy, branch retinal vein occlusion, anterior ischemic optic neuropathy, non-retinopathy diabetic retinal dysfunction, retinitis pigmentosa, ocular tumors, ocular neoplasms, and the like.

[0121] Kits according to the present disclosure may include one or more of the present implant devices and instructions for using the implant device. For example, the instructions may describe how to administer the implant device to a patient and the types of conditions that may be treated with the implant device. The kits may also further include, for example, an injection device or other applicator tool.

[0122] The implant device of the present invention can be easily manufactured. Exemplary and preferred manufacturing protocols are described in the Examples below. Injection molding and compression molding are the preferred manufacturing methods.

[0123] In general, a desired implant device layer, e.g., a polymer matrix having a desired distribution of one or more therapeutic agents, can be prepared. The mixture can be applied, such as by coating onto a substrate, which may be a removable substrate if the mixture is the first layer to be deposited, or the mixture can be applied over one or more previously applied layers. A mold can be utilized in forming the implant device. The device composite can be cured under heat and / or pressure in one or more steps, such as an injection molding or compression molding process.

[0124] general definition The following general definitions are provided to facilitate understanding of the present disclosure.

[0125] As used herein, the term "radius of curvature" refers to the radius of the circle that best fits the curved surface at a given point.

[0126] As used herein, the term "penetration agent" refers to a molecule that increases the permeability of a therapeutic agent. Ophthalmic penetrants increase the permeability of a therapeutic agent to ocular tissues.

[0127] As used herein, the term "ophthalmic penetrant" (also known as a "transport enhancer") refers to a compound that increases the permeability of a therapeutic agent into ocular tissues. Methylsulfonylmethane is a non-limiting example of an ophthalmic penetrant.

[0128] As used herein, the term "microperimetry" refers to a technique used to evaluate the visual function of specific regions of the retina and fovea. It provides a quantifiable method of measuring the regression or progression of retinal visual function in the examined eye. A dot of light is projected onto the retina at a specific intensity and the patient is asked to confirm reception of the light. The change in stimulus intensity following the patient's response provides a means of assessing retinal visual function. Variations of microperimetry include dynamic perimetry, two-color (red and blue) perimetry, and static perimetry, and are known to those skilled in the art.

[0129] As used herein, the term "multifocal electroretinography" refers to a technique for determining the activity of retinal cells. When bioelectrical changes occur within the retina, they propagate to the corneal surface. These small (and often very fast) signals can be captured by electrodes placed on the surface of the cornea. The subject stares at the center of a display that contains an array of hexagons that increase in size from the center outward.

[0130] Because the number of cone photoreceptors per area varies in different parts of the retina, the size of the hexagons is adjusted so that approximately the same number of cones are stimulated by each hexagon. A single continuous electroretinogram recording is obtained while the subject is viewing the display.

[0131] As used herein, an "intraocular implant" refers to a device or element that is structured, sized, or otherwise configured to be placed in the eye. Intraocular implants are generally biocompatible with the physiological conditions of the eye and do not cause adverse side effects. An intraocular implant device may be placed in the eye without disrupting the vision of the eye.

[0132] As used herein, "ocular region" or "ocular site" generally refers to any region of the eyeball, including the anterior and posterior segments of the eye, and generally includes, but is not limited to, any functional (e.g., for vision) or structural tissue found in the eyeball, or tissue or cell layer that partially or completely lines the interior or exterior of the eyeball. Specific examples of regions of the eyeball in an ocular region include the anterior chamber, posterior chamber, vitreous cavity, choroid, suprachoroidal space, conjunctiva, subconjunctival space, episcleral space, intracorneal space, epicorneal space, sclera, pars plana, surgically induced avascular region, macula, and retina.

[0133] As used herein, an "ocular condition" is a disease, illness, or condition that affects or involves the eye or one of the parts or regions of the eye. Broadly speaking, the eye includes the eyeball, as well as the tissues and fluids that make up the eyeball, the periocular muscles (such as the oblique and rectus muscles), and the portion of the optic nerve that is within or adjacent to the eyeball.

[0134] An "anterior ocular condition" is a disease, illness, or condition that affects or involves anterior (i.e., front of the eye) ocular regions or sites, such as periocular muscles, eyelids, or ocular tissues or fluids located in front of the posterior wall of the lens capsule or ciliary muscle. Thus, anterior ocular conditions primarily affect or involve the conjunctiva, cornea, anterior chamber, iris, posterior chamber (behind the retina but in front of the posterior wall of the lens capsule), lens or lens capsule, and blood vessels and nerves that vascularize or innervate the anterior ocular region or site. Thus, anterior ocular conditions can include diseases, illnesses, or conditions, such as aphakia, pseudophakia, astigmatism, blepharospasm, cataracts, conjunctival diseases, conjunctivitis, corneal diseases, corneal ulcers, dry eye syndrome, eyelid diseases, lacrimal system diseases, lacrimal duct obstruction, myopia, presbyopia, pupil disorders, refractive disorders, and strabismus. Glaucoma may also be considered an anterior segment condition, as the clinical goal of glaucoma treatment may be to reduce high aqueous humor pressure in the anterior chamber of the eye (ie, reduce intraocular pressure).

[0135] A "posterior ocular condition" is a disease, illness, or condition that primarily affects or involves a posterior ocular region or region, such as the choroid or sclera (which lie posterior to a plane passing through the posterior wall of the lens capsule), vitreous body, vitreous cavity, retina, optic nerve (i.e., optic disc), and the blood vessels and nerves that vascularize or innervate the posterior ocular region or region. Thus, posterior ocular conditions include, for example, acute macular neuroretinopathy; Behcet's disease; choroidal neovascularization; diabetic uveitis; histoplasmosis; infections, such as fungal or viral infections; macular degeneration, such as acute macular degeneration, nonexudative 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 affecting the posterior segment or posterior ocular site; ocular tumors; retinal disorders, such as central retinal vein occlusion, diabetic retinopathy (including proliferative diabetic retinopathy), proliferative vitreous retinopathy (PVR), retinal artery occlusion disease, retinal detachment, uveitic retinal disease; sympathetic ophthalmia; Vogt's disease; These conditions may include Koyanagi-Harada (VKH) syndrome, uveal diffusion, posterior ocular conditions caused or affected by ocular laser procedures, photodynamic therapy, photocoagulation, radiation retinopathy, epiretinal membrane disorder, retinal branch 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 treatment goal is to prevent or reduce the occurrence of vision loss due to damage or loss of retinal cells or optic nerve cells (i.e., neuroprotection).

[0136] The term "biodegradable polymer" refers to a polymer or polymers that degrade in vivo, where degradation of the polymer or polymers over time occurs simultaneously with or subsequent to the release of a therapeutic agent. Specifically, hydrogels such as methylcellulose, which act to release drugs via swelling of the polymer, are specifically excluded from the term "biodegradable polymer". The terms "biodegradable" and "bioerodible" are equivalent and are used interchangeably herein. Biodegradable polymers can be homopolymers, copolymers, or polymers that contain more than two different polymer units.

[0137] As used herein, the terms "treat," "treating," or "treatment" refer to the reduction or resolution or prevention of an ocular condition, ocular injury or damage, or promoting the healing of injured or damaged ocular tissue.

[0138] As used herein, the term "therapeutically effective amount" refers to the level or amount of agent required 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 ocular area.

[0139] The following non-limiting examples are illustrative. EXAMPLES

[0140] Example 1 The implant device, shown diagrammatically in FIG. 1, is prepared as follows.

[0141] The drug layer composition is prepared by mixing the drug compound (nepafenac or other therapeutic agent) with ethylene-vinyl acetate (EVA). The mixture is heated at 70° C. for about 30 minutes.

[0142] The EVA-therapeutic agent composition is then placed into a mold where heat and pressure can be applied to establish the device 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 the opposite side of the EVA-therapeutic agent layer. An intervening adhesive material can be used to secure the layers. Silicone adhesive (e.g., BIO-PSA 7-4302, DOW CORNING) is one suitable material.

[0143] The resulting multi-layer implant device preferably has a diameter (dimension b in FIG. 1) of 8-10 mm and an overall thickness (dimension a in FIG. 1) of 1.8-2.0 mm. The implant device preferably has an outer layer that is a 0.065 mm EVA film bonded to a 0.050 mm thick LDPE barrier layer. The nepafenac or other therapeutic agent is contained in a 1.3 mm thick core EVA layer covered by a 0.45 mm EVA film.

[0144] Example 2: Further preparation of implant devices A preferred multi-layered implant device was prepared according to the procedure of Example 1 above. A photograph of the cross-section of the implant device is shown in Figure 3. As shown in Figure 3, the implant device has an inner layer of vinyl acetate polymer containing 5 weight percent of a therapeutic agent. A 450 μm vinyl acetate (5%) layer is adjacent to one surface of the implant device layer and a low density polyethylene (LDPE) layer abuts the opposing inner layer surface. An outer 450 μm vinyl acetate (5%) layer overcoats the LDPE layer.

[0145] Example 3: Administration of a multi-layered ocular implant device containing nepafenac in a mouse model of dry AMD Hydroquinone is known as an oxidant component of cigarette smoke. It has been found that mice treated with hydroquinone can 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 to 4 weeks as an alternative model. Other models of macular degeneration can also be used, including Y402H CFH transgenic under the control of the ApoE promoter, Cc12- / -Cx3crl- / - mice, Sod1- / - mice, OXY rats, as well as other animal models.

[0146] Treated mice are administered a multi-layered ocular implant device as described above in Example 1. The implant device is circular, 2.0 mm in diameter and 1 mm thick, and contains doses of 3 mg and 5 mg of nepafenac.

[0147] It has been disclosed that placement of a test implant device in the sub-Tenon's space of rodents results in episcleral clearance of the test material (Chan, Pridgen and Csaky, 2010, Exp. Eye Res. 90,501). Thus, surgical placement of the implant is performed by dissecting the conjunctiva and Tenon's fascia as posteriorly as possible prior to placing the device in the sub-Tenon's space.

[0148] The mice are then monitored to determine the release of drug over time by examining the eye using histology, electroretinography, or changes in gene expression in the retinal pigment epithelium or photoreceptors. Identification of cellular morphological changes that indicate the presence of drug indicates the effectiveness of the implant device in transferring nepafenac from the device to the surrounding tissue in the process of treating macular degeneration.

[0149] Example 4: Administration Protocol On day 1, prior to test device administration, the subject's eyes are dilated with 1% tropicamide HCl and each subject is administered buprenorphine (approximately 0.03 mg / kg SQ). Subjects may be sedated for injection using 20-50 mg / kg ketamine and 4-10 mg / kg xylazine IM and the eyes may be aseptically prepared using topical 5% betadine solution followed by rinsing with sterile eyewash. One drop of 0.5% proparacaine HCl is then 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 Westcott scissors, the sub-Tenon's space is opened and tunneled superiorly. The graft is then placed into the sub-Tenon's space and the Tenon's capsule and conjunctiva are closed with 8-0 or 9-0 nylon without tension. The implant of Example 1 containing NACA can be used for administration. This process can be repeated for the contralateral eye. Following the surgical procedure, a digital photograph of the implant can be taken and a drop of neomycin polymyxin B sulfate gramicidin ophthalmic solution or ofloxacin can be applied topically to the ocular surface.

[0150] Example 5: Treatment of patients with macular degeneration. The patient is diagnosed as suffering from age-related macular degeneration.

[0151] A four-layered ocular implant device (circular, 2.0 mm diameter, 1.0 mm thickness) containing a 3 mg dose of nepafenac is provided as described in Example 1 above. The implant device is placed behind the surface epithelium in the sub-Tenon space. The eyelid speculum is placed and a radial conjunctival incision is made through the conjunctiva over the area where the implant device will be placed. An incision is made posterior to the Tenon's capsule using Westcott scissors and the implant device is inserted. The conjunctiva is reapproximated using a continuous 10-0 vicryl suture.

[0152] Equivalents and Scope Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments following the disclosure set forth 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.

[0153] All cited sources, such as references, publications, databases, database entries, and techniques cited herein, are incorporated by reference into this application, even if not explicitly stated in the citation. In the event of a conflicting statement between a cited source and this application, the statement in this application shall control.

Claims

1. 1. An ocular implant device comprising: a first layer comprising a polymer; a second layer 1) different from the first layer, and 2) comprising one or more therapeutic agents; a third layer; and Devices that include:

2. The device of claim 1 , wherein the third layer is different from the first and second layers.

3. The device of claim 1 or 2, wherein the third layer comprises one or more rate control agents.

4. The device according to any one of claims 1 to 3, wherein the third layer is interposed between the first layer and the second layer.

5. The device of any one of claims 1 to 4, wherein the cross-sectional thickness of the third layer is less than the cross-sectional thickness of the first layer.

6. The device of any one of claims 1 to 5, wherein the cross-sectional thickness of the third layer is less than the cross-sectional thickness of the second layer.

7. The device of any one of claims 1 to 6, wherein the third layer does not include a therapeutic agent.

8. The device of any one of claims 1 to 7, wherein the third layer comprises a polymer.

9. The device of claim 8 , wherein the third layer comprises polyimide.

10. The device of any one of claims 1 to 9, wherein the first layer does not contain a therapeutic agent. 。

11. 1. An implant device for use in a method for delivering a therapeutic agent to an eye of a patient, comprising: (a) providing an implant device according to any one of claims 1 to 10, said device comprising one or more therapeutic agents; (b) inserting the device into the patient's eye; 12. An implant device for use in a method comprising:

12. (a) an implant device according to any one of claims 1 to 11; (b) instructions for using the device to treat an eye disorder; and Kit including:

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