Coated ocular implants

Abstract

To provide a coated ocular implant for the controlled release of a therapeutic agent or drug, and to provide a method for producing the same.SOLUTION: The present invention is characterized by comprising: a) at least 0.1 w / w% of a therapeutic agent; b) 5 to 95 w / w% of a crosslinked polymer matrix; and c) 0.1 to 40 w / w% of a biodegradable polymer such as lactide / glycolide copolymer (including poly(lactide-co-glycolide)) and poly (L-lactide), the crosslinked polymer matrix being obtained by crosslinking a photopolymerizable composition such as polyalkylene glycol mono-acrylate and polyalkylene glycol diacrylate, and an ocular implant being partially coated on its external surface with at least one coating layer.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to coated ocular implants for the controlled release of a therapeutic agent or drug. [Background technology]

[0002] Chronic retinal diseases are the leading cause of visual impairment and blindness worldwide. Loss of vision has a significant personal impact on people's daily lives and has a huge economic impact on individuals, families, public health, and society. The World Health Organization estimates that approximately 285 million people worldwide suffer from visual impairment, of which 39 million are blind and 246 million have low vision. Diseases originating from the posterior segment (PS) or back of the eye can lead to permanent vision loss if left untreated and are responsible for most cases of blindness, including age-related macular degeneration (AMD), diabetic retinopathy (DR), diabetic macular edema (DME), cytomegalovirus (CMV) retinitis, retinitis pigmentosa, uveitis, and glaucoma. The posterior segment of the eye, which includes the retina, choroid, and vitreous, is difficult to access due to its recessed location within the orbit. Thus, delivery of therapeutic agents to the posterior segment of the eye remains one of the most difficult challenges for pharmaceutical scientists and retina specialists.

[0003] Several approaches are used to deliver therapeutic agents to the posterior segment of the eye, including systemic, topical, periocular (or transscleral), and intravitreal. Topical (e.g., eye drops) and systemic (e.g., oral tablets) routes result in low or subtherapeutic drug levels due to multiple ocular barriers, cause therapeutic-associated toxicity, and require the administration of unnecessarily high concentrations of therapeutic agents, resulting in poor therapeutic efficacy.

[0004] WO2017081154A1 discloses ophthalmic compositions that can be administered to the eye in various forms to achieve controlled release of a therapeutic agent. These compositions can be used to form ocular implants by crosslinking the formulation in situ after injection into a patient's eye, or can be preformed prior to injection into the eye.

[0005] There is a need for alternative systems for intraocular delivery of therapeutic agents. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2017081154A1 Summary of the Invention

[0007] In a first aspect, the present invention relates to coated ocular implants that can be administered to the eye in a variety of forms to achieve controlled release of a therapeutic agent or drug. Such ophthalmic compositions include: (a) at least 0.1 w / w% of a therapeutic agent; and (b) 5-95 w / w% of a crosslinked polymer matrix; and (c) 0.1 to 40 w / w % of a biodegradable polymer selected from the group consisting of lactide / glycolide copolymers (including poly(lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), polyhydroxyalkanoates including polyhydroxybutyrate, polyglycolic acid (PGA), polycaprolactone (PCL), poly(DL-lactide) (PDL), poly(D-lactide), lactide / caprolactone copolymers, poly-L-lactide-co-caprolactone (PLC), and mixtures, copolymers, and block copolymers thereof; wherein the crosslinked polymer matrix is ​​obtained by crosslinking a photopolymerizable composition selected from the group consisting of polyalkylene glycol monoacrylates, polyalkylene glycol diacrylates, polyalkylene glycol monomethacrylates, and polyalkylene glycol dimethacrylate fragments or monomers, and mixtures, copolymers, and block copolymers thereof; The ocular implant is characterized in that it is at least partially coated on its outer surface with at least one coating layer selected from the group consisting of lactide / glycolide copolymers (including poly(lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), polyhydroxyalkanoates including polyhydroxybutyrate, polyglycolic acid (PGA), polycaprolactone (PCL), lactide / caprolactone copolymers, poly(DL-lactide) (PDL), poly(D-lactide), poly-L-lactide-co-caprolactone (PLC), and mixtures, copolymers, and block copolymers thereof; crosslinked fragments or monomers of polyalkylene glycol monoacrylates, polyalkylene glycol diacrylates, polyalkylene glycol methacrylates, and polyalkylene glycol dimethacrylates, and mixtures, copolymers, and block copolymers thereof.

[0008] In a further aspect, the present invention relates to a method of making the above-described ocular implant.

[0009] The present invention provides ocular implants that can be administered to the eye in a variety of forms to achieve controlled release of therapeutic agents. The present invention allows the flexibility to administer a wide range of small and large therapeutic molecules, including proteins, peptides and gene therapy agents, and maintain their activity for controlled periods of time.

[0010] The ocular implants of the present invention can achieve extended release by customizing and controlling the profile according to the patient's needs, which is a function of the particular therapeutic agent(s) used.

[0011] The ocular implant of the present invention allows for the suppression of the so-called "burst release" or "rapid initial release" effect, thus preventing a large portion of the therapeutic agent from being released on the first day of treatment. The patient is thus never exposed to a therapeutic agent dose that may exceed the maximum tolerated amount, while at the same time the effectiveness of the treatment is ensured by the sustained release of the agent(s) throughout the treatment period. [Brief description of the drawings]

[0012] [Figure 1] FIG. 1 shows Scanning Electronic Microscopy (SEM) images of implants DEX1 and comparative example DEX2. [Diagram 2] FIG. 2 shows the in vitro release of DEX from implants DEX1 and DEX2, expressed as cumulative release percentage (mean±standard deviation, n=3). [Diagram 3] FIG. 3 shows the in vitro release of TM from implants TM1 and TM2, expressed as cumulative release percentage (mean±standard deviation, n=3). [Figure 4] FIG. 4 shows the in vitro drug release profiles of FITC-dextran from implants D1 and CD1, expressed as cumulative release percentage (mean±standard deviation, n=3). [Diagram 5] FIG. 5 shows the in vitro drug release profiles of LP from implants LP1, LP2, LPC1, and LPC2, expressed as cumulative release percentage (mean±standard deviation, n=3). [Figure 6] FIG. 6 shows the in vitro drug release profiles of LP from implants LPC1 and LPC3, expressed as cumulative release percentage (mean±standard deviation, n=3). [Figure 7] FIG. 7 shows the in vitro drug release profiles of LP from implants LPC1 and LPC4, expressed as cumulative release percentage (mean±standard deviation, n=3). [Figure 8]FIG. 8 shows the in vitro drug release profiles of LP from implants LP40 and LPC40, expressed as cumulative release percentage (mean±standard deviation, n=3). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] As used herein, the term "w / w %" refers to the percentage by weight of a given component relative to the total weight of the copolymer, composition, or implant containing such component, as the case may be.

[0014] As used herein, "biodegradable" is chemical degradation by biological means. In some embodiments, biodegradation is 100%, 98%, 90%, 85%, 80%, 60%, 50%, or 45% degradation of one or more of the composition, monomers, oligomers, fragments, polymers, photoinitiators, solvents, co-solvents, or coinitiators.

[0015] As used herein, a "copolymer" is a mixture of two or more different types of monomer units. As used herein, a "block copolymer" is a mixture of two or more homopolymer subunits.

[0016] The therapeutic agents of the compositions of the invention can be selected from a wide range of small and large molecules. Exemplary therapeutic agents include, but are not limited to, polypeptides, nucleic acids, such as DNA, RNA and siRNA, growth factors, steroids, antibody therapy, antibacterial agents, antibiotics, antiretroviral therapy, anti-inflammatory compounds, anti-tumor agents, anti-angiogeneic agents, anti-VEGF (vascular endothelial growth factor) agents, and chemotherapeutic agents.

[0017] In one embodiment, the therapeutic agents of the present invention include ketorolac, naphazoline, lidocaine, bevacizumab, aflibercept, pegaptanib, brimonidine tartrate, dorzolamide, bromfenac sodium, azithromycin, rapamycin, bepotastine besylate, diclofenac, besifloxacin, cysteamine hydrochloride, fluocinolone acetonide, difluprednate, tasimelteon, ocriplasmin, enoxaparin sodium, ranibizumab, latanoprost, timolol maleate, bimatoprost, ofloxacin, cefazolin, phenylephrine, dexamethasone, cyclosporine ... These include, but are not limited to, samethasone, triamcinolone acetonide, levofloxacin, cyclophosphamide, melphalan cyclosporine, methotrexate, azathioprine, travoprost, verteporfin, tafluprost, ketotifen fumarate, foscarnet, amphotericin B, fluconazole, voriconazole, ganciclovir, acyclovir, gatifloxacin, mitomycin C, prednisolone, prednisone, vitamins (vitamin A, vitamin C, and vitamin E), zinc, copper, lutein, zeaxanthin, or combinations thereof.

[0018] In another embodiment, the therapeutic agent of the present invention is dexamethasone, timolol maleate, brimonidine tartrate, triamcinolone acetonide, bromfenac sodium, latanoprost, or a mixture thereof.

[0019] In one embodiment, the implants of the invention can deliver a bioactive agent, a large molecular weight therapeutic agent, such as aflibercept, pegaptanib, or an antibody therapeutic agent, such as ranibizumab, bevacizumab, trastuzumab, rituximab, gentuzumab, ozagamycin, brolucizumab, or cetuximab.

[0020] In some embodiments, the molecular weight of the therapeutic agent is greater than 200 Da, 500 Da, 1000 Da, 10 kDa, 30 kDa, 50 kDa, 75 kDa, 100 kDa, 150 kDa, 200 kDa.

[0021] According to other embodiments of the invention, the therapeutic agent is present in an amount between 0.5-70 w / w%, 10-70 w / w%, 20-70 w / w%, 30-70 w / w%, 40-70%, 5-50%, 10-50 w / w%, 20-50 w / w%, 30-50%, and 40-50% of the total weight of the ocular implant.

[0022] The therapeutic agent can be used as is or in the form of a solution in which a certain amount of the therapeutic agent is dissolved in a suitable solvent. The therapeutic agent can also be freeze-dried or spray-dried prior to use in the preparation of the ophthalmic composition of the present invention to facilitate the incorporation of high concentrations of the therapeutic agent into the implant. The amount of the therapeutic agent dissolved depends on the final loading that the ophthalmic composition or implant is to have. The choice of solvent depends on the polarity of the therapeutic agent.

[0023] According to one embodiment of the present invention, the solvent may be selected from water, dimethyl sulfoxide, decyl methyl sulfoxide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, N-vinyl-pyrrolidine, N-methyl-2-pyrrolidone, N-ethyl-pyrrolidone, glycerol formal, glycerol, polyethylene glycol, propylene glycol, benzyl alcohol, benzyl benzoate, ethyl benzoate, triacetin, triethyl citrate, dimethylformamide, dimethylacetamide, and tetrahydrofuran.

[0024] In one embodiment, a co-solvent may be used, which may be selected from dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, acetic acid, methanol, ethanol, isopropanol, glycofurol, or butanol.

[0025] For hydrophilic therapeutic agents, the solvent can be an aqueous solvent such as water or a phosphate buffered saline (PBS) solution.

[0026] According to another embodiment, the solvent may be selected from dimethyl sulfoxide, decyl methyl sulfoxide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, N-methyl-2-pyrrolidone, and glycerol formal.

[0027] Additionally, the above solvents and co-solvents can be used in combination with any of the other photopolymerizable compositions, biodegradable polymers, photoinitiators, pore formers, and co-initiators described herein in the preparation of any of the implants of the present invention.

[0028] In one embodiment, when the biodegradable polymer is PLGA, PCL, PLC, and / or PLA, a solvent is used. In one embodiment, when the biodegradable polymer is PLGA, PCL, PLC, and / or PLA, the solvent is N-methyl-2-pyrrolidone and N-vinyl-2-pyrrolidine. In another embodiment, when the photopolymerizable composition is PEGDA, a solvent is used.

[0029] The photopolymerizable fragments or monomers of the present invention can be used in any of the compositions and implants of the present invention in combination with any of the other biodegradable polymers, therapeutic agents, photoinitiators, solvents, cosolvents, drug modifiers, and coinitiators described herein or known in the common general knowledge.

[0030] In one embodiment, the photopolymerizable composition of the present invention can be biodegradable. In some embodiments, biodegradation occurs over 1 minute, 10 minutes, 20 minutes, 2 hours, 6 hours, 12 hours, 24 hours, 2 days, 5 days, 1 week, 1 month, 2 months, 5 months, 6 months, 8 months, or 12 months. In some embodiments, biodegradation occurs between 1 month and 12 months, between 6 months and 12 months, or between 8 months and 12 months.

[0031] As used herein, the term "photopolymerizable composition" is a composition that can form a crosslinked polymer network upon exposure to light, particularly UV light. As used herein, photopolymerizable compositions include photopolymerizable monomers and oligomers (e.g., dimers, trimers, and tetramers). The terms "oligomer" and "fragment" can be used interchangeably to mean 2-20 monomers, optionally 2-10 monomers, further optionally 2-5 monomers, or 2-4 monomers. A "photopolymerizable monomer" is a single unit of a photopolymerizable polymer that can be chemically bonded to other monomers to form a polymer.

[0032] The photopolymerizable compositions of the present invention can be crosslinked with UV radiation to form the crosslinked polymer matrix of the ocular implants of the present invention.

[0033] In one embodiment, the photopolymerizable composition is selected from the group consisting of polyalkylene glycol monoacrylates, polyalkylene glycol diacrylates, polyalkylene glycol methacrylates, polyalkylene glycol dimethacrylate fragments or monomers, and mixtures, copolymers, and block copolymers thereof.

[0034] In one embodiment, the photopolymerizable composition is a polyalkylene glycol diacrylate fragment or monomer incorporating diacrylate terminal units selected from the group including polyether fragments or monomers, polyester fragments or monomers, polycarbonate fragments or monomers, or mixtures, copolymers or block copolymers thereof.

[0035] In one embodiment, the photopolymerizable composition includes monomers incorporating diacrylate terminal units, such as 4-arm or 8-arm PEG acrylate.

[0036] In another embodiment, the photopolymerizable composition is polyethylene glycol diacrylate, diethylene glycol diacrylate, polyethylene glycol dimethacrylate, diethylene glycol dimethacrylate, polypropylene glycol diacrylate, dipropylene glycol diacrylate, dipropylene glycol dimethacrylate, and polypropylene glycol dimethacrylate, or mixtures, copolymers, or block copolymers thereof.

[0037] In another embodiment, the photopolymerizable composition is polyethylene glycol diacrylate (PEGDA), polyethylene glycol monoacrylate (PEGMoA), or polyethylene glycol dimethacrylate (PEGDMA).

[0038] In yet another embodiment, the photopolymerizable composition is polyethylene glycol diacrylate (PEGDA).

[0039] In yet another embodiment, the photopolymerizable composition is polyethylene glycol methacrylate (PEGMA) or a mixture of PEGMA with other polyalkylene glycol monoacrylates, diacrylates, methacrylates and / or dimethacrylates, hi one embodiment, the polymerizable composition is a mixture of PEGDA, PEGMoA, and / or PEGMA.

[0040] PEGDA is a synthetic polymer available in a variety of molecular weights. PEGDA is highly amenable to mechanical, structural, and chemical modification, resulting in hydrogels with a variety of properties for drug delivery and other biomedical applications. PEGDA is formed by end-functionalization of each PEG molecule with an acrylate group. PEGDA is also non-toxic and induces minimal immunogenic responses. PEGDA has double bond-containing acrylate end groups that exhibit rapid polymerization when exposed to light in the presence of a suitable initiator to produce a hydrogel network.

[0041] The average molecular weight of the photopolymerizable composition of the present invention is typically 100 to 300,000 Da, 200 to 100,000 Da, 200 to 50,000 Da, 200 to 20,000 Da, 200 to 10,000 Da, 200 to 8,000 Da, 200 to 5,000 Da, or 200 to 1,000 Da.

[0042] For the compositions and implants of the present invention, it has been found that an increase in the molecular weight of the photopolymerizable composition results in an increase in the therapeutic agent release rate. Without wishing to be bound by theory, it is believed that photopolymerizable compositions having a lower molecular weight have a higher crosslink density and therefore a slower therapeutic agent release rate.

[0043] The photopolymerizable composition of the present invention typically has a viscosity of 0.1 to 7 dL / g, 0.2 to 5 dL / g, or 0.5 to 2 dL / g.

[0044] In one embodiment, the photopolymerizable composition is present in an amount of 10-90 w / w%, 10-75 w / w%, 20-75 w / w%, 30-75 w / w%, and 30-60 w / w%, 40-60 w / w%.

[0045] The biodegradable polymers of the present invention can be used in any of the compositions and implants of the present invention in combination with any of the other photopolymerizable compositions, therapeutic agents, photoinitiators, solvents, cosolvents, therapeutic agent release modifiers, and co-initiators described herein or known in the common general knowledge.

[0046] In one embodiment of the present invention, the biodegradable polymer is an aliphatic polyester-based polyurethane, a polylactide, a polycaprolactone, a polyorthoester, or a mixture, copolymer, or block copolymer thereof.

[0047] In another embodiment of the invention, the biodegradable polymer is chitosan, poly(propylene fumarate), lactide / glycolide copolymer (poly(lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), lactide / caprolactone copolymer (PLC), polyhydroxybutyrate, natural biodegradable polymers such as collagen and hyaluronic acid, or mixtures, copolymers or block copolymers thereof.

[0048] In another embodiment, the biodegradable polymer is selected from the group consisting of lactide / glycolide copolymers (including poly(lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), polyhydroxyalkanoates, including polyhydroxybutyrate, polyglycolic acid (PGA), polycaprolactone (PCL), poly(DL-lactide) (PDL), poly(D-lactide), lactide / caprolactone copolymers, poly-L-lactide-co-caprolactone (PLC), and mixtures, copolymers, and block copolymers thereof.

[0049] In one embodiment, the biodegradable polymer is lactide / glycolide copolymer (including poly(lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), poly(DL-lactide) (PDL), and lactide / caprolactone copolymer (PLC).

[0050] In certain embodiments, the biodegradable polymer is poly(lactide-co-glycolide) (PLGA).

[0051] PLGA is typically prepared by polymerization of lactic and glycolic acid monomers. The glass transition temperature (Tg) of PLGA copolymers is higher than the physiological temperature of 37°C, resulting in a moderately rigid chain configuration and thus imparting mechanical strength at ambient temperatures. The use of PLGA with different lactide (LA) to glycolide (GA) ratios and molecular weights allows for different drug release profiles. Increasing the GA content increases the water uptake of PLGA, thus resulting in more rapid degradation. The degradation of PLGA with LA / GA 50 / 50 is typically 1-3 months. In one embodiment, the molar ratio of lactic acid to glycolic acid in the PLGA is 90% lactic acid to 10% glycolic acid, 85% lactic acid to 15% glycolic acid, 75% lactic acid to 25% glycolic acid, 65% lactic acid to 35% glycolic acid, 50% lactic acid to 50% glycolic acid, 35% lactic acid to 65% glycolic acid, 25% lactic acid to 75% glycolic acid, 15% lactic acid to 85% glycolic acid, and 10% lactic acid to 90% glycolic acid.

[0052] In another embodiment, the biodegradable polymer is PCL, PLC, PLA, or a mixture, copolymer, or block copolymer thereof.

[0053] In one embodiment, the biodegradable polymer is present in an amount of 1-40 w / w%, 1-30 w / w%, 1-20 w / w%, 2-10 w / w%, and 5-10 w / w%.

[0054] In one embodiment of the invention, at least one coating layer comprises lactide / glycolide copolymers, including poly(lactide-co-glycolide) (PLGA), poly(DL-lactide) (PDL), poly(L-lactide) (PLA) and poly(D-lactide), and lactide / caprolactone copolymers, including poly-L-lactide-co-caprolactone (PLC), or combinations thereof.

[0055] In another embodiment, at least one coating layer is a lactide / caprolactone copolymer, including poly(L-lactide) (PLA), poly(DL-lactide) (PDL), and poly-L-lactide-co-caprolactone (PLC), or a combination thereof.

[0056] In another embodiment, at least one coating layer is poly-L-lactide-co-caprolactone (PLC), poly(L-lactide) (PLA), or a mixture thereof.

[0057] In one embodiment, at least one coating layer is a crosslinked photopolymerizable composition selected from the group consisting of polyethylene glycol diacrylate, diethylene glycol diacrylate, polyethylene glycol dimethacrylate, diethylene glycol dimethacrylate, polypropylene glycol diacrylate, dipropylene glycol diacrylate, dipropylene glycol dimethacrylate, and polypropylene glycol dimethacrylate.

[0058] In another embodiment, at least one coating layer is crosslinked polyethylene glycol diacrylate (PEGDA).

[0059] In one embodiment, the ocular implant of the present invention is at least partially coated on its outer surface with at least two coating layers, hi another embodiment, the ocular implant is at least partially coated on its outer surface with at least three coating layers.

[0060] According to another embodiment, an ocular implant has first and second portions of an outer surface, wherein the first and second portions of the outer surface are each coated with at least one coating layer independently selected from the group consisting of lactide / glycolide copolymers (including poly(lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), polyhydroxyalkanoates including polyhydroxybutyrate, polyglycolic acid (PGA), polycaprolactone (PCL), lactide / caprolactone copolymers, poly(DL-lactide) (PDL), poly(D-lactide), poly-L-lactide-co-caprolactone (PLC), and mixtures, copolymers, and block copolymers thereof; crosslinked fragments or monomers of polyalkylene glycol monoacrylates, polyalkylene glycol diacrylates, polyalkylene glycol methacrylates, and polyalkylene glycol dimethacrylates, and mixtures, copolymers, and block copolymers thereof.

[0061] In another embodiment, the ocular implant of the present invention is coated with at least one coating layer, at least two coating layers, or at least three coating layers on its entire outer surface. The number of coating layers required depends on the viscosity of the solution of coating material, and therefore on the layer thickness that such a solution can provide. The viscosity of the coating solution can be modified, inter alia, by changing the polymer concentration and polymer molecular weight, to optimize the release profile of each specific therapeutic agent.

[0062] In one embodiment, the implants of the present invention include a release modifier. An appropriate release modifier can be selected taking into consideration the particular therapeutic agent and the composition of the implant, as well as the desired elution profile or release rate. The release modifier can be a naturally occurring drug or polymer, or a synthetic drug or polymer.

[0063] All of the release modifiers described herein can be used in any of the implants and compositions of the present invention in combination with any of the other photopolymerizable compositions, biodegradable polymers, therapeutic agents, photoinitiators, solvents, co-solvents, and co-initiators described herein.

[0064] The release modifier may be present in an amount of 0.1-40 w / w%, 1-30 w / w%, 1-20 w / w%, 1-10 w / w%, 5-10 w / w%.

[0065] In some cases, the release regulator alters water absorption into the implant matrix, thus controlling the release rate of the therapeutic agent and the implant degradation. In one embodiment, suitable water absorption regulators are one or more polysaccharides, such as, for example, cellulosic materials including chitosan and hydroxypropyl methylcellulose (HPMC); hyaluronic acid; poloxamer; polyethers, such as polyethylene glycol; gelatin; polyvinylpyrrolidone; polyvinyl alcohol, and mixtures thereof. In one embodiment, suitable water absorption regulators are hydroxypropyl methylcellulose (HPMC) and polyethylene glycol (PEG).

[0066] In one embodiment, the release modifier is a pore-forming agent, optionally lactose, maltose, glucose, mannitol, sodium chloride, magnesium carbonate, magnesium hydroxide, potassium chloride, sodium bicarbonate, ammonium bicarbonate, potassium bicarbonate, agarose, or sucrose.

[0067] In another embodiment, the release modifier is a mixture of two or more modifiers as described above to provide two or more functionalities to the ophthalmic compositions or implants of the present invention.Optionally, the release modifier is polyethylene glycol, hydroxypropyl methylcellulose (HPMC), or a mixture thereof.

[0068] Optionally, at least one coating layer may be prepared in the presence of a porosinogen to adjust the coating porosity and thereby affect drug release. The pore size of the coating layer prepared by this porosinogen technique depends on the size of the porosinogen.

[0069] In another embodiment of the invention, the ocular implant does not contain a release modifier.

[0070] According to another embodiment, at least one coating layer of the implant is porous.

[0071] According to another embodiment, the at least one coating layer has a thickness of 1 to 150 μm, In another embodiment, the at least one coating layer has a thickness of 15 to 40 μm.

[0072] In another embodiment, at least one layer of the ocular implant of the present invention comprises at least a portion of a therapeutic agent. This may be the case, for example, when a second therapeutic agent must be delivered from the same ocular implant. The second therapeutic agent may only be present in the coating, while the first therapeutic agent is only present in the core of the implant, thus creating different release profiles for the two agents. In another embodiment, the same therapeutic agent may be present in both at least one coating layer and the core of the implant, where the at least one coating layer is photocrosslinked to a different extent than the core of the implant. Thus, a differentiated release profile of the same therapeutic agent from the core of the implant and at least one coating layer is obtained.

[0073] The implants of the present invention may be of any desired shape, including, but not limited to, rectangular, square, spherical, cylindrical, circular, oval, film, dumbbell, rod, and bead.

[0074] The implants of the present invention can be of any desired size, for example, in the macro, micro, or nanoparticle size range.

[0075] In one embodiment of the invention, the ocular implant is an implant having one of its dimensions less than 10 mm, or less than 5 mm, or less than 3 mm. In one embodiment, the implant is a rectangular implant having dimensions 10 x 5 x 0.5 mm. In one embodiment of the invention, the ocular implant is a nanoparticle or microparticle.

[0076] In one embodiment, the nanoparticle ocular implant is less than 1,000 nm, less than 900 nm, less than 750 nm, less than 500 nm, or less than 100 nm.

[0077] In one embodiment, the particulate ocular implant is less than 1,000 μm, less than 900 μm, less than 750 μm, less than 500 μm, or less than 25 μm.

[0078] In one embodiment, the ocular implant of the present invention has a concentration of 200 μg to 2000 μg / μm 3 , 1000μg~2000μg / μm 3 , 1200μg~1800μg / μm 3 , 1200μg~1500μg / μm 3 The therapeutic agent is present in a concentration of

[0079] Another aspect of the present invention is a method for making the above ocular implant, comprising the steps of: (a) providing a therapeutic agent; (b) obtaining an ocular composition by mixing the therapeutic agent with a polymerizable composition, a biodegradable polymer, a photoinitiator, and optionally a release modifier; (c) irradiating the ocular composition obtained in step (b) with light having a wavelength of 200-550 nm for a period of 1 second to 60 minutes to form an uncoated ocular implant; and (d) coating at least a portion of the outer surface of the uncoated ocular implant with at least one coating layer.

[0080] Optionally, in step (b), the therapeutic agent is first mixed with the photopolymerizable composition and the mixture so obtained is mixed with the biodegradable polymer, photoinitiator, and optionally, the release modifier, in any order of addition. Alternatively, the therapeutic agent is first mixed with a portion of the photopolymerizable composition and another portion of the photopolymerizable composition is mixed with the biodegradable polymer, photoinitiator, and optionally, the release modifier.

[0081] The photoinitiators described herein can be used in any of the compositions and implants of the invention in combination with any of the other photopolymerizable compositions, biodegradable polymers, therapeutic agents, photoinitiators, solvents, co-solvents, and co-initiators described herein.

[0082] In certain embodiments, the photoinitiator is designed to work with light between 200 and 550 nm. In some embodiments, the photoinitiator is designed to work with UV light between 200 and 500 nm. In other embodiments, the photoinitiator is designed to work with UV light between 200 and 425 nm.

[0083] In certain embodiments, the light source can allow for variation in wavelength and / or intensity of light. Light sources useful in the present invention include, but are not limited to, lamps and fiber optic devices.

[0084] In one embodiment, the photoinitiator is a ketone (i.e., RCOR'). In one embodiment, the compound is an azo compound (i.e., a compound having a -N=N- group). In one embodiment, the photoinitiator is an acylphosphine oxide. In one embodiment, the photoinitiator is a sulfur-containing compound. In one embodiment, the initiator is a quinone. In certain embodiments, a combination of photoinitiators is used.

[0085] In another embodiment, the photoinitiator may be selected from a hydroxyketone photoinitiator, an aminoketone photoinitiator, a hydroxyketone / benzophenone photoinitiator, a benzyl dimethyl ketal photoinitiator, a phenylglyoxylate photoinitiator, an acylphosphine oxide photoinitiator, an acylphosphine oxide / alphahydroxyketone photoinitiator, a benzophenone photoinitiator, a ribitylisoalloxazine photoinitiator, a peroxide photoinitiator, a persulfate photoinitiator, or a phenylglyoxylate photoinitiator, or any combination thereof. Optionally, the photoinitiator is 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone, 1-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propanone, 2,2-dimethoxy-2-phenylacetophenone (DMPA), diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide (DPPO), or riboflavin. In another embodiment, the photoinitiator is benzoyl peroxide, 2,2″-azobisisobutyronitrile, dicumyl peroxide, lauroyl peroxide, and / or camphorquinone.

[0086] In one embodiment, the composition of the present invention further comprises a coinitiator. In one embodiment, the coinitiator is eosin Y, triethanolamine, camphorquinone, 1-vinyl-2 pyrrolidinone (NVP), eosin, dimethylaminobenzoic acid (DMAB), Irgacure® D-2959 (Sigma Aldrich, Basingstoke, UK), Irgacure® 907 (Sigma Aldrich, Basingstoke, UK), Irgacure® 651 (Sigma Aldrich, Basingstoke, UK), diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide (DPPO / Darocur TPO) (Sigma Aldrich, Basingstoke, UK), or ethyl-4-N,N-dimethylaminobenzoate (4EDMAB). Optionally, the photoinitiator is riboflavin and the coinitiator is L-arginine.

[0087] In another embodiment, the therapeutic agent is first dissolved in a solvent to obtain a solution, and then the solution so obtained is mixed with the polymerizable composition, the biodegradable polymer, the photoinitiator, and optionally the release modifier in step b.

[0088] The choice of solvent that can be used in accordance with the present invention depends on the polarity of the therapeutic agent.

[0089] Optionally, the solvent may be selected from water, dimethyl sulfoxide, decyl methyl sulfoxide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, N-vinyl-pyrrolidine, N-methyl-2-pyrrolidone, N-ethyl-pyrrolidone, glycerol formal, glycerol, polyethylene glycol, propylene glycol, benzyl alcohol, benzyl benzoate, ethyl benzoate, triacetin, triethyl citrate, dimethylformamide, dimethylacetamide, acetonitrile, dichloromethane and tetrahydrofuran.

[0090] In one embodiment, a co-solvent may be used, which may be selected from dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, acetic acid, methanol, ethanol, isopropanol, glycofurol, or butanol.

[0091] In the case of hydrophilic therapeutic agents, the solvent can be an aqueous solvent such as water or a phosphate buffered saline (PBS) solution.

[0092] According to another embodiment, the solvent may be selected from dimethyl sulfoxide, decyl methyl sulfoxide, acetonitrile, 2-pyrrolidone, 1-methyl-2-pyrrolidone, N-methyl-2-pyrrolidone, and glycerol formal.

[0093] Alternatively, the therapeutic agent is not dissolved in a solvent prior to mixing with the other components. Thus, the therapeutic agent, polymerizable composition, biodegradable polymer, photoinitiator, and optionally release controlling agent are mixed together in any order of addition. Alternatively, the therapeutic agent is first mixed with a portion of the photopolymerizable composition, and another portion of the photopolymerizable composition is mixed with the biodegradable polymer, photoinitiator, and optionally release controlling agent.

[0094] In one embodiment, the ophthalmic composition obtained in step (b) is irradiated with light at a wavelength of 200-500 nm, 200-490 nm, or 200-425 nm for 1 second to 60 minutes, 30 seconds to 30 minutes, 2.5 minutes to 20 minutes, or 5 minutes to 10 minutes. In one embodiment, the crosslinking is for 3 seconds, 6 seconds, 9 seconds, 15 seconds, 30 seconds, 1 minute, 2.5 minutes, 5 minutes, 10 minutes, 20 minutes, or 30 minutes.

[0095] In another embodiment, the uncoated ocular implant is coated over its entire exterior surface with at least one coating layer in step (d).

[0096] In one embodiment, the coating step (d) is performed by manual dipping, controlled dip coating, ultrasonic coating, spray coating, or 3D printing.

[0097] A further aspect of the present invention is an ocular implant obtainable by the method described above.

[0098] In one embodiment of the present invention, the coated implant can be obtained by injecting an ophthalmic composition comprising a therapeutic agent, a photopolymerizable composition, a biodegradable polymer, a photoinitiator, and optionally a release modifier into a preformed hollow tube of required dimensions made of at least one coating layer material as described above. Thus, the coated implant of this embodiment has a surface coating but no side coating.

[0099] In one embodiment, the rate and extent of drug release can be controlled by varying polymer molecular weight, type and copolymer ratio, drug type and loading, implant size, time and extent of UV crosslinking, amount and type of photoinitiator, release modifier, solvent and / or co-solvent. Variation of these factors provides compositions of the invention that can be easily tailored to provide desired drug release periods to address specific clinical / patient needs in the treatment of various ocular diseases.

[0100] The implants of the present invention can be photocrosslinked prior to application to the eye to form implants of desired shape and size (e.g., films, rods, or nano / microparticles) that can be administered intraocularly to provide the desired drug delivery period, referred to as Preformed Photocrosslinked Implants (PPcIs).

[0101] The PPcI of the present invention can be inserted into the eye, for example, into the fornix, subconjunctivally, intracamerally, intrastromally / intracorneally, transscleral / periocularly, intrasclerally, or intravitreally, subretinaly, to treat diseases of the anterior or posterior parts of the eye. The PPcI can be manufactured in a variety of shapes, including, but not limited to, rods, films, cylindrical or round shapes, and sizes including micro- or nanoparticle forms.

[0102] In one embodiment, PPcI nanoparticles and microparticles are obtained by sonicating a mixture of therapeutic agent, photopolymerizable composition, biodegradable polymer, photoinitiator, and optionally release modifier in an aqueous medium. In one embodiment, the aqueous medium is a combination of water and phosphate buffered saline (PBS). Irradiation can be applied during sonication, i.e. while sonicating the mixture under UV light, or it can be performed after the sonication step.

[0103] The PPcIs of the present invention have the advantage of high crosslink density and / or tight polymer network structure, which can be configured to control drug release and / or eliminate burst release.

[0104] The PPcIs of the present invention can be fabricated to have single and / or multiple layers that allow the loading of two or more drugs or the same drug with different release profiles or release rates.

[0105] The PPcI of the present invention typically comprises a photopolymerizable polymer having a molecular weight of 100 to 300,000 Da, 200 to 100,000 Da, 200 to 50,000 Da, 200 to 20,000 Da, or 200 to 10,000 Da.

[0106] In one embodiment, the present invention is a PLGA / PEGDA PPcI.

[0107] In one embodiment, the biodegradable polymer is essentially contained within the matrix of the photopolymerizable composition. Optionally, the biodegradable polymer is essentially contained within the matrix of the photopolymerizable composition that forms a gel upon mixing. In one embodiment, the photopolymerizable polymer is crosslinked in the presence of a photoinitiator and the biodegradable polymer and the therapeutic agent(s). In one embodiment, the biodegradable polymer is hydrophobic in nature and the photopolymerizable polymer is hydrophilic in nature. In one embodiment, the degree of crosslinking of the composite implant governs the rate and extent of release of the therapeutic agent.

[0108] In the implants of the present invention, the rate and duration of drug release can be controlled by varying the UV crosslinking time. In some embodiments, increasing the UV crosslinking time causes a decrease in drug release. Furthermore, the rate and duration of drug release can be controlled by varying the concentration of photoinitiator. Furthermore, the rate and duration of drug release can be controlled by varying both the UV crosslinking time and the concentration of photoinitiator. In one embodiment, decreasing the concentration of biodegradable polymer (such as PLGA) increases the drug release rate. In one embodiment, adding a pore-forming agent (e.g., MgCO3) increases the drug release rate. In one embodiment, longer UV crosslinking time and higher concentration of photoinitiator can sustain drug release for a longer period of time. In one embodiment, drug release can be sustained for more than 1 day, 2 days, 1 week, 1 month, 2 months, 3 months, or 6 months.

[0109] In some embodiments, sensitive molecules such as peptides and proteins are protected due to the slow degradation rate of the PPcIs of the invention.

[0110] In one embodiment, the present invention is a PPcI with a high crosslink density that significantly slows drug diffusion.

[0111] Any of the implants and compositions described herein are suitable for use in any of the methods of the invention described herein.

[0112] In one embodiment, the invention is a method of treating an ocular disease or disorder in a subject in need thereof comprising administering a composition or implant of the invention to the ocular area of ​​the subject.

[0113] In one embodiment, the invention is a composition or implant of the invention for use in treating an ocular disease or disorder in a subject in need thereof.

[0114] As used herein, an "ocular region" is a region inside, outside, or adjacent to the eye of a subject. In one embodiment, the ocular region is the sclera (intrascleral), extrascleral (transscleral), vitreous, choroid, cornea, corneal stroma, anterior chamber, aqueous humor, lens, fornix, or optic nerve.

[0115] In one embodiment, the compositions and implants can be administered by injection, including intravitreal, subconjunctival, peribulbar, sub-Tenon, or retrobulbar injections and corneal.

[0116] In some embodiments, the implant is administered by a surgical procedure, hi some embodiments, the implant is secured in place after surgical implantation by gluing or suturing.

[0117] The term "subject" refers to animals (e.g., birds such as chickens, quails, or turkeys, or mammals), specifically "mammals," including non-primates (e.g., cows, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (e.g., monkeys, chimpanzees, and humans), and more specifically humans. In one embodiment, the subject is a non-human animal, such as a farm animal (e.g., a horse, cow, pig, or sheep) or a pet (e.g., a dog, cat, guinea pig, or rabbit). In another embodiment, the subject is a "human."

[0118] As used herein, the terms "treat", "treatment" and "treating" refer to therapeutic treatment, including the reduction or amelioration of the progression, severity and / or duration of a disease, disorder or condition, or the amelioration of one or more symptoms (particularly one or more identifiable symptoms) of a disease, disorder or condition, resulting from administration of a composition or implant of the invention. In certain embodiments, therapeutic treatment includes the amelioration of at least one measurable physical parameter of a disease, disorder or condition. In other embodiments, therapeutic treatment includes the inhibition of progression of a condition, either by a physical state, e.g., by stabilization of an identifiable symptom, a physiological state, e.g., by stabilization of a physical parameter, or both. In other embodiments, therapeutic treatment includes the alleviation or stabilization of a disease, disorder or condition.

[0119] In one embodiment, the disease or disorder is pain, inflammation, cataract, allergy, age-related macular degeneration (AMD), diabetic retinopathy (DR), macular edema, diabetic macular edema (DME), cytomegalovirus (CMV), retinitis, retinitis pigmentosa, uveitis, dry eye syndrome, keratitis, glaucoma, blepharitis, blephariconjunctivtis, ocular hypertension, conjunctivitis, cystinosis, vitreomacular adhesion, corneal neovascularization, corneal ulcer, and post-operative ocular inflammation / wound healing.

[0120] The following list of numbered items are embodiments encompassed by the present invention.

[0121] 1. An ocular implant comprising: (a) at least 0.1 w / w% of a therapeutic agent; and (b) 5-95 w / w% of a crosslinked polymer matrix; and 0.1-40 w / w% of a biodegradable polymer selected from the group consisting of lactide / glycolide copolymers (including poly(lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), polyhydroxyalkanoates including polyhydroxybutyrate, polyglycolic acid (PGA), polycaprolactone (PCL), poly(DL-lactide) (PDL), poly(D-lactide), lactide / caprolactone copolymers, poly-L-lactide-co-caprolactone (PLC), and mixtures, copolymers, and block copolymers thereof; wherein the crosslinked polymer matrix is ​​obtained by crosslinking a photopolymerizable composition selected from the group consisting of polyalkylene glycol monoacrylates, polyalkylene glycol diacrylates, polyalkylene glycol monomethacrylates, and polyalkylene glycol dimethacrylate fragments or monomers, and mixtures, copolymers, and block copolymers thereof; 1. The ocular implant, characterized in that the ocular implant is at least partially coated on its outer surface with at least one coating layer selected from the group consisting of lactide / glycolide copolymers (including poly(lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), polyhydroxyalkanoates including polyhydroxybutyrate, polyglycolic acid (PGA), polycaprolactone (PCL), lactide / caprolactone copolymers, poly(DL-lactide) (PDL), poly(D-lactide), poly-L-lactide-co-caprolactone (PLC), and mixtures, copolymers and block copolymers thereof; crosslinked fragments or monomers of polyalkylene glycol monoacrylates, polyalkylene glycol diacrylates, polyalkylene glycol methacrylates, and polyalkylene glycol dimethacrylates, and mixtures, copolymers and block copolymers thereof.

[0122] 2. The ocular implant of embodiment 1 or 2, wherein the therapeutic agent is present in an amount of 0.5 to 70 w / w %.

[0123] 3. The ocular implant of embodiment 2, wherein the therapeutic agent is present in an amount of 10-50 w / w %.

[0124] 4. The ocular implant of any one of embodiments 1 to 3, wherein the therapeutic agent is present in an amount of 20 to 50 w / w %.

[0125] 5. The ocular implant of any one of embodiments 1-4, wherein the photopolymerizable composition is selected from the group consisting of polyalkylene glycol diacrylates, fragments or monomers of polyalkylene glycol dimethacrylates, and mixtures, copolymers, and block copolymers thereof.

[0126] 6. The ocular implant of any one of embodiments 1-5, wherein the photopolymerizable composition is selected from the group consisting of polyethylene glycol diacrylate, diethylene glycol diacrylate, polyethylene glycol dimethacrylate, diethylene glycol dimethacrylate, polypropylene glycol diacrylate, dipropylene glycol diacrylate, dipropylene glycol dimethacrylate, and polypropylene glycol dimethacrylate.

[0127] 7. The ocular implant of embodiment 6, wherein the photopolymerizable composition is polyethylene glycol diacrylate (PEGDA).

[0128] 8. The ocular implant of any one of embodiments 1-7, wherein the biodegradable polymer is present in an amount of 1-30 w / w %.

[0129] 9. The ocular implant of any one of embodiments 1-8, wherein the biodegradable polymer is lactide / glycolide copolymer (including poly(lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), poly(DL-lactide) (PDL), and lactide / caprolactone copolymer (PLC).

[0130] 10. The ocular implant of embodiment 9, wherein the biodegradable polymer is a lactide / glycolide copolymer, including poly(lactide-co-glycolide) (PLGA).

[0131] 11. The ocular implant of any one of embodiments 1-10, wherein the at least one coating layer is poly(L-lactide) (PLA), poly(DL-lactide) (PDL), poly-L-lactide-co-caprolactone (PLC), and combinations thereof.

[0132] 12. The ocular implant of embodiment 11, wherein the at least one coating layer is poly-L-lactide-co-caprolactone (PLC), poly(L-lactide) (PLA), or a mixture thereof.

[0133] 13. The ocular implant of any one of embodiments 1-10, wherein the at least one coating layer is a crosslinked photopolymerizable composition selected from the group consisting of polyethylene glycol mono / diacrylate, diethylene glycol diacrylate, polyethylene glycol dimethacrylate, diethylene glycol dimethacrylate, polypropylene glycol diacrylate, dipropylene glycol diacrylate, dipropylene glycol dimethacrylate, and polypropylene glycol dimethacrylate.

[0134] 14. The ocular implant of embodiment 13, wherein the at least one coating layer is crosslinked polyethylene glycol diacrylate (PEGDA).

[0135] 15. An ocular implant according to any one of embodiments 1-14, at least partially coated on its outer surface with at least two coating layers.

[0136] 16. An ocular implant according to any one of embodiments 1-15, at least partially coated on its outer surface with at least three coating layers.

[0137] 17. The ocular implant of any one of embodiments 1-16, wherein the implant is coated over its entire outer surface with at least one coating layer.

[0138] 18. The ocular implant of embodiment 17, wherein the implant is coated over its entire outer surface with at least three coating layers.

[0139] 19. The ocular implant of any one of the preceding embodiments, having first and second portions of an outer surface, wherein the first and second portions of the outer surface are each coated with at least one coating layer independently selected from the group consisting of lactide / glycolide copolymers (including poly(lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), polyhydroxyalkanoates including polyhydroxybutyrate, polyglycolic acid (PGA), polycaprolactone (PCL), lactide / caprolactone copolymers, poly(DL-lactide) (PDL), poly(D-lactide), poly-L-lactide-co-caprolactone (PLC), and mixtures, copolymers, and block copolymers thereof; crosslinked fragments or monomers of polyalkylene glycol monoacrylates, polyalkylene glycol diacrylates, polyalkylene glycol methacrylates, and polyalkylene glycol dimethacrylates, and mixtures, copolymers, and block copolymers thereof.

[0140] 20. The ocular implant of any one of embodiments 1-19, further comprising a release modifier.

[0141] 21. The ocular implant of embodiment 20, wherein the release modifying agent is selected from polyethylene glycol, hydroxypropyl methylcellulose (HPMC), maltose, glucose, agarose, mannitol, gelatin, sodium chloride, magnesium carbonate, magnesium hydroxide, potassium chloride, sodium bicarbonate, potassium bicarbonate, and sucrose.

[0142] 22. The ocular implant of embodiment 21, wherein the release modifier is polyethylene glycol, hydroxypropyl methylcellulose (HPMC), or a mixture thereof.

[0143] 23. The ocular implant of any one of embodiments 1-19, wherein the composition does not contain any release modifier.

[0144] 24. The ocular implant of any one of embodiments 1-23, wherein the at least one coating layer is porous.

[0145] 25. The ocular implant of any one of embodiments 1 to 24, wherein the at least one coating layer is 1 to 150 μm thick.

[0146] 26. The ocular implant of any one of embodiments 1-25, wherein the at least one layer further comprises the therapeutic component or an additional therapeutic component.

[0147] 27. An ocular implant according to any one of the preceding embodiments, which is a macro-, micro- or nanoparticle.

[0148] 28. The therapeutic agent is an ocular implant of 1 μm 3 28. The ocular implant of any one of embodiments 1-27, wherein the ocular implant is present in a concentration of 200 μg to 2000 μg per unit area.

[0149] 29. (a) providing said therapeutic agent; and (b) obtaining an ophthalmic composition by combining the therapeutic agent with the polymerizable composition, the biodegradable polymer, the photoinitiator, and optionally the release modifier; and (c) irradiating the ophthalmic composition in step (b) with light having a wavelength of 200 to 550 nm for a period of 1 second to 60 minutes to form the uncoated ophthalmic implant; and (d) coating at least a portion of the uncoated outer surface of the ocular implant with at least one coating layer.

[0150] 30. The method of embodiment 29, wherein the therapeutic agent is first dissolved in a solvent to obtain a solution, and then the solution so obtained is mixed with the polymerizable composition, the biodegradable polymer, the photoinitiator, and optionally the release modifier.

[0151] 31. The method of embodiment 29 or 30, wherein the photoinitiator is a hydroxyketone photoinitiator, an aminoketone photoinitiator, a hydroxyketone / benzophenone photoinitiator, a benzyl dimethyl ketal photoinitiator, a phenylglyoxylate photoinitiator, an acylphosphine oxide photoinitiator, an acylphosphine oxide / alphahydroxyketone photoinitiator, a benzophenone photoinitiator, a ribitylisoalloxazine photoinitiator, or a phenylglyoxylate photoinitiator, or any combination thereof.

[0152] 32. The method of embodiment 31, wherein the photoinitiator is 1-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propanone, 2,2-dimethoxy-2-phenylacetophenone (DMPA), or 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl-1-propanone (Irgacure 2959), or riboflavin.

[0153] 33. The method of any one of embodiments 29-32, wherein the uncoated ocular implant is coated in step (d) with at least one coating layer over its entire outer surface.

[0154] 34. The method of any one of embodiments 29 to 33, wherein the coating step (d) is carried out by manual dipping, controlled dip coating, ultrasonic coating, spray coating, or 3D printing.

[0155] 35. (a) providing said therapeutic agent; and (b) obtaining an ophthalmic composition by combining the therapeutic agent with the polymerizable composition, the biodegradable polymer, the photoinitiator, and optionally the release modifier; and (c) injecting the ophthalmic composition obtained in step (b) into a preformed hollow coating layer; and (d) irradiating the ophthalmic composition in the hollow coating layer with light having a wavelength of 200 to 550 nm for a period of 1 second to 60 minutes.

[0156] 36. The method of embodiment 35, wherein the hollow coating layer is a hollow tube.

[0157] The following examples serve to illustrate the invention but should not be understood as limiting the scope of the invention. EXAMPLES

[0158] Example 1. Dexamethasone (DEX) and Timolol Maleate (TM) with and without Poly(L-lactide) PLA Coating 1.1.Materials Poly(ethylene glycol) diacrylate (Mn=700, PEGDA 700), poly(ethylene glycol) diacrylate (Mn=250, PEGDA 250), dichloromethane, sodium hydroxide (NaOH), Irgacure 2959, N-methyl-2-pyrrolidone (NMP), and acetonitrile were purchased from Sigma (Dorset, UK). Dexamethasone (DEX) was purchased from Bufa (Hilversum, The Netherlands). Poly(lactide-co-glycolide) (PURASORB® PDLG 5002, 50:50, PLGA 50 / 50), poly(lactide-co-glycolide) (PURASORB® PDLG 7502, 75:25, PLGA 75 / 25), and poly(L-lactide) (PURASORB® PL 65, PLA) were obtained from Purac Biochem (Gorinchem, Netherlands), timolol maleate from Gangwal Chemicals Pvt Ltd (Maharashtra, India).

[0159] 1.2. Preparation of rod-shaped implants for DEX (DEX 10 w / w%, PLGA 20 w / w%, PEGDA 700 70 w / w%) PEGDA 700 (280 mg), PLGA 50 / 50 (80 mg), and DEX (40 mg) were mixed and stirred overnight. 90 μL of photoinitiator solution (40 mg / mL solution of Irgacure 2959 in pure ethanol) was added, and the mixture was stirred for 10 min. The resulting mixture was injected into silicone tubing and photocrosslinked using a light hammer (LightHammer® 6, Heraeus Noblelight Fusion UV Inc., Gaithersburg, MD, USA). The intensity of the UV light was set to 100% and the silicone tubing was exposed to the UV light for 30 s (10 times, 5 times on each side). The rod-shaped implant was then removed from the tube. To prepare the coated implant, the uncoated implant was dipped into a PLA solution (2.5% PLA in dichloromethane) for 3 s and then dried in a fume hood for 48 s.

[0160] 1.3. Preparation of rod-shaped implants for TM (TM 10 w / w%, PLGA 75 / 25 20 w / w%, PEGDA 250 70 w / w%) TM (20 mg) was first dissolved in NMP (30 μL) and then mixed with PEGDA 250 (140 mg) and PLGA 75 / 25 (40 mg). The mixture was stirred overnight. 45 μL of photoinitiator solution (40 mg / mL solution of Irgacure 2959 in ethanol) was added and the mixture was stirred for 10 min. The resulting mixture was injected into silicone tubing and photocrosslinked using a light hammer (LightHammer® 6, Heraeus Noblelight Fusion UV Inc., Gaithersburg, MD, USA). The intensity of the UV light was set to 100% and the silicone tube was exposed to the UV light for 30 s (10 times). The rod-shaped implant was then removed from the tube. To prepare the coated implant, the uncoated implant was dipped into a PLA solution (2.5% PLA in dichloromethane) for 3 s and then dried in a fume hood for 48 s.

[0161] 1.4. Evaluation of DEX using high-performance liquid chromatography (HPLC) DEX was determined by reversed-phase HPLC. The HPLC instrument consisted of an Agilent 1260 Infinity pump equipped with a sample injection port with a 20 μL sample loop, a UV-VIS detector, and a Chromato-integrator (Agilent Technologies, Germany). The mobile phase consisted of acetonitrile and water in a ratio of 40:60. The flow rate of the mobile phase was 0.8 mL / min, and the eluted drug was detected at a wavelength of 245 nm. Chromatographic separation of DEX was achieved at ambient room temperature (24 ± 2 °C) using a Poroshell 120 EC-C 18 4 μm (250 × 4.60 mm) analytical column equipped with a refillable guard column. The mobile phase was filtered under vacuum through a 0.45 μm membrane filter (Whatman International, UK) and degassed before use.

[0162] 1.5. TM determination using high performance liquid chromatography (HPLC) TM content was determined by reversed-phase HPLC. The HPLC instrument consisted of an Agilent 1260 Infinity pump equipped with a sample injection port with a 20 μL sample loop, a UV-VIS detector, and a Chromato-integrator (Agilent Technologies, Germany). The mobile phase consisted of acetonitrile (0.05 v / v% TFA) and water (0.05 v / v% TFA) in a ratio of 40:60. The flow rate of the mobile phase was 0.8 mL / min, and the eluted drug was detected at a wavelength of 295 nm. Chromatographic separation of TM was achieved at ambient room temperature (24 ± 2 °C) using a Poroshell 120 EC-C 18 4 μm (250 × 4.60 mm) analytical column equipped with a refillable guard column. The mobile phase was filtered under vacuum through a 0.45 μm membrane filter (Whatman International, UK) and degassed before use.

[0163] 1.6. In vitro drug release testing Drug-loaded implants (4 mg, diameter 0.635 mm, length 10 mm) were immersed in 20 mL of PBS (pH=7.4) and kept in a horizontal shaking incubator at 37°C and 40 rpm. Drug release supernatants (1.7 mL) were collected periodically (24, 48, 72 hours, etc.) and replaced with fresh medium. Drug content in aliquots was determined by HPLC. All release experiments were performed in triplicate and all data were the average of triplicate determinations.

[0164] Table 1 summarizes the parameters of implants DEX1, DEX2, TM1, and TM2.

[0165] JPEG2024167340000002.jpg42170

[0166] The surface morphology of the implants was characterized by SEM, as shown in Figure 1. DEX2 has a slightly rough surface, whereas DEX1 appears to have a smooth surface. The diameter of the rod-shaped implants is approximately 0.635 mm. The thickness of the coating is approximately 0.029 mm, i.e. 29 μm.

[0167] As can be seen from Figures 2 and 3, comparative implants DEX1 and TM1 show a substantial burst release on day 1. This effect is largely suppressed in DEX2 and TM2. The implants of the present invention can provide a sustainable release of therapeutic agents over an extended period of time.

[0168] Example 2. Fluorescein isothiocyanate (FITC)-dextran implants with and without poly-L-lactide-co-caprolactone (PLC) and poly(DL-lactide) (PDL) coatings

[0169] JPEG2024167340000003.jpg36170

[0170] 2.1. Preparation of D1 Solution A was prepared by dissolving 10 mg of PLGA 75 / 25 (Purac Biochem, Gorinchem, The Netherlands) in 190 mg of PEGDA with molecular weight (MW) of 700 Da (Sigma Aldrich, Basingstoke, UK). Solution B was prepared by dissolving 5 mg of Irgacure 2559 (Sigma Aldrich, Basingstoke, UK) in 1 mL of PBS. Solution C was prepared by dissolving 10 mg of FITC dextran (average MW 4000 Da, Sigma Aldrich., Basingstoke, UK) in 60 μL of solution B in an Eppendorf tube. 85 mg of solution A was weighed into an empty Eppendorf tube and 60 μL of solution C was slowly added to the mixture through the Eppendorf tube wall with continuous stirring at 900 rpm for 15 min. The final mixture was drawn into a silicone tube with an inner diameter of 0.635 mm (Polymer System Technology, UK) and cross-linked using UV light (LightHammer® 6, Heraeus Noblelight Fusion UV Inc., Gaithersburg, MD, USA). The intensity of the UV light was set to 50% and the silicone tube was exposed to the UV light for 15 seconds (i.e., a total of 5 runs). The implants were then removed from the silicone tube and dried under vacuum at 25° C. for 4 hours. Rod-shaped implants were cut into lengths of 7.5 mm each.

[0171] 2.2. Preparation of CD1 (coated with PLC) Implants CD1 were produced according to item 2.1 as described above (except the last sentence). They were cut into lengths of 20 mm and coated with a 17 w / v% solution of poly-L-lactide-co-caprolactone (PLC 8516) (Purac Biochem, Gorinchem, The Netherlands) in dichloromethane (DCM) using a texture analysis instrument (TA-XT plus, Stable Micro Systems, USA). The implants were dipped at a speed of 10 mm / s, held in the coating solution for 1 s, and then withdrawn at a speed of 10 mm / s. A single coat layer was applied with a thickness of about 20-25 μm. The implants were then cut into lengths of 7.5 mm and the sides of these surface-coated implants were coated with a 15 w / v% solution of poly-DL-lactide (PDL) in acetonitrile (ACN) by using a 29 G needle syringe under a digital microscope.

[0172] 2.3 In vitro drug release setting Two implants of D1 and two implants of CD1 (length 7.5 mm) were placed in two glass vials containing 2 mL of PBS (phosphate buffered saline) with 0.01 w / v% sodium azide (NaN2) (pH 7.4 ± 0.2) as release medium. All experiments were performed in triplicate. The glass vials containing the implants were placed in a shaking orbital incubator at a speed of 40 rpm and 37°C (GFL Orbital Shaking Incubator, Gesellschaft fur Labortechnik mbH, Germany). Sampling followed by complete replacement of the PBS medium was performed on day 1 and every week thereafter, i.e., on days 7, 14, 21, and 28, etc. The concentration of released drug molecules in the PBS samples was analyzed as described in the following section. The vials were then incubated at 37°C and at given time intervals the entire medium was removed and replaced with fresh medium.

[0173] 2.4 Sample analysis Analysis of the FITC-dextran in vitro drug release samples was performed using fluorescence spectrophotometry. Detection was performed by a micro 96-well plate spectrophotometer (BMG Labtech FLUOstar Optima fluorescence plate reader (BMG Labtech GmbH, Ortenberg, Germany). Excitation was set at 485 nm, emission at 520 nm, and gain was set at 750.

[0174] Figure 4 shows the in vitro release of D1 and CD1 expressed as cumulative release percentages, which shows that the presence of the coating polymer layer on the implant matrix significantly reduces the burst effect and controls the overall release of FITC-dextran over the entire period.

[0175] Example 3 - Latanoprost (LP) implants of different diameter sizes with or without poly-L-lactide-co-caprolactone (PLC) coating.

[0176] JPEG2024167340000004.jpg63170

[0177] 3.1. Preparation of LP1 and LP2 Solution A was prepared by dissolving 20 mg of Irgacure 2959 (Sigma Aldrich, Basingstoke, UK) in acetonitrile. Solution B was prepared by dissolving 50 mg of latanoprost (LP) (Alfa Chemistry, New York, USA) in 2.5 mL of acetonitrile. Solution C was prepared by dissolving 75 mg of PEGDA 250 and 15 mg of PLGA 75 / 25 (Purac Biochem, Gorinchem, Netherlands) in 250 μL of acetonitrile in a 2 mL Eppendorf tube.

[0178] Then, 37.5 μL of solution A and 1 mL of solution B were added to solution C, followed by stirring at 250 rpm for 30 min (Multisterer, Velp Scientifica™, Italy). Acetonitrile was then evaporated at room temperature for 6 h under a gauge pressure of -0.1 MPa (OV-12 vacuum oven, JeioTech, Korea). The final mixture was drawn into a silicone tube with an inner diameter of 0.32 or 0.63 mm (HelixMark® Standard Silicone Tubing, Freudenberg, Germany) using a 25G needle attached to a 10 mL syringe. Photocrosslinking was carried out 10 times under a UV D lamp operated at 100% intensity with a belt speed of 11.5 m / min (LightHammer 6, Heraeus Noblelight Fusion UV, USA). The solidified rod-shaped implants were removed from the silicone tube and cut into 2 mm lengths. The weight of the implants was approximately 0.2 mg (LP1 for diameter 0.3 mm) and 0.9 mg (LP2 for diameter 0.6 mm).

[0179] 3.2 Preparation of LPC1 and LPC2 (PLC-coated LP1 and LP2) Implants LP1 and LP2 were coated by an automated dip-coating method to obtain LPC1 and LPC2, respectively. A single coat layer was applied with a thickness of about 20–25 μm. They were coated on the front side with a 17 w / v% solution of poly-L-lactide-co-caprolactone (PLC) (Purac Biochem, Gorinchem, The Netherlands) polymer solution in dichloromethane (DCM) using a texture analysis instrument, and on the sides with a 15 w / v% solution of poly-DL-lactide (PDL) (Purac Biochem, Gorinchem, The Netherlands) in acetonitrile (ACN) using a 29G needle syringe under a digital microscope.

[0180] 3.3 In vitro drug release setting Implants LP1, LP2, LPC1, and LPC2 were each placed in a centrifuge tube containing 2 mL of PBS (phosphate buffered saline) with 0.01 w / v% sodium azide (NaN2) (pH 7.4±0.2) as the release medium. All experiments were performed in triplicate. The centrifuge tubes containing the implants were placed in a shaking orbital incubator at a speed of 40 rpm and 37° C. (GFL Orbital Shaking Incubator, Gesellschaft fur Labortechnik mbH, Germany). Sampling followed by complete replacement of the PBS medium was performed on days 1, 3, 7, and every week thereafter. The concentration of the released drug was analyzed using the HPLC method developed for latanoprost.

[0181] 3.4 Sample analysis Analysis of LP1, LP2, LPC1, and LPC2 samples was performed using a HPLC system (Agilent 1260 Infinity II Quaternary System) with fluorescence detection using a Poroshell 120 EC-C18 column (length 250 mm, internal diameter 4.6 mm, particle size 4 μm). Samples were analyzed in isocratic mode with a mobile phase of acetonitrile:0.1 v / v% formic acid (60:40) at an injection volume of 50 μL and a flow rate of 1 mL / min. The column temperature was maintained at 40° C. The fluorescence detector was set at an excitation wavelength of 265 nm and an emission wavelength of 285 nm.

[0182] Figure 5 shows the in vitro release of LP1, LP2, LPC1 and LPC2 expressed as cumulative percentages. As can be seen, the presence of the coating polymer layer on the implant matrix significantly reduces the burst effect and controls the overall release of LP over the entire period.

[0183] Example 4 - Latanoprost (LP) Implants with One or More Layers of Poly-L-lactide-co-caprolactone (PLC) - Effect of Layers.

[0184] JPEG2024167340000005.jpg41170

[0185] 4.1. Preparation of LP3 LPC3 implants were prepared from LP1 implants using the coating method described in section 3.2, whereby automated dip coating was repeated twice on the dried LPC1 implants to achieve two layers of PLC coating.

[0186] 4.2 In vitro drug release setup and sample analysis LPC1 and LPC3 implants with a length of 2 mm and a weight of approximately 0.2 mg were placed in centrifuge tubes containing 2 mL of PBS (phosphate buffered saline) with 0.01 w / v% sodium azide (NaN2) (pH 7.4 ± 0.2) as the release medium. All experiments were performed in triplicate. The centrifuge tubes containing the implants were placed in a shaking orbital incubator at a speed of 40 rpm and 37°C (GFL Orbital Shaking Incubator, Gesellschaft fur Labortechnik mbH, Germany). Sampling followed by complete replacement of the PBS medium was performed on days 1, 3, 7, and every week thereafter. The concentration of the released drug was analyzed using an HPLC method developed for latanoprost.

[0187] Figure 6 shows the in vitro release of LPC1 and LPC3 expressed as cumulative percentages. As can be seen, the additional coating polymer layer on the implant matrix further reduces the burst effect and controls the overall release of latanoprost over the entire period.

[0188] Example 5 - Latanoprost (LP) Implants Coated with Layers of Poly-L-lactide-co-caprolactone (PLC) and Poly(L-lactide) (PLA) - Effect of Composition of Coating Materials.

[0189] JPEG2024167340000006.jpg40170

[0190] 5.1. Preparation of LPC4 LPC4 implants were prepared by coating LP1 implants by an automated dip-coating method: the LPC4 implants were coated on the front with a 2.5 w / v% solution of poly(L-lactide) (PLA) polymer solution in dichloromethane (DCM) using a texture analysis instrument, and on the sides with a 15 w / v% solution of poly(DL-lactide) (PDL) (Purac Biochem, Gorinchem, The Netherlands) in acetonitrile (ACN) using a 29G needle syringe under a digital microscope.

[0191] 5.2 In vitro drug release setup and sample analysis LPC1 and LPC4 implants with a length of 2 mm and a weight of approximately 0.2 mg were placed in centrifuge tubes containing 2 mL of PBS (phosphate buffered saline) with 0.01 w / v% sodium azide (NaN2) (pH 7.4 ± 0.2) as the release medium. All experiments were performed in triplicate. The centrifuge tubes containing the implants were placed in a shaking orbital incubator at a speed of 40 rpm and 37°C (GFL Orbital Shaking Incubator, Gesellschaft fur Labortechnik mbH, Germany). Sampling followed by complete replacement of the PBS medium was performed on days 1, 3, 7, and every week thereafter. The concentration of the released drug was analyzed using an HPLC method developed for latanoprost.

[0192] Figure 4 shows the in vitro release of LPC1 and LPC4 expressed as cumulative percentages. As can be seen from these figures, the polymeric coating material of the therapy reduces the burst effect (compared to LP1) and controls the overall release of latanoprost over the entire period.

[0193] Example 6 - Highly loaded Latanoprost (LP) implants with or without PLC coating.

[0194] JPEG2024167340000007.jpg36170

[0195] 6.1. Preparation of LP40 Solution A was prepared by dissolving 20 mg of Irgacure 2959 (Sigma Aldrich, Basingstoke, UK) in acetonitrile. Solution B was prepared by dissolving 50 mg of latanoprost (LP) (Alfa Chemistry, New York, USA) in 2.5 mL of acetonitrile. Solution C was prepared by dissolving 29 mg of PEGDA 250 and 1 mg of PLGA 75 / 25 (Purac Biochem, Gorinchem, Netherlands) in 250 μL of acetonitrile in a 2 mL Eppendorf tube.

[0196] Then, 14.5 μL of solution A and 1000 μL of solution B were added to solution C, followed by stirring at 250 rpm for 30 min (Multisterer, Velp Scientifica™, Italy). Acetonitrile was then evaporated at room temperature for 6 h under a gauge pressure of -0.1 MPa (OV-12 vacuum oven, JeioTech, Korea). The final mixture was drawn into a 0.32 inner diameter silicone tube (HelixMark® Standard Silicone Tubing, Freudenberg, Germany) using a 25G needle attached to a 10 mL syringe. Photocrosslinking was carried out five times under a UV D lamp operated at 50% intensity with a belt speed of 11.5 m / min (LightHammer 6, Heraeus Noblelight Fusion UV, USA). The solidified rod-shaped implant was removed from the silicone tube and cut into a length of 2 mm. The weight of the implant was approximately 0.2 mg.

[0197] 6.2 Preparation of LPC40 Implants LP40 were coated by an automated dip-coating method to obtain LPC40. A single coat layer was applied with a thickness of approximately 20-25 μm. They were coated on the front side with a 17 w / v% solution of poly-L-lactide-co-caprolactone (PLC) (Purac Biochem, Gorinchem, The Netherlands) polymer solution in dichloromethane (DCM) using a texture analysis instrument, and on the sides with a 15 w / v% solution of poly-DL-lactide (PDL) (Purac Biochem, Gorinchem, The Netherlands) in acetonitrile (ACN) using a 29G needle syringe under a digital microscope.

[0198] 6.3 In vitro drug release setup and sample analysis LP40 and LPC40 implants with a length of 2 mm and a weight of approximately 0.2 mg were placed in centrifuge tubes containing 2 mL of PBS (phosphate buffered saline) with 0.01 w / v% sodium azide (NaN2) (pH 7.4±0.2) as the release medium. All experiments were performed in triplicate. The centrifuge tubes containing the implants were placed in a shaking orbital incubator at a speed of 40 rpm and 37° C. (GFL Orbital Shaking Incubator, Gesellschaft fur Labortechnik mbH, Germany). Sampling followed by complete replacement of the PBS medium was performed on days 1, 3, 7, and every week thereafter. The concentration of released drug was analyzed using an HPLC method developed for latanoprost.

[0199] Figure 8 shows the in vitro release of LP40 and LPC40 expressed as cumulative release percentage. As can be seen from this figure, the coating on the surface of the implant significantly reduced the initial burst release and sustained the release over a longer period of time compared to the uncoated implant. The coated LPC40 implant maintained a near zero order release for 180 days (6 months), while the uncoated LP40 implant was able to achieve a sustained release for 20 days.

Claims

1. 1. An ocular implant comprising: (a) at least 10% w / w of a therapeutic agent; and (b) at least 50 w / w% crosslinked polymer matrix; and (c) 2-30 wt % of a biodegradable polymer, including poly(lactide-co-glycolide) (PLGA); and Including, wherein the crosslinked polymer matrix is ​​obtained by crosslinking a photopolymerizable composition comprising polyalkylene glycol diacrylate (PEGDA); 1. An ocular implant, characterized in that the ocular implant is at least partially coated on its outer surface with at least one coating layer selected from the group consisting of poly(L-lactide) (PLA), polycaprolactone (PCL), poly(DL-lactide) (PDL), and poly-L-lactide-co-caprolactone (PLC), and any combination thereof.

2. The ocular implant of claim 1 , wherein the therapeutic agent is present in an amount of about 10% w / w.

3. The ocular implant of claim 1 , wherein the therapeutic agent is present in an amount of about 20% w / w.

4. The ocular implant of claim 1, wherein the therapeutic agent is present in an amount of about 40 w / w %.

5. 10. The ocular implant of claim 1, wherein the amount of polyethylene glycol diacrylate (PEGDA) is about 50 w / w%.

6. The ocular implant of any one of claims 1 to 5, wherein the biodegradable polymer is present in an amount of 20 to 30 w / w %.

7. The ocular implant of any one of claims 1 to 6, wherein the biodegradable polymer is 75 / 25 PLGA.

8. The ocular implant of any one of claims 1 to 7, wherein the biodegradable polymer is 50 / 50 PLGA.

9. 10. The ocular implant of claim 1, wherein the implant comprises one coating layer of poly-L-lactide-co-caprolactone (PLC).

10. The ocular implant of claim 9, wherein the one coating layer of poly-L-lactide-co-caprolactone (PLC) is about 20 μm to about 25 μm thick.

11. The ocular implant of claim 1, wherein the implant comprises two coating layers of poly-L-lactide-co-caprolactone (PLC).

12. An ocular implant described in any one of claims 1 to 11, wherein the ocular implant is rod-shaped.

13. An ocular implant described in any one of claims 1 to 12, wherein the ocular implant has a weight of about 0.2 mg to about 0.9 mg.

14. An ocular implant described in any one of claims 1 to 13, wherein there is sustained release of the therapeutic agent from the ocular implant for at least 28 days.

15. An ocular implant comprising: (a) about 10% w / w of a therapeutic agent; and (b) about 70 w / w% crosslinked polymer matrix; and (c) 20% w / w of a biodegradable polymer comprising poly(lactide-co-glycolide) (PLGA); and Including, 10. The ocular implant of claim 1, wherein the ocular implant is at least partially coated on its outer surface with at least one coating layer of poly(L-lactide) (PLA).

16. The ocular implant of claim 15, wherein the biodegradable polymer is 75 / 25 PLGA.

17. The ocular implant of claim 15, wherein the biodegradable polymer is 50 / 50 PLGA.

18. An ocular implant comprising: (a) about 10% w / w of a therapeutic agent; and (b) about 85 w / w% crosslinked polymer matrix; and (c) 5 w / w % biodegradable polymers including 75 / 25 poly(lactide-co-glycolide) (PLGA); and Including, 10. The ocular implant of claim 1, wherein the ocular implant is at least partially coated on its outer surface with at least one coating layer of poly-L-lactide-co-caprolactone (PLC).

19. An ocular implant comprising: (a) about 20% w / w of a therapeutic agent; and (b) about 50 w / w% crosslinked polymer matrix; and (c) 30 wt % biodegradable polymers including 75 / 25 poly(lactide-co-glycolide) (PLGA); and Including, 10. The ocular implant of claim 1, wherein the ocular implant is at least partially coated on its outer surface with at least one coating layer of poly-L-lactide-co-caprolactone (PLC).

20. The ocular implant of claim 19, wherein the ocular implant comprises two coating layers of poly-L-lactide-co-caprolactone (PLC).

21. An ocular implant comprising: (a) about 40% w / w of a therapeutic agent; and (b) about 58 w / w% crosslinked polymer matrix; and (c) 2 w / w % biodegradable polymers including 75 / 25 poly(lactide-co-glycolide) (PLGA); and Including, 10. The ocular implant of claim 1, wherein the ocular implant is at least partially coated on its outer surface with at least one coating layer of poly-L-lactide-co-caprolactone (PLC).

22. The ocular implant of claim 21, wherein there is sustained release of the therapeutic agent from the ocular implant for at least 180 days.

23. A method of making an ocular implant according to any one of claims 1 to 22, comprising the steps of: (a) providing said therapeutic agent; and (b) obtaining an ophthalmic composition by mixing the therapeutic agent with the polymerizable composition, the biodegradable polymer, a photoinitiator, and optionally a release modifier; and (c) irradiating the ophthalmic composition obtained in step (b) with light having a wavelength of 200 to 550 nm for a period of time ranging from 1 second to 60 minutes to form an uncoated ophthalmic implant; and (d) coating at least a portion of the uncoated exterior surface of the ocular implant with at least one coating layer; A method comprising:

24. The method of claim 23, wherein the uncoated ocular implant is coated by an automated dip coating method.

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