Coated ocular implant

Abstract

The present invention relates to an ocular implant for the controlled release of a therapeutic agent or drug, comprising: a) at least 0.1% w / w of a therapeutic agent; b) 5% to 95% w / w of a cross-linked polymer matrix; c) and 0.1% to 40% w / w of a biodegradable polymer wherein the cross-linked polymer matrix is obtained by cross-linking a photopolymerizable composition, characterized in that the outer surface of the ocular implant is at least partially coated with at least one coating layer. The invention also relates to a method of manufacturing the above ocular implant.

Description

[0001] This application is a divisional application of the Chinese patent application with application number 201980089271.X (application date: December 20, 2019, invention name: coated ocular implant). Technical Field

[0002] The present invention relates to coated ocular implants for the controlled release of therapeutic agents or drugs. Background Art

[0003] Chronic retinal diseases are the main causes of global visual impairment and blindness. Blindness has a significant personal impact on people's daily lives and has a profound economic impact on individuals, families, public health and society. The World Health Organization estimates that approximately 285 million people in the world suffer from visual impairment, of which 39 million are blind and 246 million have low vision. Diseases originating from the posterior segment (PS) or the back of the eye, if not treated, lead to permanent vision loss and are the cause of most blindness, such as in age-related macular degeneration (AMD), diabetic retinopathy (DR), diabetic macular edema (DME), cytomegalovirus (CMV) retinitis, retinitis pigmentosa, uveitis and glaucoma. The PS of the eye (including retina, choroid and vitreous body) is difficult to enter due to its sunken position in the orbit. Therefore, for pharmaceutical scientists and retinal specialists, delivering therapeutic agents to the PS of the eye remains one of the most challenging tasks.

[0004] A variety of methods have been used to deliver therapeutic agents to the PS of the eye, such as systemic, topical, periocular (or transscleral), and intravitreal. Due to various ocular barriers, local (e.g., eye drops) and systemic (e.g., oral tablets) routes result in low or subtherapeutic agent levels, requiring the administration of unnecessarily high concentrations of therapeutic agents, which leads to therapeutic agent-related toxicity and produces low therapeutic efficacy.

[0005] WO 2017081154A1 discloses ocular 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 the patient's eye, or they can be preformed prior to injection into the eye.

[0006] There is a need for alternative systems for ocular delivery of therapeutic agents. Summary of the Invention

[0007] In a first aspect, the present invention relates to a coated ocular implant that can be administered to the eye in a variety of forms to achieve controlled release of a therapeutic agent or drug. Such an ocular composition comprises:

[0008] a) at least 0.1% w / w of a therapeutic agent;

[0009] b) 5% to 95% w / w of a cross-linked polymer matrix;

[0010] c) and 0.1% to 40% w / w of a biodegradable polymer selected from lactide / glycolide copolymers (including poly(lactide-co-glycolide)

[0011] (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;

[0012] wherein the cross-linked polymer matrix is ​​obtained by cross-linking a photopolymerizable composition selected from segments or monomers of polyalkylene glycol monoacrylates, polyalkylene glycol diacrylates, polyalkylene glycol monomethacrylates and polyalkylene glycol dimethacrylates, and mixtures, copolymers, and block copolymers thereof,

[0013] The ocular implant is characterized in that the ocular implant is at least partially coated on its outer surface with at least one coating layer, wherein the coating layer 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); lactide / caprolactone copolymers; poly(DL-lactide) (PDL); poly(D-lactide); poly-L-lactide-co-caprolactone (PLC) and mixtures, copolymers, and block copolymers thereof; and cross-linked segments or monomers of polyalkylene glycol monoacrylates, polyalkylene glycol diacrylates, polyalkylene glycol methacrylates, and polyalkylene glycol dimethacrylates, and mixtures, copolymers, and block copolymers thereof.

[0014] In a further aspect, the present invention relates to a method of manufacturing the above-described ocular implant.

[0015] 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 range of small and large therapeutic molecules (including proteins, peptides, and gene therapy agents) and maintain their activity over a controlled period of time.

[0016] The ocular implants of the present invention are capable of achieving long-term release by tailoring and controlling the profile to the specific therapeutic agent or agents being used and according to the needs of the patient.

[0017] The ocular implants of the present invention are capable of suppressing the so-called "burst release" or "fast initial release" effect, thereby preventing the majority of the therapeutic agent from being released on the first day of treatment. Thus, the patient is never exposed to a dose of the therapeutic agent that could exceed the maximum acceptable amount, while at the same time, the efficacy of the therapy is maintained through the sustained release of the one or more agents throughout the treatment period. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 Scanning electron microscope (SEM) images of implant DEX 1 and comparative example DEX 2 are shown.

[0019] Figure 2 Shown is the in vitro release of DEX from implants DEX1 and DEX2, expressed as percentage of cumulative release (mean ± SD, n = 3).

[0020] Figure 3 Shown is the in vitro release of TM from implants TM1 and TM2, expressed as percentage cumulative release (mean ± SD, n = 3).

[0021] Figure 4 Shown are the in vitro drug release profiles of FITC-dextran from implants D1 and CD1, expressed as the cumulative percentage release (mean ± SD, n = 3).

[0022] Figure 5 Shown are the in vitro drug release profiles of LP from implants LP1, LP2, LPC1, and LPC2, expressed as the cumulative percentage release (mean ± SD, n = 3).

[0023] Figure 6 Shown are the in vitro drug release profiles of LP from implants LPC1 and LPC3, expressed as the cumulative percentage release (mean ± SD, n = 3).

[0024] Figure 7 Shown are the in vitro drug release profiles of LP from implants LPC1 and LPC4, expressed as percentage cumulative release (mean ± SD, n = 3).

[0025] Figure 8 Shown are the in vitro drug release profiles of LP from implants LP40 and LPC40, expressed as the cumulative percentage release (mean ± SD, n = 3). DETAILED DESCRIPTION

[0026] As used herein, the term "% w / w" means the weight percentage of a given component relative to the total weight of the copolymer, composition, or implant, as the case may be, in which such component is contained.

[0027] As used herein, "biodegradable" is chemically degradable 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, monomer, oligomer, fragment, polymer, photoinitiator, solvent, cosolvent, or co-initiator.

[0028] 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.

[0029] The therapeutic agent of the composition of the present invention can be selected from a wide range of small molecules and macromolecules. Exemplary therapeutic agents include, but are not limited to, polypeptides, nucleic acids (such as DNA, RNA, and siRNA), growth factors, steroid agents, antibody therapies, antimicrobials, antibiotics, antiretroviral therapeutics, anti-inflammatory compounds, antitumor agents, anti-angiogenic agents, anti-VEGF (vascular endothelial growth factor) agents, and chemotherapeutic agents.

[0030] In one embodiment, therapeutic agents of the invention include but are not limited to ketorolac, naphazoline, lidocaine, bevacizumab, aflibercept, pegaptanib, brimonidine tartrate, dorzolamide, bromfenac sodium, azithromycin, rapamycin, bepotastine besylate, diclofenac, besifloxacin, cysteamine hydrochloride, fluocinoloneacetonide, difluprednate, tasimelteon, ocriplasmin, enoxaparin sodium, ranibizumab, latanoprost, Timolol maleate, bimatoprost, ofloxacin, cefazolin, phenylephrine, dexamethasone, 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 a combination thereof.

[0031] In another embodiment, the therapeutic agent of the invention is dexamethasone, timolol maleate, brimonidine tartrate, triamcinolone acetonide, bromfenac sodium, latanoprost, or a mixture thereof.

[0032] In one embodiment, the implants of the invention can deliver a bioactive agent, a large molecular weight therapeutic agent (such as aflibercept, pegaptanib), or a therapeutic antibody (such as ranibizumab, bevacizumab, trastuzumab, rituximab, gentuzumab, ozagamicin, brolucizumab, or cetuximab).

[0033] 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.

[0034] According to other embodiments of the invention, the therapeutic agent is present in an amount between 0.5% and 70% w / w, between 10% and 70% w / w, between 20% and 70% w / w, between 30% and 70% w / w, between 40% and 70%, between 5% and 50%, between 10% and 50% w / w, between 20% and 50% w / w, between 30% and 50%, and between 40% and 50% of the total weight of the ocular implant.

[0035] 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 lyophilized or spray-dried prior to use in preparing the ophthalmic composition of the present invention to facilitate incorporation of a high concentration of the therapeutic agent into the implant. The amount of therapeutic agent to be dissolved depends on the final load that the ophthalmic composition or implant must have. The choice of solvent depends on the polarity of the therapeutic agent.

[0036] According to an embodiment of the present invention, the solvent can 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.

[0037] In one embodiment, co-solvents may be used and may be selected from dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, acetic acid, methanol, ethanol, isopropanol, glycofurol or butanol.

[0038] In the case of a hydrophilic therapeutic agent, the solvent may be an aqueous-based solvent, such as water or phosphate buffered saline (PBS) solution.

[0039] 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.

[0040] Furthermore, the above-described solvents and cosolvents can be combined with any of the other photopolymerizable compositions, biodegradable polymers, photoinitiators, porogens, and co-initiators described herein to prepare any of the implants of the present invention.

[0041] 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.

[0042] The photopolymerizable segments 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 modulators, and co-initiators described herein or known in the common general knowledge.

[0043] 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.

[0044] As used herein, the term "photopolymerizable composition" is a composition that can form a crosslinked polymer network after exposure to light (particularly UV light). As used herein, a photopolymerizable composition includes photopolymerizable monomers and oligomers (such as dimers, trimers, and tetramers). The terms "oligomer" and "fragment" are used interchangeably to refer to between 2 and 20 monomers, optionally between 2 and 10 monomers, further optionally between 2 and 5 monomers, or between 2 and 4 monomers. A "photopolymerizable monomer" is a single unit of a photopolymerizable polymer that can be chemically combined with other monomers to form a polymer.

[0045] 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.

[0046] In one embodiment, the photopolymerizable composition is selected from segments or monomers of polyalkylene glycol monoacrylates, polyalkylene glycol diacrylates, polyalkylene glycol methacrylates, polyalkylene glycol dimethacrylates, and mixtures, copolymers, and block copolymers thereof.

[0047] In one embodiment, the photopolymerizable composition is a polyalkylene glycol diacrylate segment or monomer incorporating diacrylate end units selected from the group consisting of polyether segments or monomers, polyester segments or monomers, polycarbonate segments or monomers, or mixtures, copolymers, or block copolymers thereof.

[0048] In one embodiment, the photopolymerizable composition comprises monomers incorporating diacrylate end units, such as 4-arm or 8-arm PEG acrylates.

[0049] 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.

[0050] In another embodiment, the photopolymerizable composition is polyethylene glycol diacrylate (PEGDA), polyalkylene glycol monoacrylate (PEGMoA), or polyethylene glycol dimethacrylate (PEGDMA).

[0051] In yet another embodiment, the photopolymerizable composition is polyethylene glycol diacrylate (PEGDA).

[0052] 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. In an embodiment, the polymerizable composition is a mixture of PEGDA, PEGMoA and / or PEGMA.

[0053] PEGDA is a synthetic polymer that is available in various molecular weights. PEGDA is highly amenable to mechanical, structural, and chemical changes and therefore produces hydrogels with variable properties for drug delivery and other biomedical applications. PEGDA is formed by functionalizing the ends of each PEG molecule with acrylate groups. PEGDA is also non-toxic and elicits only minimal immunogenic responses. PEGDA has acrylate end groups containing double bonds that exhibit rapid polymerization to produce hydrogel networks when exposed to light in the presence of an appropriate initiator.

[0054] The average molecular weight of the photopolymerizable composition of the present invention is typically between 100 and 300,000 Da, between 200 and 100,000 Da, between 200 and 50,000 Da, between 200 and 20,000 Da, between 200 and 10,000 Da, between 200 and 8,000 Da, between 200 and 5,000 Da, or between 200 and 1,000 Da.

[0055] 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 rate of release of the therapeutic agent. Without wishing to be bound by theory, it is believed that photopolymerizable compositions with lower molecular weights have higher crosslinking densities and, therefore, slower rates of release of the therapeutic agent.

[0056] The photopolymerizable composition of the present invention typically has a viscosity between 0.1 and 7 dL / g, between 0.2 and 5 dL / g, or between 0.5 and 2 dL / g.

[0057] In embodiments, the photopolymerizable composition is present in an amount between 10% and 90% w / w, between 10% and 75% w / w, between 20% and 75% w / w, between 30% and 75% w / w, between 30% and 60% w / w, between 40% and 60% w / w.

[0058] The biodegradable polymers of the present invention may 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.

[0059] In one embodiment of the present invention, the biodegradable polymer is an aliphatic polyester-based polyurethane, polylactic acid, polycaprolactone, polyorthoester, or a mixture, copolymer or block copolymer thereof.

[0060] In another embodiment of the present invention, the biodegradable polymer is chitosan, poly(propylene fumarate), lactide / glycolide copolymers (including poly(lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), lactide / caprolactone copolymers (PLC), polyhydroxybutyrate, natural biodegradable polymers (such as collagen and hyaluronic acid), or mixtures, copolymers, or block copolymers thereof.

[0061] In another embodiment, the biodegradable polymer is selected from 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.

[0062] In one embodiment, the biodegradable polymer is a lactide / glycolide copolymer (including poly(lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), poly(DL-lactide) (PDL), and lactide / caprolactone copolymer (PLC).

[0063] In a particular embodiment, the biodegradable polymer is poly(lactide-co-glycolide) (PLGA).

[0064] PLGA is typically prepared by polymerization of lactic acid and glycolic acid monomers. The glass transition temperature (Tg) of the PLGA copolymer is above the physiological temperature of 37°C, which imparts a moderately rigid chain configuration and therefore mechanical strength at ambient temperature. The use of PLGA with different ratios of lactide (LA) to glycolide (GA) and molecular weights allows for different drug release profiles. An increase in GA content will result in increased water uptake of PLGA and therefore faster degradation. The degradation of PLGA with a 50 / 50 ratio of LA / GA is typically between one and three months. In one embodiment, the molar ratio of lactic acid to glycolic acid in 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.

[0065] In another embodiment, the biodegradable polymer is PCL, PLC, PLA, or a mixture, copolymer, or block copolymer thereof.

[0066] In embodiments, the biodegradable polymer is present in an amount between 1 and 40% w / w, between 1 and 30% w / w, between 1 and 20% w / w, between 2 and 10% w / w, and between 5 and 10% w / w.

[0067] In one embodiment of the present invention, the 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 a combination thereof.

[0068] In another embodiment, the at least one coating layer is poly(L-lactide) (PLA), poly(DL-lactide) (PDL) and lactide / caprolactone copolymers, including poly-L-lactide-co-caprolactone (PLC), or a combination thereof.

[0069] In another embodiment, the at least one coating layer is poly-L-lactide-co-caprolactone (PLC), poly(L-lactide) (PLA), or a mixture thereof.

[0070] In an embodiment, the 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.

[0071] In another embodiment, the at least one coating layer is cross-linked polyethylene glycol diacrylate (PEGDA).

[0072] 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. In another embodiment, the ocular implant is at least partially coated on its outer surface with at least three coating layers.

[0073] According to another embodiment, the ocular implant has a first portion and a second portion of an outer surface, wherein the first portion and the second portion of the outer surface are each coated with at least one coating layer, the at least one coating layer being 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; and cross-linked segments or monomers of polyalkylene glycol monoacrylates, polyalkylene glycol diacrylates, polyalkylene glycol methacrylates, and polyalkylene glycol dimethacrylates, and mixtures, copolymers, and block copolymers thereof.

[0074] In another embodiment, the ocular implant of the present invention is coated over its entire outer surface with at least one coating layer, at least two coating layers, or at least three coating layers. The number of coating layers required depends on the viscosity of the coating material solution and, therefore, on the layer thickness that such a solution can provide. The viscosity of the coating solution can be varied by, among other things, varying the polymer concentration and polymer molecular weight to optimize the release profile for each specific therapeutic agent.

[0075] In one embodiment, implant of the present invention comprises a release regulator. Suitable release regulators can be selected according to the specific therapeutic agent and composition of the implant and desired elution curve or release rate. The release regulator can be a naturally occurring medicament or polymer or a synthetic medicament or polymer.

[0076] All of the release-modifying agents 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, cosolvents, and co-initiators described herein.

[0077] The release modifier may be present in an amount between 0.1% and 40% w / w, between 1% and 30% w / w, between 1% and 20% w / w, between 1% and 10% w / w, between 5% and 10% w / w.

[0078] Optionally, a release modifier modifies the water absorption into the implant matrix, thereby controlling the release rate of the therapeutic agent and the degradation of the implant. In embodiments, suitable water absorption modifiers are one or more polysaccharides, such as, for example, chitosan and cellulose-based materials, including hydroxypropyl methylcellulose (HPMC); hyaluronic acid; poloxamers; polyethers, such as, for example, polyethylene glycol; gelatin; polyvinyl pyrrolidone; polyvinyl alcohol, and mixtures thereof. In one embodiment, suitable water absorption modifiers are hydroxypropyl methylcellulose (HPMC) and polyethylene glycol (PEG).

[0079] In one embodiment, the release modifier is a pore former. Optionally, it is lactose, maltose, glucose, mannitol, sodium chloride, magnesium carbonate, magnesium hydroxide, potassium chloride, sodium bicarbonate, ammonium bicarbonate, potassium bicarbonate, agarose or sucrose.

[0080] In another embodiment, the release modifier is a mixture of two or more of the above modifiers to provide more than one function to the ocular composition or implant of the invention. Optionally, the release modifier is polyethylene glycol, hydroxypropyl methylcellulose (HPMC) or a mixture thereof.

[0081] Optionally, the at least one coating layer may be prepared in the presence of a porosinogen in order to adjust the coating porosity and thereby influence drug release. The pore size of the coating layer prepared by this porosinogen technology depends on the size of the porosinogen.

[0082] In another embodiment of the invention, the ocular implant does not contain any release modifiers.

[0083] According to another embodiment, at least one coating layer of the implant is porous.

[0084] According to another embodiment, the at least one coating layer has a thickness between 1 and 150 μm. In another embodiment, the at least one coating layer has a thickness between 15 and 40 μm.

[0085] In another embodiment, at least one layer of the ocular implant of the present invention comprises at least some therapeutic agent. This may be the case, for example, if a second therapeutic agent must be delivered from the same ocular implant. The second therapeutic agent may be present only in the coating, while the first therapeutic agent is present only in the core of the implant, thereby generating differential release profiles for the two agents. In another embodiment, the same therapeutic agent may be present in both at least one coating layer and in the core of the implant, wherein the at least one coating layer and the core of the implant are photocrosslinked to different degrees. Thus, differential release profiles of the same therapeutic agent from the core of the implant and from the at least one coating layer are obtained.

[0086] The implants of the present invention may have any desired shape, such as, but not limited to, rectangular, square, spherical, cylindrical, circular, elliptical, membrane, dumbbell, rod, and bead.

[0087] The implants of the present invention may have any desired size and may, for example, be in the macroscopic, microscopic or nanoscopic size range.

[0088] In one embodiment of the invention, the ocular implant is an implant having a size of less than 10 mm, or less than 5 mm, or less than 3 mm. In one embodiment, the implant is a rectangular implant having a size of 10 x 5 x 0.5 mm. In one embodiment of the invention, the ocular implant is a nanoparticle or a microparticle.

[0089] 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.

[0090] In one embodiment, the microparticle 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.

[0091] In one embodiment, the ocular implant of the present invention is administered at 200 μg / μm 3 with 2000 μg / μm 3 Between 1000μg / μm 3 with 2000 μg / μm 3 Between 1200μg / μm 3 and 1800 μg / μm 3 Between 1200μg / μm 3 with 1500 μg / μm 3 Concentrations between include therapeutic agents.

[0092] Another aspect of the present invention is a method for producing an ocular implant as described above. The method comprises the following subsequent steps: a) providing the therapeutic agent; b) obtaining an ocular composition by mixing the therapeutic agent with the polymerizable composition, the biodegradable polymer, a photoinitiator, and optionally the release modifier; c) irradiating the ocular composition obtained in step b) with light having a wavelength between 200 and 550 nm for a period between 1 second and 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.

[0093] Optionally, in step b), the therapeutic agent is first mixed with the photopolymerizable composition and the mixture thus obtained is mixed with the biodegradable polymer, the 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, the photoinitiator and optionally the release modifier.

[0094] 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, cosolvents, and co-initiators described herein.

[0095] In certain embodiments, the photoinitiator is designed to operate using light from 200 to 550 nm. In some embodiments, the photoinitiator is designed to operate using UV light from 200 to 500 nm. In other embodiments, the photoinitiator is designed to operate using UV light from 200 to 425 nm.

[0096] In certain embodiments, the light source may allow for variations in light wavelength and / or light intensity.Light sources useful in the present invention include, but are not limited to, lamps and fiber optic devices.

[0097] 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 an -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.

[0098] In another embodiment, the photoinitiator can be selected from hydroxyketone photoinitiators, aminoketone photoinitiators, hydroxyketone / benzophenone photoinitiators, benzyl dimethyl ketal photoinitiators, phenylglyoxylate photoinitiators, acylphosphine oxide photoinitiators, acylphosphine oxide / α-hydroxyketone photoinitiators, benzophenone photoinitiators, ribitol-based isoalloxazine photoinitiators, peroxide photoinitiators, persulfate photoinitiators or phenylglyoxylate photoinitiators 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.

[0099] 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 pyrrolidone (NVP), eosin, dimethylaminobenzoate (DMAB), D-2959 (Sigma Aldrich, Basingstoke, UK), 907 (SigmaAldrich, Basingstoke, UK), 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 co-initiator is L-arginine.

[0100] In another embodiment, the therapeutic agent is first dissolved in a solvent to obtain a solution, and the solution thus obtained is then mixed with the polymerizable composition, the biodegradable polymer, the photoinitiator and optionally the release modifier in step b.

[0101] The choice of solvent that can be used according to the present invention depends on the polarity of the therapeutic agent.

[0102] 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.

[0103] In one embodiment, co-solvents may be used and may be selected from dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, acetic acid, methanol, ethanol, isopropanol, glycofurol or butanol.

[0104] In the case of a hydrophilic therapeutic agent, the solvent may be an aqueous-based solvent, such as water or phosphate buffered saline (PBS) solution.

[0105] According to another embodiment, the solvent may be selected from dimethyl sulfoxide, decylmethyl sulfoxide, acetonitrile, 2-pyrrolidone, 1-methyl-2-pyrrolidone, N-methyl-2-pyrrolidone and glycerol formal.

[0106] 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-modifying agent can be 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-modifying agent.

[0107] In an embodiment, the ophthalmic composition obtained in step b) is irradiated with light having a wavelength of between 200 and 500 nm, 200 and 490 nm, or 200 and 425 nm for a period of between 1 second and 60 minutes, between 30 seconds and 30 minutes, between 2.5 minutes and 20 minutes, or between 5 minutes and 10 minutes. In one embodiment, crosslinking lasts for 3 seconds, 6 seconds, 9 seconds, 15 seconds, 30 seconds, 1, 2.5, 5, 10, 20, or 30 minutes.

[0108] In another embodiment, in step d), the uncoated implant is coated with at least one coating layer over its entire outer surface.

[0109] In one embodiment, step d) of coating is performed by manual dipping, controlled dip coating, ultrasonic coating, spray coating or 3D printing.

[0110] A further aspect of the invention is an ocular implant obtainable by the above method.

[0111] In an embodiment of the present invention, a coated implant can be obtained by injecting an ocular composition comprising a therapeutic agent, a photopolymerizable composition, a biodegradable polymer, a photoinitiator, and optionally a release modifier into a preformed hollow tube of desired dimensions, the hollow tube being made of a material having at least one coating layer as described above. Thus, the coated implant of this embodiment has a surface coating but no side coatings.

[0112] In one embodiment, the polymer molecular weight, type and copolymer ratio, drug type and loading, implant size, time and extent of UV crosslinking, photoinitiator, release modifier, amount and type of solvent and / or cosolvent can be varied to control the rate and extent of drug release. Variation of these factors provides the compositions of the present invention that can be readily tailored to produce the desired drug release time period to meet specific clinical / patient needs for the treatment of various ocular diseases.

[0113] The implants of the present invention can be cross-linked prior to use in the eye to form implants of a desired shape and size (e.g., films, rods, or nano / microparticles) that can be administered intraocularly to provide the desired drug delivery time period, referred to as Pre forming Optical Intersection Prosthetic joint implant (PPcI).

[0114] The PPcI of the present invention can be inserted into the eye, for example, in the fornix, subconjunctiva, intra-anterior chamber, intrastromal / intracorneal, transscleral / periocular, intrascleral or intravitreal, subretinal, to treat diseases of the anterior or posterior portion of the eye. The PPcI can be manufactured in a variety of shapes and sizes, including but not limited to rods, films, cylinders, or circles and in the form of micro- or nanoparticles.

[0115] In one embodiment, PPcI nanoparticles and microparticles are obtained by ultrasonicating a therapeutic agent, a photopolymerizable composition, a biodegradable polymer, a photoinitiator, and optionally a mixture of a release regulator 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 ultrasound, i.e., the mixture is ultrasounded under UV light, or alternatively, irradiation can be performed after the ultrasound step.

[0116] The PPcI of the present invention has the advantages of high cross-linking density and / or compact polymer network structure, which can be configured to control drug release and / or eliminate any burst release.

[0117] The PPcI of the present invention can be manufactured to have a single layer and / or multiple layers, which will enable loading of more than one drug or the same drug with different release profiles or rates.

[0118] The PPcI of the present invention comprises a photopolymerizable polymer having a molecular weight typically between 100 and 300,000 Da, between 200 and 100,000 Da, between 200 and 50,000 Da, between 200 and 20,000 Da, or between 200 and 10,000 Da.

[0119] In one embodiment, the present invention is PLGA / PEGDA PPcI.

[0120] In one embodiment, the biodegradable polymer is substantially contained in the matrix of the photopolymerizable composition. Optionally, the biodegradable polymer is substantially contained in the matrix of the photopolymerizable composition that forms a gel after mixing. In one embodiment, the photopolymerizable polymer is cross-linked in the presence of a photoinitiator and a biodegradable polymer and one or more therapeutic agents. 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 will control the release rate and degree of one or more therapeutic agents.

[0121] In the implant of the present invention, changing the UV cross-linking time can control the rate and duration of drug release. In some embodiments, the increase in the UV cross-linking time leads to a reduction in drug release. In addition, changing the concentration of the photoinitiator can control the rate and duration of drug release. In addition, changing both the UV cross-linking time and the concentration of the photoinitiator can control the rate and duration of drug release. In one embodiment, reducing the concentration of a biodegradable polymer (such as PLGA) increases the drug release rate. In one embodiment, adding a pore former (e.g., MgCO 3 ) increases the drug release rate. In one embodiment, a higher UV cross-linking time and a higher photoinitiator concentration can cause drug release to continue for a longer period of time. In one embodiment, drug release can continue for a period of time greater than 1 day, 2 days, 1 week, 1 month, 2 months, 3 months, or 6 months.

[0122] In some embodiments, the slow degradation rate of the PPcI of the present invention provides protection for sensitive molecules such as peptides and proteins.

[0123] In one embodiment, the present invention is a PPcI with a high cross-link density that significantly slows drug diffusion.

[0124] Any of the implants and compositions described herein are suitable for use with any of the methods of the invention described herein.

[0125] In one embodiment, the invention is a method of treating a disease or disorder of the eye of a subject in need thereof, the method comprising administering to the ocular region of the subject a composition or implant of the invention.

[0126] In one embodiment, the invention is a composition or implant of the invention for use in treating a disease or disorder of the eye of a subject in need thereof.

[0127] As used herein, an "ocular area" is an area within, outside, or near a subject's eye. In one embodiment, the ocular area is the sclera (intrasclera), extrasclera (transsclera), vitreous body, choroid, cornea, stroma, anterior chamber, aqueous humor, lens, fornix, or optic nerve.

[0128] In one embodiment, the compositions and implants can be administered by injection, including intravitreal, subconjunctival, peribulbar, subtenon, or retrobulbar injection and corneal.

[0129] In some embodiments, the implant is administered via a surgical procedure. In some embodiments, following surgical implantation, the implant is secured in place via an adhesive or sutures.

[0130] The term "subject" refers to an animal (e.g., a bird, such as a chicken, quail, or turkey, or a mammal), particularly a "mammal," including non-primates (e.g., cattle, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (e.g., monkeys, chimpanzees, and humans), and more particularly humans. In one embodiment, the subject is a non-human animal, such as livestock (e.g., horses, cattle, pigs, or sheep) or a pet (e.g., dogs, cats, guinea pigs, or rabbits). In another embodiment, the subject is a "human."

[0131] As used herein, the terms "treat," "treatment," and "treating" refer to therapeutic treatment, including a reduction or improvement in the progression, severity, and / or duration of a disease, disorder, or condition, or an improvement in one or more symptoms (particularly, one or more discernible symptoms) of a disease, disorder, or condition resulting from the administration of a composition or implant of the invention. In specific embodiments, the therapeutic treatment includes improvement in at least one measurable physical parameter of the disease, disorder, or condition. In other embodiments, the therapeutic treatment includes inhibiting the progression of the condition physically, for example, by stabilizing a discernible symptom, physiologically, for example, by stabilizing a physical parameter, or both. In other embodiments, the therapeutic treatment includes alleviating or stabilizing the disease, disorder, or condition.

[0132] In one embodiment, the disease or disorder is pain, inflammation, cataracts, 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, blepharoconjunctivitis, ocular hypertension, conjunctivitis, cystinosis, vitreomacular adhesion, corneal neovascularization, corneal ulcer, and post-operative ocular inflammation / wound healing.

[0133] The following list of numbered items are embodiments included in the present invention:

[0134] 1. An ocular implant comprising:

[0135] a) at least 0.1% w / w of a therapeutic agent;

[0136] b) 5% to 95% w / w of a cross-linked polymer matrix;

[0137] and 0.1% to 40% w / w of a biodegradable polymer selected from lactide / glycolide copolymers (including poly(lactide-co-glycolide)

[0138] (PLGA)); poly(L-lactide) (PLA); polyhydroxyalkanoates, including polyhydroxybutyrate; polyglycolic acid (PGA), polycaprolactone (PCL), poly(DL-

[0139] Lactide) (PDL), poly (D-lactide), lactide / caprolactone copolymer, poly-L-

[0140] Lactide-co-caprolactone (PLC) and its mixtures, copolymers, and block copolymers;

[0141] wherein the cross-linked polymer matrix is ​​obtained by cross-linking a photopolymerizable composition selected from segments or monomers of polyalkylene glycol monoacrylates, polyalkylene glycol diacrylates, polyalkylene glycol monomethacrylates and polyalkylene glycol dimethacrylates, and mixtures, copolymers, and block copolymers thereof,

[0142] The ocular implant is characterized in that the ocular implant is at least partially coated on its outer surface with at least one coating layer, wherein the coating layer 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); lactide / caprolactone copolymers; poly(DL-lactide) (PDL); poly(D-lactide); poly-L-lactide-co-caprolactone (PLC) and mixtures, copolymers, and block copolymers thereof; and cross-linked segments or monomers of polyalkylene glycol monoacrylates, polyalkylene glycol diacrylates, polyalkylene glycol methacrylates, and polyalkylene glycol dimethacrylates, and mixtures, copolymers, and block copolymers thereof.

[0143] 2. The ocular implant of embodiment 1 or 2, wherein the therapeutic agent is present in an amount of 0.5% to 70%

[0144] The amount exists between w / w.

[0145] 3. The ocular implant of embodiment 2, wherein the therapeutic agent is present in an amount between 10% and 50% w / w.

[0146] 4. The ocular implant according to any preceding embodiment, wherein the therapeutic agent is present in an amount between 20% and 50% w / w.

[0147] 5. The ocular implant according to any preceding embodiment, wherein the photopolymerizable composition is selected from the group consisting of fragments or monomers of polyalkylene glycol diacrylates, polyalkylene glycol dimethacrylates, and mixtures, copolymers, and block copolymers thereof.

[0148] 6. The ocular implant of any preceding embodiment, 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.

[0149] 7. The ocular implant of embodiment 6, wherein the photopolymerizable composition is polyethylene glycol diacrylate (PEGDA).

[0150] 8. The ocular implant according to any preceding embodiment, wherein the biodegradable polymer is present in an amount between 1% and 30% w / w.

[0151] 9. The ocular implant of any preceding embodiment, wherein the biodegradable polymer is a lactide / glycolide copolymer (including poly(lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), poly(DL-lactide) (PDL), and lactide / caprolactone copolymer (PLC).

[0152] 10. The ocular implant of embodiment 9, wherein the biodegradable polymer is a lactide / glycolide copolymer, including poly(lactide-co-glycolide) (PLGA).

[0153] 11. The ocular implant of any preceding embodiment, 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.

[0154] 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.

[0155] 13. The ocular implant of any one of embodiments 1 to 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.

[0156] 14. The ocular implant of embodiment 13, wherein the at least one coating layer is cross-linked polyethylene glycol diacrylate (PEGDA).

[0157] 15. The ocular implant according to any preceding embodiment, wherein it is at least partially coated on its outer surface with at least two coating layers.

[0158] 16. The ocular implant according to any preceding embodiment, wherein it is at least partially coated on its outer surface with at least three coating layers.

[0159] 17. The ocular implant according to any preceding embodiment, wherein the implant is coated with at least one coating layer over its entire outer surface.

[0160] 18. The ocular implant of embodiment 17, wherein the implant is coated with at least three coating layers over its entire outer surface.

[0161] 19. The ocular implant of any preceding embodiment, comprising a first portion and a second portion of an outer surface, wherein the first portion and the second portion of the outer surface are each coated with at least one coating layer independently selected from lactide / glycolide copolymers (including poly(lactide-co-glycolide) (PLGA)); poly(L-lactide);

[0162] (PLA); polyhydroxyalkanoates, including polyhydroxybutyrate; polyglycolic acid (PGA);

[0163] 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 segments or monomers of polyalkylene glycol monoacrylates, polyalkylene glycol diacrylates, polyalkylene glycol methacrylates, and polyalkylene glycol dimethacrylates, and mixtures, copolymers, and block copolymers thereof.

[0164] 20. The ocular implant of any preceding embodiment, further comprising a release modifier.

[0165] 21. The ocular implant of embodiment 20, wherein the release modifier 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.

[0166] 22. The ocular implant of embodiment 21, wherein the release modifier is polyethylene glycol, hydroxypropyl methylcellulose (HPMC), or a mixture thereof.

[0167] 23. The ocular implant of any one of embodiments 1 to 19, wherein the composition does not contain any release modifier.

[0168] 24. The ocular implant according to any preceding embodiment, wherein the at least one coating layer is porous.

[0169] 25. The ocular implant according to any preceding embodiment, wherein the at least one coating layer has a thickness between 1 and 150 μm.

[0170] 26. The ocular implant of any preceding embodiment, wherein the at least one coating layer further comprises the therapeutic agent component or an additional therapeutic agent component.

[0171] 27. The ocular implant according to any preceding embodiment, which is a macro-, micro- or nanoparticle.

[0172] 28. The ocular implant of any preceding embodiment, wherein the therapeutic agent is administered at 200 μg / μm 3 with 2000 μg / μm 3 concentrations present in ocular implants.

[0173] 29. A method of manufacturing the ocular implant according to any one of embodiments 1 to 28, the method comprising the steps of:

[0174] a) providing the therapeutic agent;

[0175] b) obtaining an ophthalmic composition by mixing the therapeutic agent with the polymerizable composition, the biodegradable polymer, a photoinitiator, and optionally the release modifier;

[0176] c) irradiating the ocular composition obtained in step b) with light having a wavelength between 200 and 550 nm for a period of time between 1 second and 60 minutes to form an uncoated ocular implant;

[0177] d) coating at least a portion of the uncoated outer surface of the ocular implant with at least one coating layer.

[0178] 30. The method according to embodiment 29, wherein the therapeutic agent is first dissolved in a solvent to obtain a solution, and then the solution thus obtained is mixed with the polymerizable composition, the biodegradable polymer, the photoinitiator and optionally the release modifier.

[0179] 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 / α-hydroxyketone photoinitiator, a benzophenone photoinitiator, a ribitol-based isoalloxazine photoinitiator, or a phenylglyoxylate photoinitiator, or any combination thereof.

[0180] 32. The method according to embodiment 31, wherein the photoinitiator is 1-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propanone, 2,2-dimethoxy-2-phenylacetophenone (DMPA)

[0181] or 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl-1-propanone (Irgacure 2959) or riboflavin.

[0182] 33. The method according to any one of embodiments 29 to 32, wherein in step d) the uncoated ocular implant is coated with at least one coating layer over its entire outer surface.

[0183] 34. The method according to any one of embodiments 29 to 33, wherein step d) of coating is performed by manual dipping, controlled dip coating, ultrasonic coating, spray coating or 3D printing.

[0184] 35. A method of manufacturing an ocular implant according to any one of embodiments 1 to 28, the method comprising the steps of:

[0185] a) providing the therapeutic agent;

[0186] b) obtaining an ophthalmic composition by mixing the therapeutic agent with the polymerizable composition, the biodegradable polymer, a photoinitiator, and optionally the release modifier;

[0187] c) injecting the ocular composition obtained in step b) into the preformed hollow coating layer;

[0188] d) irradiating the ophthalmic composition within the hollow coating layer with light having a wavelength between 200 and 550 nm for a period of time between 1 second and 60 minutes.

[0189] 36. The method of embodiment 35, wherein the hollow coating layer is a hollow tube.

[0190] However, the following examples are intended to illustrate the present invention and should not be construed as limiting the scope of the present invention.

[0191] Example

[0192] Example 1. With or without Poly(L-glycolide) PLA-coated dexamethasone (DEX) and timolol maleate (TM)

[0193] 1.1. Materials

[0194] 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) ( PDLG 5002, 50:50, PLGA 50 / 50), poly (lactide-co-glycolide) ( PDLG7502, 75:25, PLGA75 / 25) and poly (L-lactide) ( PL 65, PLA) was obtained from Purac Biochem (Gorinchem, The Netherlands) and timolol maleate was obtained from Gangwal Chemicals Pvt Ltd (Maharashtra, India).

[0195] 1.2. Preparation of rod-shaped implants of DEX (DEX 10% w / w, PLGA 20% w / w, PEGDA 700 70% w / w) Preparation

[0196] PEGDA700 (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 a silicone tube and irradiated using a light hammer. 6, Heraeus Noblelight Fusion UV Inc., Gaithersburg, Maryland, USA) for photocrosslinking. The UV light intensity was set to 100% and the silicone tubing was exposed to UV light for 30 seconds (10 runs, 5 runs per side). The rod-shaped implant was then removed from the tube. To prepare the coated implant, the uncoated implant was immersed in a PLA solution (2.5% PLA in dichloromethane) for 3 seconds and then left to dry in a fume hood for 48 hours.

[0197] 1.3. Rod implantation for TM (TM 10% w / w, PLGA 75 / 25 20% w / w, PEGDA 250 70% w / w) Preparation of

[0198] 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 a 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 a silicone tube and quenched using a light hammer. Photocrosslinking was performed using a UV light microscope (Heraeus Noblelight Fusion UV Inc., Gaithersburg, MD, USA). The UV light intensity was set to 100% and the silicone tubing was exposed to UV light for 30 seconds (10 runs). The rod-shaped implant was then removed from the tube. To prepare the coated implant, the uncoated implant was immersed in a PLA solution (2.5% PLA in dichloromethane) for 3 seconds and then left to dry in a fume hood for 48 hours.

[0199] 1.4. Determination of DEX using high performance liquid chromatography (HPLC)

[0200] DEX was determined by reverse phase HPLC. The HPLC instrument consisted of an Agilent 1260 Infinity pump, a UV-VIS detector, and a Chromato-Integrator (Agilent Technologies, Germany), and the pump was equipped with a sample injection port equipped with a 20 μl sample loop. 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. The chromatographic separation of DEX was achieved using a Poroshell 120EC-C18 4 μm (250 × 4.60 mm) analytical column equipped with a refillable guard column at ambient room temperature (24°C ± 2°C). The mobile phase was filtered through a 0.45 μm membrane filter (Whatman International, UK) under vacuum and degassed before use.

[0201] 1.5. Determination of TM using high performance liquid chromatography (HPLC)

[0202] The TM content was determined by reverse phase HPLC. The HPLC instrument consisted of an Agilent 1260 Infinity pump, a UV-VIS detector, and a Chromato-Integrator (Agilent Technologies, Germany). The pump was equipped with a sample injection port equipped with a 20 μl sample loop. 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. The chromatographic separation of TM was achieved at ambient room temperature (24°C ± 2°C) using a Poroshell 120EC-C18 4 μm (250 × 4.60 mm) analytical column equipped with a refillable guard column. The mobile phase was filtered through a 0.45 μm membrane filter (Whatman International, UK) under vacuum and degassed before use.

[0203] In vitro drug release studies

[0204] The implant (4 mg, diameter 0.635 mm, length 10 mm) loaded with the drug was immersed in 20 mL PBS (pH = 7.4) and maintained in a horizontal shaking incubator at 37 ° C and 40 rpm. Regularly (24, 48, 72 h, etc.) the drug release supernatant (1.7 mL) was collected and replaced with fresh culture medium. The drug content in the aliquot was determined by HPLC. All release experiments were performed in 3 times, and all data were the mean values ​​determined three times.

[0205] Table 1 summarizes the parameters for implants DEX 1, DEX 2, TM 1, and TM 2.

[0206]

[0207] The surface morphology of the implants was characterized by SEM. Figure 1 As shown in the figure, DEX 2 has a slightly rough surface, while DEX 1 appears to have a smooth surface. The diameter of the rod-shaped implant is approximately 0.635 mm. The thickness of the coating is approximately 0.029 mm, or 29 μm.

[0208] As from Figure 2 and 3 As can be seen, the comparative implants DEX 1 and TM 1 showed a considerable burst release on day 1. This effect was greatly suppressed in DEX 2 and TM 2. The implants according to the present invention can provide a sustained release of a therapeutic agent over an extended period of time.

[0209] Example 2. Poly(L-lactide-co-caprolactone) (PLC) and poly(DL-lactide) (PDL) coatings Fluorescein isothiocyanate (FITC)-dextran implants

[0210]

[0211] Preparation of D1

[0212] 10 mg of PLGA 75 / 25 (Purac Biochem, Gorinchem, The Netherlands) was dissolved in 190 mg of PEGDA (Sigma Aldrich, Basingstoke, UK) with a molecular weight (MW) of 700 Da to prepare Solution A 5 mg of Irgacure 2559 (Sigma Aldrich, Basingstoke, UK) was dissolved in 1 ml of PBS to prepare Solution B 10 mg of FITC-dextran (average MW 4000 Da, Sigma Aldrich, Basingstoke, UK) was dissolved in 60 μl of solution B in an Eppendorf tube to prepare Solution C 85mg of Solution A 60 μl of the ethanol was weighed in an empty Eppendorf tube and stirred at 900 rpm for 15 minutes. Solution C The mixture was slowly added to the mixture through the wall of the Eppendorf tube. The final mixture was withdrawn into a silicon tube with an ID of 0.635 mm (Polymer System Technology, UK) and the mixture was dried using UV light (Light Crosslinking was performed using a UV light analyzer (Heraeus Noblelight Fusion UV Inc., Gaithersburg, MD, USA). The UV light intensity was set to 50% and the silicone tubing was exposed to UV light for 15 seconds (i.e., a total of 5 runs). The implants were then removed from the silicone tubing and dried under vacuum at 25°C for 4 hours. The rod-shaped implants were cut into 7.5 mm lengths.

[0213] 2.2. Preparation of CD1 (coated with PLC)

[0214] Implants CD1 were manufactured according to section 2.1 (except the last sentence) as described above. They were cut into 20 mm lengths 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 analyzer (TA-XT plus; Stable Micro Systems, USA). The implants were immersed 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 coating layer was applied at a thickness of approximately 20-25 μm. The implants were then cut into 7.5 mm lengths and the sides of these surface-coated implants were coated with a 15% w / v solution of poly-DL-lactide (PDL) in acetonitrile (ACN) using a 29G needle syringe under a digital microscope.

[0215] 2.3 In vitro drug release setup

[0216] Two D1 implants and two CD1 implants (7.5 mm length) 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 the release medium. All experiments were performed in triplicate. The glass vials containing the implants were placed in an orbital incubator (GFL orbital shaking incubator; Gesellschaft für Labortechnik mbH, Germany) with a speed of 40 rpm and shaking at 37 ° C. Samples were taken on the 1st day and thereafter weekly (i.e., the 7th, 14th, 21st, 28th day, etc.), and the PBS culture medium was then completely replaced. The concentration of the drug molecules released in the PBS samples was analyzed as described in the following section. The vials were then incubated at 37 ° C, and the entire culture medium was removed at predetermined time intervals and replaced with fresh culture medium.

[0217] 2.4 Sample analysis

[0218] The FITC-dextran in vitro drug release samples were analyzed using a fluorescence spectrophotometric method. Detection was performed using a micro-96 well plate spectrophotometer (BMG Labtech FLUOstar Optima fluorescence plate reader (BMG Labtech GmbH, Ortenberg, Germany). Excitation was set to 485 nm, emission was set to 520 nm, and gain was set to 750.

[0219] Figure 4 The in vitro release of D1 and CD1 is shown, expressed as percentage cumulative release. As can be seen from this figure, 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 time period.

[0220] Example 3 - Different diameter sizes with or without poly-L-lactide-co-caprolactone (PLC) coating Latanoprost (LP) implant.

[0221]

[0222]

[0223] Preparation of LP1 and LP2

[0224] 20 mg of Irgacure 2959 (Sigma Aldrich, Basingstoke, UK) was dissolved in acetonitrile to prepare Solution A 50 mg of latanoprost (LP) (Alfa Chemistry, New York, USA) was dissolved in 2.5 mL of acetonitrile to prepare dissolve Liquid B75 mg of PEGDA 250 and 15 mg of PLGA 75 / 25 (Purac Biochem, Gorinchem, The Netherlands) were placed in a 2 mL Eppendorf tube and dissolved in 250 μL of acetonitrile to prepare Solution C .

[0225] Then 37.5 μL of Solution A and 1 mL Solution B Add to Solution C and then stirred at 250 rpm for 30 minutes (Multistirrer, Velp Scientifica TM , Italy). Acetonitrile was then evaporated at room temperature at a gauge pressure of -0.1 MPa for 6 h (OV-12 vacuum oven; JeioTech, Korea). The resulting mixture was withdrawn into a silicon tube (0.32 or 0.63 mm inner diameter) using a 25G needle attached to a 10 mL syringe. Standard Silicone Tubing (Freudenberg, Germany) was used. Photocrosslinking was performed under a UV D-lamp (Light Hammer 6; Heraeus Noblelight Fusion UV, USA) at a belt speed of 11.5 m / min for 10 cycles at 100% intensity. The cured rod-shaped implants were removed from the silicone tubing and cut into 2 mm lengths. The implants weighed approximately 0.2 mg (for 0.3 mm diameter, LP1) and 0.9 mg (for 0.6 mm diameter, LP2).

[0226] 3.2 Preparation of LPC1 and LPC2 (LP1 and LP2 coated with PLC)

[0227] Implants LP1 and LP2 were coated by an automated dip coating method to obtain LPC1 and LPC2, respectively. A single coating layer was applied at a thickness of approximately 20-25 μm. They were coated on the surface 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 analyzer, 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.

[0228] 3.3 In vitro drug release setup

[0229] 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 an orbital incubator (GFL orbital shaking incubator; Gesellschaft für Labortechnik mbH, Germany) with shaking at 40 rpm and 37 ° C. Samples were taken on the 1st, 3rd, 7th day and weekly thereafter, and the PBS medium was completely replaced. The concentration of the released drug was analyzed using an HPLC method developed for latanoprost.

[0230] 3.4 Sample analysis

[0231] LP1, LP2, LPC1, and LPC2 samples were analyzed using an Agilent 1260 Infinity II Quaternary System (Agilent 1260 Infinity II Quaternary System) with fluorescence detection using a Poroshell 120 EC-C18 column (250 mm length, 4.6 mm internal diameter, and 4 μm particle size). Samples were analyzed in isocratic mode using a mobile phase of acetonitrile:0.1% v / v formic acid (60:40) with 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.

[0232] Figure 5 The in vitro release of LP1, LP2, LPC1 and LPC2 is shown, expressed as cumulative percentages. As can be seen from the figure, 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 time period.

[0233] Example 4 - Latanoprost (LP) Implants with One or More Poly-L-lactide-co-caprolactone (PLC) Layers The role of the material-layer.

[0234]

[0235] Preparation of LP3

[0236] LPC3 implants were prepared from LP1 implants using the coating method described in Section 3.2, whereby a 2-layer PLC coating was achieved by repeating the automated dip coating a second time on the dried LPC1 implants. 4.2 In vitro drug release setup and Sample analysis

[0237] Each LPC1 and LPC3 implant, 2 mm long and weighing approximately 0.2 mg, was 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 an orbital incubator (GFL orbital shaking incubator; Gesellschaft für Labortechnik mbH, Germany) with shaking at 40 rpm and at 37 ° C. Samples were taken on the 1st, 3rd, 7th day, and weekly thereafter, and the PBS medium was completely replaced. The concentration of the released drug was analyzed using an HPLC method developed for latanoprost.

[0238] Figure 6 The in vitro release of LPC1 and LPC3 is shown, expressed as cumulative percentages. As can be seen from the figure, the additional coating polymer layer on the implant matrix further reduces the burst effect and controls the overall release of latanoprost over the entire time period.

[0239] Example 5 - Latanoprotease coated with poly-L-lactide-co-caprolactone (PLC) and poly(L-lactide) (PLA) layers Columnar phospholipid (LP) implants - the role of the composition of the coating material.

[0240]

[0241] Preparation of LPC4

[0242] LPC4 implants were prepared by coating LP1 implants by an automated dip coating method. LPC4 implants were coated on the surface with a 2.5% w / v solution of poly(L-lactide) (PLA) polymer solution in dichloromethane (DCM) using a texture analyzer 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.

[0243] 5.2 In vitro drug release setup and sample analysis

[0244] LPC1 and LPC4 implants, 2 mm long and weighing approximately 0.2 mg, 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 an orbital incubator (GFL orbital shaking incubator; Gesellschaft für Labortechnik mbH, Germany) with shaking at 40 rpm and at 37 ° C. Samples were taken on the 1st, 3rd, 7th day, and weekly thereafter, and the PBS medium was completely replaced. The concentration of the released drug was analyzed using an HPLC method developed for latanoprost.

[0245] Figure 4 The in vitro release of LPC1 and LPC4 is shown, expressed as cumulative percentages. As can be seen from the figures, both coating polymer materials reduce the burst effect (compared to LPI) and control the overall release of latanoprost over the entire time period.

[0246] Example 6 - Highly loaded latanoprost (LP) implants with or without PLC coating.

[0247]

[0248] Preparation of LP40

[0249] 20 mg of Irgacure 2959 (Sigma Aldrich, Basingstoke, UK) was dissolved in acetonitrile to prepare Solution A 50 mg of latanoprost (LP) (Alfa Chemistry, New York, USA) was dissolved in 2.5 mL of acetonitrile to prepare dissolve Liquid B 29 mg of PEGDA 250 and 1 mg of PLGA 75 / 25 (Purac Biochem, Gorinchem, The Netherlands) were placed in a 2 mL Eppendorf tube and dissolved in 250 μL of acetonitrile to prepare Solution C .

[0250] Then 14.5 μL of Solution A and 1000 μL Solution B Add to Solution C and then stirred at 250 rpm for 30 minutes (Multistirrer, Velp Scientifica TM, Italy). Acetonitrile was then evaporated at room temperature at a gauge pressure of -0.1 MPa for 6 h (OV-12 vacuum oven; JeioTech, Korea). The resulting mixture was withdrawn into a 0.32 mm inner diameter silicon tube ( Standard Silicone Tubing (Freudenberg, Germany) was used. Photocrosslinking was performed under a UV D-lamp (Light Hammer 6; Heraeus Noblelight Fusion UV, USA) at a belt speed of 11.5 m / min for five runs at 50% intensity. The cured rod-shaped implants were removed from the silicone tubing and cut into 2 mm lengths. The implants weighed approximately 0.2 mg.

[0251] 6.2 Preparation of LPC40

[0252] Implants LP40 were coated by an automated dip coating process to obtain LPC40. A single coating layer was applied at a thickness of approximately 20-25 μm. They were coated on the surface 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 analyzer, 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.

[0253] 6.3 In vitro drug release setup and sample analysis

[0254] LP40 and LPC40 implants, 2 mm long and weighing approximately 0.2 mg, 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 an orbital incubator (GFL orbital shaking incubator; Gesellschaft für Labortechnik mbH, Germany) with shaking at 40 rpm and at 37 ° C. Samples were taken on the 1st, 3rd, 7th day, and weekly thereafter, and the PBS medium was completely replaced. The concentration of the released drug was analyzed using the HPLC method developed for latanoprost.

[0255] Figure 8The in vitro release of LP40 and LPC40 is shown, expressed as cumulative release percentage. As can be seen from this figure, compared with the uncoated implant, the coating on the implant surface significantly reduced the initial burst effect and maintained release over a longer period of time. The coated LPC40 implant maintained a near zero-order release for 180 days (6 months), while the uncoated LP40 implant could achieve sustained release for 20 days.

Claims

1. An ocular implant comprising: a) at least 0.1% w / w of a therapeutic agent; b) 5% to 95% w / w of a cross-linked polymer matrix; c) and 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 cross-linked polymer matrix is ​​obtained by cross-linking a photopolymerizable composition selected from the group consisting of fragments or monomers of polyalkylene glycol monoacrylates, polyalkylene glycol diacrylates, polyalkylene glycol monomethacrylates and polyalkylene glycol dimethacrylates, and mixtures, copolymers, and block copolymers thereof, The ocular implant is characterized in that the ocular implant is at least partially coated on its outer surface with at least one coating layer, wherein the coating layer 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); lactide / caprolactone copolymers; poly(DL-lactide) (PDL); poly(D-lactide); poly-L-lactide-co-caprolactone (PLC) and mixtures, copolymers, and block copolymers thereof; and cross-linked segments or monomers of polyalkylene glycol monoacrylates, polyalkylene glycol diacrylates, polyalkylene glycol methacrylates, and polyalkylene glycol dimethacrylates, and mixtures, copolymers, and block copolymers thereof.

2. The ocular implant of claim 1, wherein the therapeutic agent is present in an amount between 0.5% and 70% w / w.

3. The ocular implant of claim 2, wherein the therapeutic agent is present in an amount between 10% and 50% w / w.

4. The ocular implant of any preceding claim, 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.

5. The ocular implant of claim 4, wherein the photopolymerizable composition is polyethylene glycol diacrylate (PEGDA).

6. An ocular implant according to any preceding claim, wherein the biodegradable polymer is present in an amount between 1% and 30% (w / w).

7. The ocular implant of any preceding claim, wherein the biodegradable polymer is a lactide / glycolide copolymer, including poly(lactide-co-glycolide) (PLGA).

8. The ocular implant of any preceding claim, 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.

9. The ocular implant of claim 8, wherein the at least one coating layer is poly-L-lactide-co-caprolactone (PLC), poly(L-lactide) (PLA), or a mixture thereof.

10. An ocular implant according to any preceding claim, wherein the implant is coated with at least one coating layer over its entire outer surface.

11. The ocular implant of any preceding claim, having a first portion and a second portion of an outer surface, wherein the first portion and the second portion 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; and cross-linked segments or monomers of polyalkylene glycol monoacrylates, polyalkylene glycol diacrylates, polyalkylene glycol methacrylates, and polyalkylene glycol dimethacrylates, and mixtures, copolymers, and block copolymers thereof.

12. The ocular implant according to any preceding claim, further comprising a release modifier, preferably selected from the group consisting of polyethylene glycol, hydroxypropyl methylcellulose (HPMC), maltose, glucose, agarose, mannitol, gelatin, sodium chloride, magnesium carbonate, magnesium hydroxide, potassium chloride, sodium bicarbonate, potassium bicarbonate and sucrose.

13. An ocular implant according to any preceding claim, wherein the at least one coating layer is porous.

14. A method of manufacturing an ocular implant according to any one of claims 1 to 13, the method comprising the steps of: a) providing the therapeutic agent; b) obtaining an ophthalmic composition by mixing the therapeutic agent with the polymerizable composition, the biodegradable polymer, a photoinitiator, and optionally the release modifier; c) irradiating the ocular composition obtained in step b) with light having a wavelength between 200 and 550 nm for a period of time between 1 second and 60 minutes to form an uncoated ocular implant; d) coating at least a portion of the uncoated outer surface of the ocular implant with at least one coating layer.

15. A method of manufacturing an ocular implant according to any one of claims 1 to 13, the method comprising the steps of: a) providing the therapeutic agent; b) obtaining an ophthalmic composition by mixing the therapeutic agent with the polymerizable composition, the biodegradable polymer, a photoinitiator, and optionally the release modifier; c) injecting the ocular composition obtained in step b) into the preformed hollow coating layer d) irradiating the ophthalmic composition within the hollow coating layer with light having a wavelength between 200 and 550 nm for a period of time between 1 second and 60 minutes.

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