Biodegradable compositions and implants

Abstract

The present invention relates to an ophthalmic composition comprising a) at least 0.1 % w / w of a therapeutic agent; b) 5-95 % w / w of a photopolymerizable composition comprising 3-70 % w / w of one or more compounds of formula I: wherein R1 is hydrogen or a linear or branched C1-C3 alkyl group; R2 is an acrylate or methacrylate group; n is 2 or 3 and m is equal to or greater than 1, the weight percentage of one or more compounds of formula I being based on the total weight of the photopolymerizable composition; c) 0.1-40 % w / w of a biodegradable polymer selected from the group consisting of poly(lactide-co-glycolide), poly(L-lactide), polyhydroxyalkanoate, polyglycolic acid, polycaprolactone, poly(DL-lactide), poly(D-lactide), poly(lactide-co-caprolactone), poly-L-lactide-co-caprolactone and mixtures thereof, copolymers; d) a photoinitiator.

Description

TECHNICAL FIELD

[0001] The present invention relates to biodegradable compositions and implants for the controlled release of therapeutic agents. More particularly, the present invention relates to biodegradable ophthalmic compositions and implants for the controlled release of therapeutic agents in the eye. BACKGROUND

[0002] Chronic retinal diseases are the leading cause of vision impairment and blindness worldwide. The loss of vision has a major impact on people’s daily lives and has far-reaching economic implications for individuals, families, public health, and society. The World Health Organization estimates that approximately 285 million people worldwide are visually impaired, of which 39 million are blind, and 246 million have poor vision. Diseases originating in the posterior segment (PS) or posterior of the eye, if not treated promptly, lead to permanent loss of vision and cause most of the blindness, such as 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, which includes the retina, choroid, and vitreous, is very difficult to access due to its recessed position within the orbit. Therefore, the delivery of therapeutic agents to the PS of the eye remains one of the most challenging tasks for pharmaceutical scientists and retinal specialists.

[0003] Various approaches have been used to deliver therapeutic agents to the PS of the eye, such as systemic, topical, periocular (or transscleral), and intravitreal approaches. Due to multiple ocular barriers, topical (e.g., eye drops) and systemic (e.g., oral tablets) routes result in low or non-attainment of therapeutic agent levels, requiring the administration of unnecessarily high concentrations of therapeutic agents, which can lead to therapeutic agent-related toxicity and produce low therapeutic efficacy.

[0004] WO2017081154A1 discloses ophthalmic compositions that can be administered to the eye in various forms to achieve the controlled release of therapeutic agents. These compositions can be used to form ophthalmic implants by crosslinking in situ after injection of the formulation into the patient’s eye or can be pre-formed before injection into the eye.

[0005] There is a need for alternative systems for ocular delivery of therapeutic agents. SUMMARY

[0006] In a first aspect, the present invention relates to an ophthalmic composition that can be administered to the eye in various forms to achieve the controlled release of therapeutic agents. Such ophthalmic compositions include:

[0007] a) at least 0.1% w / w of a therapeutic agent;

[0008] b) 5-95% w / w of a photopolymerizable composition comprising 3-70% w / w of one or more compounds of Formula I:

[0009]

[0010] wherein R1 is hydrogen or a linear or branched C1-C3 alkyl group; R2 is an acrylate or methacrylate group; n is 2 or 3 and m is equal to or greater than 1, the weight percentage of the compound(s) of formula I being based on the total weight of the photopolymerizable composition.

[0011] c) 0.1-40% w / w of a biodegradable polymer selected from the group consisting of poly(lactide-co-glycolide) (including poly(lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), polyhydroxyalkanoate (including polyhydroxybutyrate), polyglycolic acid (PGA), polycaprolactone (PCL), poly(DL-lactide) (PDL), poly(D-lactide), poly(lactide-co-caprolactone), poly-L-lactide-co-caprolactone (PLC), and mixtures, copolymers and block copolymers thereof, and

[0012] d) a photoinitiator.

[0013] In another aspect, the present application relates to the above-mentioned ophthalmic composition for use in the manufacture of an ophthalmic implant.

[0014] In another aspect, the present application relates to a method of manufacturing the above-mentioned ophthalmic composition, an implant based on the above-mentioned ophthalmic composition, and an ophthalmic implant obtainable by such a method.

[0015] In another aspect, the present application relates to an ophthalmic implant comprising at least 0.1% w / w of a therapeutic agent, 5-95% w / w of a crosslinked polymeric matrix and 0.1-40% w / w of a biodegradable polymer as defined above, characterized in that the crosslinked polymeric matrix is obtained by crosslinking a photopolymerizable composition as defined above.

[0016] The present application provides ophthalmic compositions and implants that can be administered to the eye in various forms to achieve controlled release of therapeutic agents. The present application allows for the flexible administration of a range of small and large therapeutic molecules, including proteins, peptides and gene therapy agents, and to maintain their activity over a controlled period of time.

[0017] The presence of one or more compounds of formula I in the photopolymerizable composition enables the optimization of the delivery and complete degradation of the implant after the release of the therapeutic compound has ceased.

[0018] The degradation of the implant according to the present application takes place together with the release of the drug. The complete degradation of the exhausted implant also enables the injection of additional implants in the case where the treatment must be continued. Even if the organ can accommodate more than one implant at the same time, the coexistence time of the new and old implants should be reduced as much as possible in any case.

[0019] The compositions and implants of the present application show a delivery profile that can release a therapeutically effective amount of a drug over an extended period of time, while degrading completely after the drug release is completed.

[0020] Furthermore, the implants according to the present application maintain their physical structure during degradation, and thus do not disintegrate into a plurality of particles that would, inter alia, cause a series of undesirable mini-burst effects within the organ. Formation of particulate debris with the potential to clog the trabecular meshwork in the anterior and / or posterior segment of the eye is thus avoided, and proper drainage of aqueous humor from the eye is maintained. BRIEF DESCRIPTION OF DRAWINGS

[0021] Figure 1 shows the in vitro accelerated degradation profile of the O1, O2, O3 and O4 implants in 10 mM NaOH at 37°C at a shaking speed of 40 rpm.

[0022] Figure 2 shows the daily OVA release (pg) profile (Y1 axis) versus % implant weight (Y2 axis) for each implant of the O1, O2, O3 and O4 implants in PBS (pH 7.4) at 37°C and a shaking speed of 40 rpm.

[0023] Figure 3 shows scanning electron microscope (SEM) images of the morphological changes during degradation in ambient conditions of the compositions O1 and O4 implants in 10 mM PBS (pH 7.4) at 37°C and a shaking speed of 40 rpm.

[0024] Figure 4 shows the in vitro accelerated degradation profile of the OV1, OV2, OV3 and OV4 in 10 mM NaOH at 37°C at a shaking speed of 40 rpm.

[0025] Figure 5 shows the in vitro accelerated degradation profile of the OV2 and OV6 in 10 mM NaOH at 37°C at a shaking speed of 40 rpm.

[0026] Figure 6 shows the daily OVA release (pg) profile (Y1 axis) versus % implant weight (Y2 axis) for each implant of the OV1, OV2, OV3, OV4 and OV6 implants in PBS (pH 7.4) at 37°C and a shaking speed of 40 rpm.

[0027] Figure 7 shows the accelerated degradation profile of the DEX1, DEX2 and DEX3 implants in 50 mM NaOH at 37°C and a shaking speed of 40 rpm.

[0028] Figure 8 A plot showing the daily DEX release (pg) per implant (Yl axis) versus % implant weight (Y2 axis) for DEX1, DEX2, and DEX3 implants in PBS (pH 7.4) at 37°C and a shaking speed of 40 rpm.

[0029] Figure 9 A plot showing the accelerated degradation curve for LP1, LP2, and LP3 implants in 50 mM NaOH at 37°C and a shaking speed of 40 rpm.

[0030] Figure 10 A plot showing the daily LP release (pg) per implant (Yl axis) versus % implant weight (Y2 axis) for LP1, LP2, and LP3 implants in PBS (pH 7.4) at 37°C and a shaking speed of 40 rpm.

[0031] Figure 11 A plot showing the accelerated degradation curve for F19, B6, and B7 implants in 50 mM NaOH and incubated in a static incubator at 37°C.

[0032] Figure 12 A plot showing the daily BEZ release (pg / mL) per implant (Yl axis) versus % implant weight in 10 mM NaOH (Y2 axis) for F19, B6, and B7 implants in PBS (pH 7.4) incubated in a static incubator at 37°C.

[0033] Figure 13 A plot showing the in vitro accelerated degradation curve for B1, B2, and B3 implants in 10 mM NaOH at 37°C, a shaking speed of 40 rpm.

[0034] Figure 14 A plot showing the daily OVA release (pg) per implant (Yl axis) versus % implant weight (Y2 axis) for B1, B2, and B3 implants in PBS (pH 7.4) at 37°C and a shaking speed of 40 rpm. DETAILED DESCRIPTION

[0035] As used herein, unless otherwise indicated, the term "% w / w" means the weight percent of a given component to the total weight of a copolymer, composition, or implant (as the case can be) that includes that component.

[0036] 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, monomer, oligomer, fragment, polymer, photoinitiator, solvent, co-solvent, or co-initiator.

[0037] As used herein, "copolymer" is a mixture of two or more different types of monomeric units. As used herein, "block copolymer" is a mixture of two or more homopolymer subunits.

[0038] The therapeutic agent of the present application can be selected from a broad 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, steroid agents, antibody therapeutics including bispecific antibodies, antimicrobial agents, antibiotics, antiretroviral therapeutics, anti-inflammatory compounds, antineoplastic agents, anti-angiogenic agents, anti-VEGF (vascular endothelial growth factor) agents, chemotherapeutic agents, various ophthalmic pharmaceutical agents, mydriatics, ophthalmic anesthetics, ophthalmic anti-infectives, ophthalmic anti-inflammatory agents, ophthalmic antihistamines and decongestants, ophthalmic diagnostic agents, ophthalmic glaucoma agents, ophthalmic lubricating and flushing agents, ophthalmic steroids, ophthalmic steroids with anti-infectives, ophthalmic surgical agents, tyrosine kinase inhibitors.

[0039] In some other embodiments, the therapeutic agent has a molecular weight greater than 200 Da, 500 Da, 1000 Da, 10 kDa, 30 kDa, 50 kDa, 75 kDa, 100 kDa, 150 kDa, 200 kDa, and 250 kDa.

[0040] In one embodiment, the therapeutic agent of the present application includes, but is not limited to, ketorolac, naphazoline, lidocaine, bevacizumab, aflibercept, brolucizumab, pegaptanib, brimonidine tartrate, dorzolamide, bromfenac sodium, azithromycin, rapamycin, betoxoline benzenesulfonate, diclofenac, besifloxacin, cysteamine hydrochloride, fluocinolone acetonide, 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 combinations thereof.

[0041] In another embodiment, the therapeutic agent of the present application is dexamethasone, timolol maleate, brimonidine tartrate, triamcinolone acetonide, bromfenac sodium, latanoprost, or mixtures thereof.

[0042] In one embodiment, the composition or implant of the present application can deliver a bioactive agent, a large molecular weight therapeutic, such as aflibercept, pegaptanib, or an antibody therapy, such as ranibizumab, bevacizumab, trastuzumab, rituximab, gentuzumab, ozagamicin, brolucizumab, cetuximab, faricimab, conbercept, or a biosimilar thereof.

[0043] In one embodiment, the therapeutic agent of the present application is ranibizumab, bevacizumab, latanoprost, dexamethasone, or timolol maleate.

[0044] According to other embodiments of the present application, the therapeutic agent is present in an amount of 0.5-70% w / w, 5-70% w / w, 10-70% w / w, 20-70% w / w, 30-70% w / w, 40-70% w / w, 50-70% w / w, 5-50% w / w, 10-50% w / w, 20-50% w / w, 30-50% w / w, and 40-50% w / w of the total weight of the ophthalmic composition or ophthalmic implant.

[0045] The therapeutic agent can be used as is or in the form of a solution, where an 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 application to facilitate incorporation of high concentrations of the therapeutic agent into the implant. The amount of the therapeutic agent to be dissolved depends on the final loading that the ophthalmic composition or implant must have. The choice of solvent depends on the polarity of the therapeutic agent.

[0046] According to one embodiment of the present application, the solvent can be selected from water, dimethyl sulfoxide, decylmethylsulfoxide, 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.

[0047] In one embodiment, co-solvents can be used, which can be selected from dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, acetic acid, methanol, ethanol, isopropanol, sugar-based substances, or butanol.

[0048] In the case of a hydrophilic therapeutic agent, the solvent can be an aqueous-based solvent, such as water or a phosphate buffered saline (PBS) solution.

[0049] According to another embodiment, the solvent can be selected from the group consisting of dimethyl sulfoxide, decylmethyl sulfoxide, 2-pyrrolidone, 1 -methyl-2-pyrrolidine, N-methyl-2-pyrrolidone, and glycerol formal.

[0050] Further, the above-mentioned solvents and co-solvents can be used in the preparation of any of the compositions and implants of the present application in combination with any of the other photopolymerizable compositions, biodegradable polymers, photoinitiators, porogens, and cosolvents described herein.

[0051] The photopolymerizable segments or monomers of the present application can be combined with any of the other biodegradable polymers, therapeutic agents, photoinitiators, solvents, co-solvents, drug modulators, and co-initiators described herein or known in the general knowledge for use in any of the compositions and implants of the present application.

[0052] In one embodiment, complete biodegradation occurs within a time period that is between one and four times the total drug release time of the implant. As an example of this embodiment, an implant of the present application that delivers a drug over a three month period should completely degrade within three to twelve months after injection into the organ.

[0053] As used herein, the term "photopolymerizable composition" is a composition that can form a crosslinked polymer network upon exposure to light, particularly ultraviolet light. As used herein, photopolymerizable compositions include photopolymerizable monomers and oligomers (e.g., dimers, trimers, and tetramers). The terms "oligomer" and "segment" can be used interchangeably to mean two to twenty monomers, optionally two to ten monomers, further optionally two to five monomers, or two to four monomers. A "photopolymerizable monomer" is an individual unit of a photopolymerizable polymer that can chemically bond to other monomers to form a polymer.

[0054] The photopolymerizable compositions of the present application can be crosslinked with ultraviolet radiation to form the crosslinked polymer matrix of the ophthalmic implants of the present application.

[0055] In one embodiment, R1of the one or more compounds of Formula I is independently selected from the group consisting of hydrogen and methyl. In yet another embodiment, n in Formula I is equal to 2.

[0056] According to another embodiment of the application, the compound of Formula I is selected from the group consisting of poly(ethylene glycol) acrylate, poly(ethylene glycol) methacrylate, poly(ethylene glycol) methyl ether acrylate, poly(ethylene glycol) methyl ether methacrylate, ethylene glycol methyl ether acrylate, di(ethylene glycol) ethyl ether acrylate, ethylene glycol methyl ether methacrylate, di(ethylene glycol) ethyl ether methacrylate, and mixtures thereof. In one embodiment, the one or more compounds of Formula I is poly(ethylene glycol) methacrylate (PEGMA).

[0057] In one embodiment of the application, the photopolymerizable composition comprises 5-60% w / w, 5-45% w / w, or 5-20% w / w, or 10-15% w / w of the one or more compounds of Formula I, the weight percent being based on the total weight of the photopolymerizable composition.

[0058] According to another embodiment, the photopolymerizable composition further comprises a poly(alkylene glycol) diacrylate, a poly(alkylene glycol) dimethacrylate, monomers, oligomers, mixtures, copolymers, and block copolymers thereof.

[0059] In one implementation, the photopolymerizable composition comprises a monomer that incorporates diacrylate chain end units, such as 3-armed, 4-armed, or 8-armed PEG acrylate.

[0060] In another embodiment, the photopolymerizable composition further comprises one or more disubstituted acrylate or methacrylate compounds selected from the group consisting of ethylene glycol diacrylate, di(ethylene glycol) diacrylate, poly(ethylene glycol) diacrylate, ethylene glycol dimethacrylate, di(ethylene glycol) dimethacrylate, poly(ethylene glycol) dimethacrylate, propylene glycol diacrylate, di(propylene glycol) diacrylate, poly(propylene glycol) diacrylate, propylene glycol dimethacrylate, di(propylene glycol) dimethacrylate, poly(propylene glycol) dimethacrylate, 1,6-hexanediol dimethacrylate.

[0061] In one embodiment of the application, the weight ratio between such one or more disubstituted acrylate or methacrylate compounds and the one or more compounds of Formula I is 0.5 to 20, 0.5 to 15, 1 to 15, 1 to 10, and 2 to 5.

[0062] In another embodiment, the one or more disubstituted acrylate or methacrylate compounds in the photopolymerizable composition is polyethylene glycol diacrylate (PEGDA) or polyethylene glycol dimethacrylate (PEGDMA).

[0063] In yet another embodiment, the one or more di-substituted acrylate or methacrylate compounds in the photopolymerizable composition is polyethylene glycol diacrylate (PEGDA).

[0064] In yet another embodiment, the photopolymerizable composition further comprises polyethylene glycol diacrylate (PEGDA).

[0065] In yet another embodiment, the weight ratio of PEGDA:PEGMA is 0.5 to 20, 0.5 to 15, 1 to 15, 1 to 10, and 2 to 5.

[0066] PEGMA and PEGDA are synthetic polymers, with varying molecular weights. They are very susceptible to mechanical, structural, and chemical changes, thus yielding hydrogels with variable properties in drug delivery and other biomedical applications. PEGMA and PEGDA are formed by functionalization of one or both ends of each PEG molecule with acrylate groups, respectively. PEGMA and PEGDA are non-toxic and elicit only minimal immunogenic reactions. PEGMA and PEGDA have acrylate end groups containing double bonds, which will show rapid polymerization to yield hydrogel networks when exposed to light in the presence of a suitable initiator.

[0067] The photopolymerizable composition of the present application typically has an average molecular weight of 100-300000 Da, 200-100000 Da, 200-50000 Da, 200-20000 Da, 200-10000 Da, 200-8000 Da, 200-5000 Da, or 200-1000 Da.

[0068] The photopolymerizable composition of the present application typically has a viscosity of 0.1-7 dL / g, 0.2-5 dL / g, or 0.5-2 dL / g.

[0069] In one embodiment, the photopolymerizable composition is present in an amount of 10-75% w / w, 20-75% w / w, 30-75% w / w, 40-75% w / w, 45-75% w / w of the total weight of the ophthalmic composition.

[0070] The biodegradable polymers of the present application can be combined with any other photopolymerizable compositions, therapeutic agents, photoinitiators, solvents, co-solvents, therapeutic agent release modifiers, and co-initiators described herein or known in the art for use in any of the compositions and implants of the present application.

[0071] The biodegradable polymers of the present application are biodegradable but not photopolymerizable.

[0072] In one embodiment of the application, the biodegradable polymer is a polyurethane based on aliphatic polyesters, a polylactide, a polycaprolactone, a polyorthoester or mixtures, copolymers or block copolymers thereof.

[0073] In another embodiment of the application, the biodegradable polymer is chitosan, poly(propylene fumarate), a copolymer of lactide / glycolide (PLGA), poly(L-lactide) (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), a copolymer of lactide / caprolactone (PLC), polyhydroxybutyrate, a natural biodegradable polymer such as collagen and hyaluronic acid, or mixtures, copolymers or block copolymers thereof.

[0074] In another embodiment, the biodegradable polymer is selected from the group consisting of a copolymer of lactide / glycolide (including poly(lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), polyhydroxyalkanoate (including polyhydroxybutyrate), polyglycolic acid (PGA), polycaprolactone (PCL), poly(DL-lactide) (PDL), poly(D-lactide), a copolymer of lactide / caprolactone, poly-L-lactide-co-caprolactone (PLC), and mixtures, copolymers and block copolymers thereof.

[0075] In one embodiment, the biodegradable polymer is a copolymer of lactide / glycolide (including poly(L-lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), poly(DL-lactide) (PDL), and a copolymer of lactide / caprolactone (PLC).

[0076] In a particular embodiment, the biodegradable polymer is poly(lactide-co-glycolide) (PLGA).

[0077] PLGA is typically prepared by polymerization of lactic acid and glycolic acid monomers. The glass transition temperature (Tg) of the PLGA copolymer is higher than the physiological temperature of 37°C, which confers a moderately rigid chain conformation and thus mechanical strength at ambient temperature. Different drug release profiles can be achieved using PLGA with different ratios of lactide (LA) to glycolide (GA) and molecular weight. 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.

[0078] In another embodiment, the biodegradable polymer is PCL, PLC, PLA, or mixtures, copolymers or block copolymers thereof.

[0079] In one embodiment, the biodegradable polymer is present in an amount of 1-40% w / w, 1-30% w / w, 1-20% w / w, 5-20% w / w, 2-10% w / w, 5-10% w / w, 1-5% w / w of the total weight of the ophthalmic composition.

[0080] The photoinitiators described herein can be combined with any of the other photopolymerizable compositions, biodegradable polymers, therapeutic agents, photoinitiators, solvents, co-solvents, and co-initiators described herein for use in any of the compositions and implants of the present application.

[0081] In certain embodiments, the photoinitiator is designed to work using light of 200-550 nm. In some embodiments, the photoinitiator is designed to work using UV light of 200-500 nm. In other embodiments, the photoinitiator is designed to work using UV light of 200-425 nm.

[0082] In certain embodiments, the light source can allow for varying the wavelength of the light and / or the intensity of the light. Light sources that can be used in the present application include, but are not limited to, laser diodes and lamps. Fiber optic devices can be used to transmit the light.

[0083] In another embodiment, the photoinitiator can be selected from a hydroxy ketone photoinitiator, an amino ketone photoinitiator, a hydroxy ketone / benzophenone photoinitiator, a benzyl dimethyl ketal photoinitiator, a phenyl acetoacetate photoinitiator, an acyl phosphine oxide photoinitiator, an acyl phosphine oxide / alpha hydroxy ketone photoinitiator, a benzophenone photoinitiator, a ribityl isoalloxazine photoinitiator, a peroxide photoinitiator, a persulfate photoinitiator, or a phenyl acetoacetate photoinitiator, or any combination thereof. Optionally, the photoinitiator is 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone, l-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-l-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”-azobis(isobutyronitrile), dicumyl peroxide, lauryl peroxide, and / or camphorquinone.

[0084] In one embodiment, the photoinitiator is l-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-l- propanone (Irgacure 2959), phenyl-bis(2,4,6-trimethylbenzoyl)-phosphine oxide (Irgacure 819), and mixtures thereof.

[0085] In one embodiment, the photoinitiator is present in an amount that varies between 0.1-5% w / w of the total weight of the ophthalmic composition.

[0086] In one embodiment, the composition of the present application further comprises a co-initiator. In one embodiment, the co-initiator is triethanolamine, dimethylamino benzoate (DMAB), trimethylolpropane, L-arginine.

[0087] In another embodiment, the photoinitiator is riboflavin and the co-initiator is L-arginine.

[0088] According to another embodiment of the present application, the ophthalmic composition comprises or consists of:

[0089] a) 10-50% w / w of a therapeutic agent

[0090] b) 1-20% w / w of poly(lactide-co-glycolide) (PLGA)

[0091] c) 30-88.99% w / w of a photopolymerizable composition consisting of poly(ethylene glycol) methacrylate (PEGMA) and poly(ethylene glycol) diacrylate (PEGDA).

[0092] d) 0.01-5% w / w of a photoinitiator selected from the group consisting of 1-[4-(2- hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propanone, phenyl-bis(2,4,6- trimethylbenzoyl)-phosphine oxide and mixtures thereof.

[0093] wherein the weight ratio of PEGDA:PEGMA is 0.5-20, 0.5-15, 1-15, 1-10 and 2-5.

[0094] According to another embodiment of the present application, the ophthalmic composition comprises or consists of:

[0095] a) 20-50% w / w of a therapeutic agent

[0096] b) 5-20% w / w of poly(lactide-co-glycolide) (PLGA)

[0097] c) 30-74.99% w / w of a photopolymerizable composition consisting of poly(ethylene glycol) methacrylate (PEGMA) and poly(ethylene glycol) diacrylate (PEGDA).

[0098] d) 0.01-5% w / w of a photoinitiator selected from the group consisting of 1-[4-(2- hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propanone, phenyl-bis(2,4,6- trimethylbenzoyl)-phosphine oxide and mixtures thereof.

[0099] wherein the weight ratio of PEGDA:PEGMA is 0.5-20, 0.5-15, 1-15, 1-10 and 2-5.

[0100] In one embodiment, the therapeutic agent is ranibizumab, bevacizumab, latanoprost, dexamethasone, or timolol maleate.

[0101] In one embodiment, the compositions of the present application comprise a release modulator. The appropriate release modulator can be selected depending on the particular therapeutic agent and the composition of the implant, as well as the desired elution profile or release rate. The release modulator can be a naturally occurring agent or polymer or a synthetic agent or polymer.

[0102] All release modulators described herein can be combined with any of the other photopolymerizable compositions, biodegradable polymers, therapeutic agents, photoinitiators, solvents, co-solvents, and co-initiators described herein for use in any of the implants and compositions of the present application.

[0103] The release modulator can 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.

[0104] Optionally, the release modulator alters the water uptake in the implant matrix, thereby controlling the release rate of the therapeutic agent and the degradation of the implant. In one embodiment, a suitable water uptake modulator is one or more polysaccharides, such as chitosan and cellulose-based materials, including hydroxypropyl methylcellulose (HPMC); hyaluronic acid; poloxamers; polyethers, such as polyethylene glycol; gelatin; polyvinylpyrrolidone; polyvinyl alcohol; and mixtures thereof. In one embodiment, a suitable water uptake modulator is hydroxypropyl methylcellulose (HPMC) and polyethylene glycol (PEG).

[0105] In one embodiment, the release modulator is a pore-forming agent and / or a stability enhancer. Optionally, it is lactose, maltose, glucose, mannitol, sodium chloride, magnesium carbonate, magnesium hydroxide, potassium chloride, sodium bicarbonate, ammonium bicarbonate, potassium bicarbonate, agarose, or sucrose.

[0106] In another embodiment, the release modulator is a mixture of two or more of the above modulators in order to provide more than one function to the ophthalmic composition or implant of the present application. Optionally, the release modulator is polyethylene glycol, hydroxypropyl methylcellulose (HPMC), or a mixture thereof.

[0107] Optionally, the porosity of the implant can be adjusted by preparing the implant in the presence of dispersed water-soluble porosinogens, which can be later removed by washing with water to leave a network of interconnected pores (i.e., a porous hydrogel). The pore size of the hydrogel prepared by the porosinogen technique depends on the size of the porosinogens.

[0108] In another embodiment of the present application, the ophthalmic composition does not contain any release modulator.

[0109] Another aspect of the present application is to provide the ophthalmic composition as described above for use in the manufacture of an ophthalmic implant. Alternatively, the ophthalmic composition of the present application is for use in coating an ophthalmic implant or a support of an ophthalmic implant.

[0110] Another aspect of the present application is a method of manufacturing the ophthalmic composition as described above. The method comprises the step of dissolving the therapeutic agent in a solvent / co-solvent to obtain a solution or a suspension, and the subsequent step of mixing the therapeutic agent solution thus obtained with the polymerizable composition, the biodegradable polymer, the photoinitiator and the optional release modulator in any order of addition. Optionally, the therapeutic agent is first mixed with the photopolymerizable composition, and the mixture thus obtained is then mixed with the biodegradable polymer, the photoinitiator and the optional release modulator 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 the optional release modulator.

[0111] The choice of solvent that can be used according to the present application depends on the polarity of the therapeutic agent.

[0112] Optionally, the solvent can be selected from water, dimethyl sulfoxide, decylmethylsulfoxide, 2-pyrrolidone, 1 -methyl-2-pyrrolidine, 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.

[0113] In one embodiment, co-solvents can be used, which can be selected from dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, acetic acid, methanol, ethanol, isopropanol, a sugar substance or butanol.

[0114] In the case of a hydrophilic therapeutic agent, the solvent can be a water-based solvent, such as water or a phosphate buffered saline (PBS) solution.

[0115] According to another embodiment, the solvent can be selected from dimethyl sulfoxide, decylmethylsulfoxide, acetonitrile, 2-pyrrolidone, 1 -methyl-2-pyrrolidine, N-methyl-2-pyrrolidone and glycerol formal.

[0116] Alternatively, the therapeutic agent is not dissolved in the solvent prior to mixing with the other ingredients. Thus, the therapeutic agent, the polymerizable composition, the biodegradable polymer, the photoinitiator and the optional release modifier 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, the photoinitiator and the optional release control agent.

[0117] Another aspect of the present application is a method of manufacturing an ophthalmic implant comprising the step of providing the ophthalmic composition of the present application, and the subsequent step of irradiating the ophthalmic composition with light having a wavelength of 200-550 nm, 200-500 nm, 200-490 nm or 200-425 nm for a period of 1 second to 60 minutes, 30 seconds to 30 minutes, 2.5 minutes to 20 minutes, 5 minutes to 10 minutes. In one embodiment, the crosslinking lasts 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.

[0118] Another aspect of the present application is an ophthalmic implant obtainable by the above method.

[0119] In one embodiment, the 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 can be varied to control the speed and extent of drug release. The variations in these factors provide compositions of the present application that can be readily tailored to produce the desired drug release period to meet the specific clinical / patient needs for treating various ocular diseases.

[0120] The ophthalmic compositions of the present application can:

[0121] i) injected into the eye followed by application of short term UV light to induce in situ photocrosslinking resulting in the formation of an implant, referred to as in situ photocrosslinked implant (ISPcI); and

[0122] ii) photocrosslinked to form an implant (e.g. a film, rod or nano / micro-particle) having the desired shape and size prior to application to the eye, which can be administered intraocularly to provide the desired drug delivery time period, referred to as preformed photocrosslinked implant (PPcI).

[0123] Alternatively, the compositions of the present application can be used to coat ophthalmic devices, including in situ and preformed ophthalmic devices.

[0124] The implants of the present application can be of any desired shape, such as, but not limited to, rectangular, square, spherical, cylindrical, circular, oval, film, dumbbell, rod and bead shaped.

[0125] The implants of the present invention can have any desired size and can for example be in the macro-, micro- or nanoparticle size range.

[0126] In one embodiment of the present invention, the ocular implant is an implant where one dimension is less than 10 mm or less than 5 mm or less than 3 mm. In one embodiment, the implant is a rectangular implant with dimensions of 10 x 5 x 0.5 mm. In one embodiment, the implant (ISPcl) is a spherical implant with a diameter less than 10 mm or less than 5 mm or less than 3 mm. In one embodiment of the present invention, the ocular implant is a nanoparticle or a micro-particle.

[0127] In one embodiment, the nanoparticle ocular implant is less than 1000 nm, less than 900 nm, less than 750 nm, less than 500 nm or less than 100 nm.

[0128] In one embodiment, the micro-particle ocular implant is less than 1000 μιη, less than 900 μιη, less than 750 μιη, less than 500 μιη or less than 25 μιη.

[0129] Optionally, the implant is an in situ forming ocular implant. Alternatively, the implant is a pre-fabricated ocular implant.

[0130] In situ photocrosslinked implants (ISPcl) according to the present invention are implants that form and occupy their final positioned structure once inserted into the body. The ability of ISPcl to fill irregular defects is one of their advantages. ISPcl of the present invention also have other advantages including site-specific action due to relatively easy and less invasive application, local delivery to specific tissues, prolonged delivery time, reduced side effects associated with systemic delivery and excellent patient comfort and compliance. Another advantage of ISPcl of the present invention is that it does not require extreme pH conditions or elevated temperatures during processing which can cause problems when handling temperature or pH labile drugs such as proteins, peptides or genetic material. Furthermore, rapid crosslinking at physiological temperature can rapidly trap drug molecules and can result in ISPcl that provide long term controlled drug release. Photocrosslinking is also beneficial compared to spontaneous crosslinking (e.g. enzymatic crosslinking, self-assembly, Michael addition) as the initiation of the process is triggered only upon exposure to a light source, thus premature gelation is not an issue and thus material formation can be well controlled. Furthermore, the short term application of UV light does not pose any safety issues as it is considered safe for ocular applications as UV light is used clinically for corneal crosslinking. Importantly, dosing by this method allows injection of relatively low viscosity materials into the body which subsequently solidify due to phase transition and form a semi-solid depot which controls drug delivery upon photocrosslinking to provide short or long term therapeutic effects.

[0131] In one embodiment, the ISPcIs are formed by injecting the ophthalmic composition of the application into a subject in need thereof and subsequently crosslinking using an external source of UV light, which results in the formation of a solid implant that controls drug release over a desired period of time.

[0132] For the ISPcIs of the application, the molecular weight of the photopolymerizable composition is typically 100 to 6000 Da, 200 to 3000 Da, or 200 to 1000 Da.

[0133] The preformed photocrosslinked implants (PPcIs) of the application can be inserted into the eye, for example, in the fornix, subconjunctival, intracameral, intrastromal / intracorneal, transscleral / periocular, intrascleral, or intravitreal, subretinal, to treat diseases of the anterior or posterior segment of the eye. The PPcIs can be made in various shapes, including but not limited to, rods, films, cylinders, or circles, as well as various sizes, including micro- or nanoparticles.

[0134] In one embodiment, the PPcI nanoparticles and micro- particles are obtained by subjecting a mixture of a therapeutic agent, a photopolymerizable composition, a biodegradable polymer, a photoinitiator, and optionally a release modifier to ultrasonication 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 the ultrasonication, i.e., the mixture is subjected to ultrasonication under UV light, or it can be applied after the ultrasonication step.

[0135] The PPcIs of the application have the advantage of high crosslinking density and / or tight polymer network structure, which can be configured to control drug release and / or eliminate any burst release.

[0136] The PPcIs of the application can be made 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.

[0137] In addition, the PPcIs of the application have slower implant degradation rates than the ISPcIs, and the degradation rate can be controlled according to the specific disease or condition to be treated.

[0138] For the PPcIs of the application, the average molecular weight of the photopolymerizable polymer is typically 100 to 300000 Da, 200 to 100000 Da, 200 to 50000 Da, 200 to 20000 Da, or 200 to 10000 Da.

[0139] In one embodiment, the application is a PLGA / PEGDA / PEGMAPPcI. In another embodiment, the application is a PLGA / PEGDA / PEGMA ISPcI.

[0140] In one embodiment, the polymers of the photopolymerizable composition, such as PEGDA and PEGMA, can act as solvents prior to their in situ crosslinking to form the ISPcl. The polymers of the photopolymerizable composition also help to prevent the dispersion of the different components of the overall composition within the organ after injection and prior to crosslinking and solidification.

[0141] In one embodiment, the biodegradable polymer is substantially contained within the matrix of the photopolymerizable composition. Optionally, the biodegradable polymer is substantially 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 the photoinitiator and the biodegradable polymer and the one or more therapeutic agents. In one embodiment, the biodegradable polymer is hydrophobic in nature, while the photopolymerizable polymer is hydrophilic in nature. In one embodiment, the degree of crosslinking of the composite implant will control the rate and extent of release of the one or more therapeutic agents.

[0142] Another aspect of the present application is an ocular implant comprising at least 0.1% w / w of a therapeutic agent, 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 poly(lactide-co-glycolide) (PLGA), poly(L-lactide) (PLA), polyhydroxyalkanoates (including polyhydroxybutyrate), polyglycolic acid (PGA), polycaprolactone (PCL), poly(DL-lactide) (PDL), poly(D-lactide), poly(lactide-co-caprolactone), poly-L-lactide-co-caprolactone (PLC) and mixtures, copolymers and block copolymers thereof, characterized in that:

[0143] a) the crosslinked polymer matrix is obtained by crosslinking a photopolymerizable composition comprising 3-70% w / w of one or more compounds of formula I:

[0144]

[0145] wherein R1 is hydrogen or a linear or branched C1-C3 alkyl group; R2 is an acrylate or methacrylate group, n = 2 or 3 and m is equal to or greater than 1, the weight percentage of the one or more compounds of formula I being based on the total weight of the photopolymerizable composition.

[0146] b) the therapeutic agent and the biodegradable polymer are embedded in the polymer matrix.

[0147] As used herein, "embedded" means that the therapeutic agent is substantially captured within the crosslinked polymer matrix and that it is uniformly dispersed or dissolved in the crosslinked polymer matrix and / or the biodegradable polymer.

[0148] In the compositions and implants of the application, varying the UV crosslinking time can control the rate and duration of drug release. In some embodiments, an increase in UV crosslinking time results in a decrease in drug release. In addition, varying the concentration of photoinitiator can control the rate and duration of drug release. In addition, varying both the UV crosslinking time and the concentration of photoinitiator can control the rate and duration of drug release. In one embodiment, the addition of a porogen (e.g., MgC03) increases the rate of drug release. In one embodiment, a higher UV crosslinking time and a higher concentration of photoinitiator can result in drug release for a longer duration of time. In one embodiment, drug release can last for more than 1 day, 2 days, 1 week, 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months.

[0149] In some embodiments, the controlled degradation rate of the ISPcIs and PPcIs of the application provides protection for sensitive molecules, such as peptides and proteins.

[0150] In some embodiments, burst release can be eliminated or controlled by varying the UV crosslinking time and varying the formulation composition, implant volume.

[0151] In one embodiment, the application is a PPcI with no burst release or low burst release. In one embodiment, the application is a PPcI with high crosslinking density that significantly slows down drug diffusion.

[0152] Any of the implants and compositions described herein are suitable for use in any of the methods of the application described herein.

[0153] In one embodiment, the application is a method of treating an ocular disease or disorder in a subject in need thereof, comprising administering a composition or implant of the application to an ocular region of the subject.

[0154] In one embodiment, the application is a composition or implant of the application for use in treating an ocular disease or disorder in a subject in need thereof.

[0155] As used herein, an “ocular region” is a region inside, outside, or adjacent to a subject’s eye. In one embodiment, the ocular region is the sclera (intrasceral), extrascleral (transscleral), vitreous, choroid, cornea, interstitium, intracameral, aqueous humor, lens, fornix, or optic nerve.

[0156] In one embodiment, the compositions and implants can be administered by injection, including intravitreal, subconjunctival, peribulbar, retrobulbar, or retrobulbar injection, and injection onto the cornea.

[0157] In some embodiments, the implant is administered by surgical procedure. In some embodiments, the implant is secured in place by an adhesive or suture following surgical implantation.

[0158] The term "subject" refers to an animal (e.g., avian, such as a chicken, quail, or turkey, or a mammal), and specifically to a "mammal," including non-primate mammals (e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and primates (e.g., a monkey, chimpanzee, and a human), and more specifically to a human. 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."

[0159] As used herein, the terms "treat," "treatment," and "treating" refer to therapeutic treatment, including reduction or amelioration of the progression, severity, and / or duration of a disease, disorder, or condition, or an improvement in one or more symptoms (specifically, one or more discernible symptoms) of a disease, disorder, or condition, resulting from the administration of a composition or implant of the present application. In particular embodiments, therapeutic treatment includes an improvement in at least one measurable physical parameter of a disease, disorder, or condition. In other embodiments, therapeutic treatment includes physical inhibition of the progression of a condition, by, for example, stabilizing discernible symptoms, or physiological inhibition of the progression of a condition, by, for example, stabilizing physical parameters of the body, or both. In other embodiments, therapeutic treatment includes remission or stabilization of a disease, disorder, or condition.

[0160] In one embodiment, the disease or disorder is pain, inflammation, infection, cataracts, allergy, age-related macular degeneration (AMD), diabetic retinopathy (DR), macular edema, diabetic macular edema (DME), cytomegalovirus (CMV), retinitis, retinal pigmentosa, uveitis, dry eye, keratitis, glaucoma, blepharitis, blephariconjunctivtis, ocular hypertension, conjunctivitis, cystinosis, vitreomacular adhesion, corneal neovascularization, corneal ulcer, and post-surgical ocular inflammation / wound healing.

[0161] The following numbered list of items is a list of embodiments encompassed by the present application:

[0162] 1. An ophthalmic composition comprising:

[0163] a) at least 0.1% w / w of a therapeutic agent;

[0164] b) 5-95% w / w of a photopolymerizable composition comprising 3-70% w / w of one or more compounds of Formula I:

[0165]

[0166] wherein R1is hydrogen or a linear or branched C1-C3alkyl group; R2is an acrylate or methacrylate group; n is 2 or 3 and m is equal to or greater than 1, the weight percent of the one or more compounds of Formula I being based on the total weight of the photopolymerizable composition.

[0167] c) 0.1-40% w / w of a biodegradable polymer selected from the group consisting of poly(lactide-co-glycolide) (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), poly(lactide-co-caprolactone), poly-L-lactide-co-caprolactone (PLC), and mixtures, copolymers and block copolymers thereof, and

[0168] d) a photoinitiator.

[0169] 2. The ophthalmic composition according to item 1, wherein R1is hydrogen or methyl.

[0170] 3. The ophthalmic composition according to item 1 or item 2, wherein n is 2.

[0171] 4. The ophthalmic composition according to item 3, wherein the compound of Formula I is selected from the group consisting of poly(ethylene glycol) acrylate, poly(ethylene glycol) methacrylate, poly(ethylene glycol) methyl ether acrylate, poly(ethylene glycol) methyl ether methacrylate, ethylene glycol methyl ether acrylate, di(ethylene glycol) ethyl ether acrylate, ethylene glycol methyl ether methacrylate, di(ethylene glycol) ethyl ether methacrylate, and mixtures thereof.

[0172] 5. The ophthalmic composition according to item 4, wherein the compound of Formula I is poly(ethylene glycol) methacrylate (PEGMA).

[0173] 6. The ophthalmic composition according to any one of the preceding items, wherein the photopolymerizable composition comprises 5-60% w / w of one or more compounds of Formula I

[0174] 7. The ophthalmic composition according to item 6, wherein the photopolymerizable composition comprises 5-45% w / w of one or more compounds of Formula I

[0175] 8. The ophthalmic composition according to item 7, wherein the photopolymerizable composition comprises 5-20% w / w of one or more compounds of Formula I.

[0176] 9. The ophthalmic composition according to item 8, wherein the photopolymerizable composition comprises 10-15% w / w of one or more compounds of Formula I.

[0177] 10. The ophthalmic composition according to any one of the preceding items, further comprising a poly(alkylene glycol) diacrylate, a poly(alkylene glycol) dimethacrylate, monomers, oligomers, mixtures, copolymers and block copolymers thereof.

[0178] 11. The ophthalmic composition according to item 10, wherein the photopolymerizable composition further comprises one or more disubstituted acrylate or methacrylate compounds selected from the group consisting of ethylene glycol diacrylate, di(ethylene glycol) diacrylate, poly(ethylene glycol) diacrylate, ethylene glycol dimethacrylate, di(ethylene glycol) dimethacrylate, poly(ethylene glycol) dimethacrylate, propylene glycol diacrylate, di(propylene glycol) diacrylate, poly(propylene glycol) diacrylate, propylene glycol dimethacrylate, di(propylene glycol) dimethacrylate, poly(propylene glycol) dimethacrylate, 1,6-hexanediol dimethacrylate.

[0179] 12. The ophthalmic composition according to item 11, wherein the one or more disubstituted acrylate or methacrylate compounds is poly(ethylene glycol) diacrylate (PEGDA).

[0180] 13. The ophthalmic composition according to item 11 or 12, wherein the weight ratio between the one or more disubstituted acrylate or methacrylate compounds and the one or more compounds of Formula I is 0.5 to 20, 0.5 to 15, 1 to 15, 1 to 10 and 2 to 5.

[0181] 14. The ophthalmic composition according to any one of the preceding items, comprising 40-75% w / w of the photopolymerizable composition.

[0182] 15. The ophthalmic composition according to any one of the preceding items, wherein the biodegradable polymer is a lactide / glycolide copolymer (including poly(L-lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), poly(DL-lactide) (PDL) and lactide / caprolactone copolymer (PLC).

[0183] 16. The ophthalmic composition according to item 15, wherein the biodegradable polymer is poly(lactide-co-glycolide) (PLGA).

[0184] 17. The ophthalmic composition according to any one of the preceding items, wherein the therapeutic agent is present in an amount of 10-70% w / w.

[0185] 18. The ophthalmic composition according to item 17, wherein the therapeutic agent is present in an amount of 20-70% w / w.

[0186] 19. The ophthalmic composition according to item 17, wherein the therapeutic agent is present in an amount of 10-60% w / w.

[0187] 20. The ophthalmic composition according to item 17, 18 or 19, wherein the therapeutic agent is present in an amount of 20-50% w / w.

[0188] 21. The ophthalmic composition according to item 20, wherein the therapeutic agent is present in an amount of 30-50% w / w.

[0189] 22. The ophthalmic composition according to any one of the preceding items, wherein the biodegradable polymer is present in an amount of 1-20% w / w.

[0190] 23. The ophthalmic composition according to item 22, wherein the biodegradable polymer is present in an amount of 5-20% w / w.

[0191] 24. The ophthalmic composition according to any preceding item, wherein the photoinitiator is selected from a hydroxyketone photoinitiator, an aminoketone photoinitiator, a hydroxyketone / benzophenone photoinitiator, a benzyldimethylketal photoinitiator, a phenylglyoxylate photoinitiator, an acyloxyphosphine photoinitiator, an acyloxyphosphine / alpha-hydroxyketone 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”-azobis(isobutyronitrile), dicumyl peroxide, lauryl peroxide, and / or camphorquinone.

[0192] 25. The ophthalmic composition according to item 24, wherein the photoinitiator is 1-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propanone, phenyl-bis(2,4,6-trimethylbenzoyl)-phosphine oxide, and mixtures thereof.

[0193] 26. The ophthalmic composition according to any one of the preceding items, wherein the photoinitiator is present in an amount varying between 0.1-5% w / w.

[0194] 27. The ophthalmic composition according to any one of the preceding items, comprising or consisting of:

[0195] a) 10-50% w / w of a therapeutic agent

[0196] b) 1-20% w / w of poly(lactide-co-glycolide) (PLGA)

[0197] c) 30-88.99 w / w of a photopolymerizable composition consisting of poly(ethylene glycol) methacrylate (PEGMA) and poly(ethylene glycol) diacrylate (PEGDA).

[0198] d) 0.01-5% w / w of a photoinitiator selected from 1-[4-(2-hydroxyethoxy)-phenyl]-2- hydroxy-2-methyl-1-propanone, phenyl-bis(2,4,6-trimethylbenzoyl)-phosphine oxide and mixtures thereof.

[0199] wherein the weight ratio of PEGDA:PEGMA is 0.5-20, 0.5-15, 1-15, 1-10 or 2-5.

[0200] 28. The ophthalmic composition according to item 27, comprising or consisting of:

[0201] a) 20-50% w / w of a therapeutic agent

[0202] b) 5-20% w / w of poly(lactide-co-glycolide) (PLGA)

[0203] c) 30-74.99% w / w of a photopolymerizable composition consisting of poly(ethylene glycol) methacrylate (PEGMA) and poly(ethylene glycol) diacrylate (PEGDA).

[0204] d) 0.01-5% w / w of a photoinitiator selected from 1-[4-(2-hydroxyethoxy)-phenyl]-2- hydroxy-2-methyl-1-propanone, phenyl-bis(2,4,6-trimethylbenzoyl)-phosphine oxide and mixtures thereof.

[0205] wherein the weight ratio of PEGDA:PEGMA is 0.5-20, 0.5-15, 1-15, 1-10 or 2-5.

[0206] 29. The ophthalmic composition according to item 27 or 28, wherein the therapeutic agent is ranibizumab, bevacizumab, latanoprost, dexamethasone or timolol maleate.

[0207] 30. The ophthalmic composition according to any preceding item, further comprising a release modifier.

[0208] 31. The ophthalmic composition according to item 30, wherein the release modifier is selected from the group consisting of polysaccharides, including chitosan and cellulose-based materials (including hydroxypropyl methylcellulose (HPMC)); hyaluronic acid; poloxamers; polyethers, including polyethylene glycol (PEG); gelatin; polyvinylpyrrolidone; polyvinyl alcohol, lactose, maltose, glucose, mannitol, sodium chloride, magnesium carbonate, magnesium hydroxide, potassium chloride, sodium bicarbonate, ammonium bicarbonate, potassium bicarbonate, agarose, sucrose and mixtures thereof.

[0209] 32. The ophthalmic composition according to item 31, wherein the release modifier is polyethylene glycol (PEG), hydroxypropyl methylcellulose (HPMC) or a mixture thereof.

[0210] 33. The ophthalmic composition according to any one of items 1 to 29, wherein the composition is free of any release modifier.

[0211] 34. The ophthalmic composition according to any one of the preceding items for use in the manufacture of an ophthalmic implant.

[0212] 35. A method of manufacturing an ophthalmic composition according to any one of the preceding items, comprising the steps of:

[0213] a) dissolving a therapeutic agent in a solvent to obtain a solution or suspension;

[0214] b) mixing the solution obtained in step a) with a polymerizable composition, a biodegradable polymer, a photoinitiator and optionally a release modifier.

[0215] 36. The method according to item 35, wherein the solvent is a water-based solvent.

[0216] 37. A method of manufacturing an ophthalmic implant, comprising the steps of:

[0217] a) providing an ophthalmic composition according to any one of items 1 to 34; and

[0218] b) irradiating the ophthalmic composition with light having a wavelength of 200-550 nm for a time period of 1 second to 60 minutes to form an ophthalmic implant.

[0219] 38. The method according to item 37, wherein the ophthalmic composition provided in step a) is applied to an ocular region of a subject or the like prior to irradiating the ophthalmic composition in accordance with step b).

[0220] 39. The method according to item 37, wherein the ophthalmic implant formed in step b) is applied to an ocular region of a subject.

[0221] 40. An ophthalmic implant obtainable by the method of items 35 to 39.

[0222] 41. An ocular implant comprising at least 0.1% w / w of a therapeutic agent, 5-95% w / w of a crosslinked polymeric matrix, and 0.1-40% w / w of a biodegradable polymer selected from the group consisting of poly(lactide-co-glycolide) (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), poly(lactide-co-caprolactone), poly-L-lactide-co-caprolactone (PLC), and mixtures, copolymers, and block copolymers thereof, characterized in that:

[0223] a) the crosslinked polymeric matrix is obtained by crosslinking a photopolymerizable composition comprising 3-70% w / w of one or more compounds of Formula I:

[0224]

[0225] wherein R1 is hydrogen or a linear or branched C1-C3 alkyl group; R2 is an acrylate or methacrylate group; n is 2 or 3 and m is equal to or greater than 1, the weight percent of the one or more compounds of Formula I being based on the total weight of the photopolymerizable composition.

[0226] b) the therapeutic agent and the biodegradable polymer are embedded in the polymeric matrix.

[0227] 42. The ocular implant of item 41, wherein R1 is hydrogen or methyl.

[0228] 43. The ocular implant of item 41 or 42, wherein n is 2.

[0229] 44. The ocular implant according to any one of items 41 to 43, wherein the compound of Formula I is selected from the group consisting of poly(ethylene glycol) acrylate, poly(ethylene glycol) methacrylate, poly(ethylene glycol) methyl ether acrylate, poly(ethylene glycol) methyl ether methacrylate, ethylene glycol methyl ether acrylate, di(ethylene glycol) ethyl ether acrylate, ethylene glycol methyl ether methacrylate, di(ethylene glycol) ethyl ether methacrylate, and mixtures thereof.

[0230] 45. The ocular implant of item 44, wherein the compound of Formula I is poly(ethylene glycol) methacrylate (PEGMA).

[0231] 46. The ocular implant according to any one of items 41 to 45, wherein the photopolymerizable composition comprises 5-45% w / w of the one or more compounds of Formula I.

[0232] 47. The ocular implant according to item 46, wherein the photopolymerizable composition comprises 5-20% w / w of one or more compounds of Formula I.

[0233] 48. The ocular implant according to item 47, wherein the photopolymerizable composition comprises 10-15% w / w of one or more compounds of Formula I.

[0234] 49. The ocular implant according to any one of items 41 to 48, further comprising poly(alkylene glycol) diacrylate, poly(alkylene glycol) dimethacrylate, monomers, oligomers, mixtures, copolymers and block copolymers thereof.

[0235] 50. The ocular implant according to item 49, wherein the photopolymerizable composition further comprises one or more di-substituted acrylate or methacrylate polymers selected from the group consisting of poly(ethylene glycol) diacrylate, di(ethylene glycol) diacrylate, poly(ethylene glycol) dimethacrylate, di(ethylene glycol) dimethacrylate, poly(propylene glycol) diacrylate, dipropylene glycol diacrylate, dipropylene glycol dimethacrylate, poly(propylene glycol) dimethacrylate, 1,6-hexanediol dimethacrylate.

[0236] 51. The ocular implant according to item 50, wherein the one or more di-substituted acrylate or methacrylate compounds is poly(ethylene glycol) diacrylate (PEGDA).

[0237] 52. The ocular implant according to item 50 or 51, wherein the weight ratio between the one or more di-substituted acrylate or methacrylate compounds and the one or more compounds of Formula I is 0.5 to 20, 0.5 to 15, 1 to 15, 1 to 10 and 2 to 5.

[0238] 53. The ocular implant according to any one of items 41 to 52, wherein the biodegradable polymer is a lactide / glycolide copolymer (including poly(L-lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), poly(DL-lactide) (PDL) and lactide / caprolactone copolymer (PLC).

[0239] 54. The ocular implant according to item 53, wherein the biodegradable polymer is poly(lactide-co-glycolide) (PLGA).

[0240] 55. The ocular implant according to any one of items 41 to 54, wherein the therapeutic agent is present in an amount of 10-70% w / w.

[0241] 56. The ocular implant according to item 55, wherein the therapeutic agent is present in an amount of 20-70% w / w.

[0242] 57. The ocular implant according to item 55, wherein the therapeutic agent is present in an amount of 10-60% w / w.

[0243] 58. The ocular implant according to item 56 or 57, wherein the therapeutic agent is present in an amount of 20-50% w / w.

[0244] 59. The ocular implant according to item 58, wherein the therapeutic agent is present in an amount of 30-50% w / w.

[0245] 60. The ocular implant according to any one of items 40 to 59, wherein the biodegradable polymer is present in an amount of 1-20% w / w.

[0246] 61. The ocular implant according to any one of item 60, wherein the biodegradable polymer is present in an amount of 5-20% w / w.

[0247] 62. The ocular implant according to item 41, comprising or consisting of

[0248] a) 10-50% w / w of a therapeutic agent

[0249] b) 1-20% w / w of poly(lactide-co-glycolide) (PLGA)

[0250] c) 30-89% w / w of a crosslinked polymer matrix obtained by crosslinking a photopolymerizable composition consisting of poly(ethylene glycol) methacrylate (PEGMA) and poly(ethylene glycol) diacrylate (PEGDA), wherein the weight ratio of PEGDA:PEGMA is 0.5-20, 0.5-15, 1-15, 1-10, or 2-5.

[0251] 63. The ocular implant according to item 62, comprising or consisting of

[0252] a) 20-50% w / w of a therapeutic agent

[0253] b) 5-20% w / w of poly(lactide-co-glycolide) (PLGA)

[0254] c) 30-75% w / w of a crosslinked polymer matrix obtained by crosslinking a photopolymerizable composition consisting of poly(ethylene glycol) methacrylate (PEGMA) and poly(ethylene glycol) diacrylate (PEGDA), wherein the weight ratio of PEGDA:PEGMA is 0.5-15, 1-15, 1-10, or 2-5.

[0255] 64. An ophthalmic implant according to any one of claims 41 to 63, wherein the therapeutic agent is ranibizumab, bevacizumab, latanoprost, dexamethasone, or timolol maleate.

[0256] 65. An ophthalmic implant according to any one of claims 41 to 64 further comprises a release regulator.

[0257] 66. An ophthalmic implant according to claim 65, wherein the release modulator is selected from polysaccharides, including chitosan and cellulose-based materials (including hydroxypropyl methylcellulose (HPMC)); hyaluronic acid; poloxamer; polyethers, including polyethylene glycol (PEG); gelatin; polyvinylpyrrolidone; polyvinyl alcohol; lactose, maltose, glucose, mannitol, sodium chloride, magnesium carbonate, magnesium hydroxide, potassium chloride, sodium bicarbonate, ammonium bicarbonate, potassium bicarbonate, agarose, sucrose, and mixtures thereof.

[0258] 67. An ophthalmic implant according to item 66, wherein the release modulator is polyethylene glycol (PEG), hydroxypropyl methylcellulose (HPMC), or a mixture thereof.

[0259] 68. The ophthalmic implant according to any one of claims 41 to 64, wherein the composition does not contain any release modulator.

[0260] 69. An ophthalmic implant according to any one of items 40 to 68, which is a macroparticle, microparticle or nanoparticle.

[0261] Example

[0262] Example 1 : Ovalbumin (OVA, molecular weight 42.7 kDa)

[0263] 1.1 Materials

[0264] Poly(ethylene glycol) diacrylate (Mn = 700 Da, PEGDA700), 1-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propanone (Irgacure 2959), phosphate-buffered saline (PBS) tablets, and poly(ethylene glycol) methacrylate (Mn = 360 Da, PEGMA) were purchased from Sigma-Aldrich (Dorset, UK). Poly(lactide-co-glycolic acid) PDLG 7502, 75:25, PLGA 75 / 25) was obtained from Corbion Purac Biomaterials (Hollingheim, Netherlands). Ovalbumin (OVA) derived from egg white was purchased from Sigma-Aldrich (Basingstock, UK). Silicone tubing (peroxide-cured, 0.6 mm inner diameter, 0.27 mm wall thickness) was purchased from Polymer System Technology, UK.

[0265] 1.2 Preparation of O1, O2, O3, O4 implants

[0266]

[0267] 5 mg of PLGA7502 (75 / 25, Corbion Purac Biomaterials, Hollingheim, Netherlands) was dissolved in a mixture of (i) 64.7 mg PEGDA 700 Da (O1) or (ii) 58.2 mg PEGDA 700 Da and 6.5 mg PEGMA 360 Da (O2) or (iii) 51.8 mg PEGDA 700 Da and 12.9 mg PEGMA 360 Da (O3) or (iv) 45.3 mg PEGDA 700 Da and 19.4 mg PEGMA 360 Da (O4) to prepare Solution A 5 mg of Irgacure 2559 (Sigma-Aldrich, Basingstock, UK) was dissolved in 1 ml of PBS to prepare... Solution B Add 30 mg of egg white albumin, specifically ovalbumin (Sigma Aldrich, Basingstock, UK), to a 60 μL container. Solution B In the preparation of Eppendorf tubes (Sarstedt, Nymbrecht, Germany) Solution C .Will Solution A Add to the Eppendorf tube. Pass through the Eppendorf tube wall... Solution C Add slowly Solution A Meanwhile, the mixture was continuously stirred at 900 rpm for 15 minutes. The resulting mixture was then transferred to a silicone tube with an inner diameter (ID) of 0.635 mm (Polymer System Technology, UK) and subjected to 365 nm UV light (Light). 6. Photocrosslinking was performed at Heraeus Noblelight Fusion UV Inc. (Gaithersburg, MD, USA). The UV light intensity was set to 50%, and the silicone tube was exposed to UV light for 15 seconds (i.e., a total of 5 runs). The implant was then removed from the silicone tube and dried in a vacuum at 25°C for 4 hours. The rod-shaped implant was cut to lengths of 7.5 mm.

[0268] 1.3 In vitro drug release set up

[0269] In vitro release was performed by placing two (2) O1 implants into glass vials containing 2 mL of PBS (Phosphate Buffered Saline) and 0.05% w / w NaN3(pH 7.4±0.2) as release medium. Similar in vitro release was performed for implants O2, O3 and O4. All experiments were performed in triplicate. The glass vials containing the implants were placed in an incubator and incubated at 37°C and 40 rpm (SciQuip FL16-2 cold incubation shaker, SciQuip Ltd., Cheshire, UK). Sampling was performed at day 1 and then every week (i.e. day 7, day 14, day 21, day 28 etc.) with a complete change of PBS medium. The concentration of released drug molecules in the PBS samples was analysed as described in the following section.

[0270] 1.4 In vitro degradation study set up

[0271] In vitro degradation studies were performed by placing two (2) O1 implants into glass vials containing 4 mL of 10 mM NaOH as accelerated degradation condition medium or 4 mL of PBS (Phosphate Buffered Saline) and 0.05% w / w NaN2(pH 7.4±0.2) as ambient condition degradation medium. Similar in vitro degradation was performed for implants O2, O3 and O4 implants. All experiments were performed in triplicate. The glass vials containing the implants were placed in an incubator and incubated at 37°C and 40 rpm (SciQuip FL16-2 cold incubation shaker, SciQuip Ltd., Cheshire, UK). Sampling was performed at each time point with a complete change of degradation medium. Accelerated condition degradation was performed for 30 days, whereas ambient condition degradation was performed simultaneously with in vitro drug release until release was completed. Samples were analysed for wet and dry weight of the implants after each time point.

[0272] 1.5 Sample analysis

[0273] Analysis of Ovalbumin (OVA) in vitro release samples was performed using SEC-HPLC with UV detection (Agilent 1260 Infinity quaternary system, Agilent Ltd., UK) using Biosep-SEC-S3000 column (length 300 mm, internal diameter 7.8 mm and particle size 5 pm) and Security Guard Cartridges GFC 3000 (4 x 3.0 mm ID) (Phenomenex, Torrance, USA). 20 pL samples were eluted with 27 mM Phosphate buffer and 150 mM NaCl pH 6.35 at a flow rate of 1.0 ml / min for 14 minutes. Detection was performed by UV detector at 214 nm.

[0274] 1.6 Results

[0275] Figure 1 Accelerated degradation profiles of O1, O2, O3 and O4 implants are shown. The more PEGMA polymer content in the implant, the faster the implant degrades. Figure 3 The SEM images in Figure 2 show that while O4 degrades faster (decrease in diameter) than O1 and shows signs of surface erosion and pore formation, its physical structure remains intact during the degradation process. This would avoid the formation of debris in the anterior and / or posterior part of the eye, which has the potential risk of clogging the trabecular meshwork and preventing the normal drainage of aqueous humor from the eye. Moreover, maintaining the physical structure during the degradation process would prevent the occurrence of the second and third burst effects, thus achieving a more sustained and predictable drug release over time, while preventing harmful overdosing, especially in the case of highly potent drugs.

[0276] Figure 2 Daily OVA release rates and degradation profiles of implants O1, O2, O3 and O4 are shown. Figure 2 The lowest therapeutic level of 0.5 pg / day shown in Figure 3 is five times the IC50 (minimum inhibitory concentration) value of Ranibizumab (Genentech Inc. Prescribing Information for Lucentis® (Ranibizumab), 2006; J. Gaudreault, D. Fei, J. Rusit, P. Suboc, V. Shiu, Preclinical pharmacokinetics of ranibizumab (rhuFabV2) after a single intravitreal administration, Investig. Ophthalmol. Vis. Sci. 46 (2005) 726-733). The molecular weight of Ranibizumab is close to that of Ovalbumin. Implant O4 degrades faster than implant O1. Nevertheless, it still releases OVA in an acceptable therapeutic amount for more than 4 months.

[0277] Example 2: Ovalbumin (OVA), molecular weight 42.7 kDa

[0278] 2.1 Materials

[0279] ​Poly(ethylene glycol) diacrylate (Mn = 700 Da, PEGDA 700), l-[4-(2-hydroxyethoxy)- phenyl]-2-hydroxy-2-methyl-l-propanone (Irgacure 2959), Phosphate Buffered Saline (PBS) solution tablets, poly(ethylene glycol) methacrylate (Mn = 360 Da, PEGMA), poly(ethylene glycol) methyl ether methacrylate (PEGMEMA, Mn 500 Da), poly(ethylene glycol) methyl ether acrylate (PEGMEA, Mn 480 Da) and poly(ethylene glycol) dimethacrylate (PEGDMA, Mn 750 Da) were purchased from Sigma (Dorset, UK). Poly(lactide-co-glycolide) PDLG 7502,75:25, PLGA 75 / 25) were purchased from Corbion Purac Biomaterials (Hollism, Netherlands). Albumin from chicken egg white, i.e. ovalbumin (OVA) was purchased from Sigma Aldrich (Basingstoke, UK). Silicone tubing (peroxide cured, inner diameter 0.6 mm, wall thickness 0.27 mm) was purchased from Polymer System Technology, UK.

[0280] 2.2 Preparation of OV 1, OV 2, OV 3, OV 4 and OV 6 implants

[0281]

[0282] One mg of PLGA 7502, i.e. 75 / 25 (Corbion Purac Biomaterials, Hollism, Netherlands) and 0.5 mg of Irgacure 2959 (Sigma Aldrich, Basingstoke, UK) were dissolved in a mixture of (i) 68.5 mg PEGDA 700 Da (OV1) or (ii) 49.1 mg PEGDA 700 Da and 19.4 mg PEGMA 360 Da (OV2) or (iii) 49.1 mg PEGDA 700 Da and 19.4 mg PEGMEMA 500 Da (OV3) or (iv) 49.1 mg PEGDA 700 Da and 19.4 mg PEGMEA 480 Da (OV4) or (v) 49.1 mg PEGDMA 750 Da and 19.4 mg PEGMA 360 Da (OV6) to make Solution A Thirty mg of albumin from chicken egg white, i.e. ovalbumin (Sigma Aldrich, Basingstoke, UK) was placed in an Eppendorf tube (Sarstedt, Numbrecht, Germany) containing 45 pL of ultrapure water to make Solution B Solution A ​added slowly to Solution B while stirring continuously at 600 rpm for 10 minutes and then at 300 rpm for another 30 minutes. The mixture thus obtained was taken into a silica gel tube (Polymer System Technology, UK) with an inner diameter (ID) of 0.635 mm and photo-crosslinked using UV light (Light Solution A 6, Heraeus Noblelight Fusion UV Inc., Gaithersburg, MD, USA) at 365 nm. The intensity of the UV light was set to 50% and the silica gel tube was exposed to the UV light for 15 seconds (i.e. a total of 5 runs). The implant was then taken out of the silica gel tube and dried in vacuum at 25 °C for 4 hours. The rod-shaped implant was cut in lengths of every 5 mm.

[0283] 2.3 In vitro drug release set up

[0284] In vitro release was performed by placing two (2) OV 1 implants into glass vials containing 2 mL of PBS (Phosphate Buffered Saline) and 0.05% w / w NaN3(pH 7.4 ± 0.2) as release medium. Similar in vitro release was performed for implants OV 2, OV 3, OV 4 and OV 6. All experiments were performed in triplicate. The glass vials containing the implants were placed in an incubator and incubated at 37 °C and 40 rpm (GFL rotary shaking incubator; Gesellschaft fur Labortechnik GmbH, Germany). Sampling was performed at day 1 and every week thereafter (i.e. day 7, day 14, day 21, day 28, etc.) and then the PBS medium was completely changed. The concentration of the released drug molecules in the PBS samples was analyzed as described in the following section.

[0285] 2.4 In vitro degradation study set up

[0286] ​In vitro degradation studies were performed by placing two (2) OV1 implants in glass vials containing 4 mL of 10 mM NaOH as an accelerated degradation condition medium or 4 mL of PBS (phosphate buffered saline) and 0.05% w / w NaN3(pH 7.4 ± 0.2) as an environmental condition degradation medium. Similar in vitro degradation was performed for OV2, OV3, OV4 and OV6 implants. All experiments were performed in triplicate. The glass vials containing the implants were placed in an incubator and incubated at 37°C and 40 rpm (GFLOrbitai Shaking Incubator; Gesellschaft fur Labortechnik mbH, Germany). Sampling was performed at each time point followed by complete replacement of the degradation medium. Accelerated condition degradation was performed for 30 days, while environmental condition degradation was performed simultaneously with in vitro drug release until completion of release. Samples were analyzed for wet weight, dry weight, wet diameter and dry diameter of the implants after each time point.

[0287] 2.5 Sample analysis

[0288] Analysis of Ovalbumin (OVA) in vitro release samples was performed using SEC-HPLC with UV detection (Agilent 1260 Infinity Quaternary system, Agilent Ltd., UK) using Biosep-SEC-S3000 columns (length 300 mm, internal diameter 7.8 mm and particle size 5 pm) and Security Guard Cartridges GFC 3000 (4 x 3.0 mm ID) (Phenomenex, Torrance, USA) at a flow rate of 1.0 ml / min for 14 minutes. Detection was performed by UV detector at 214 nm.

[0289] 2.6 Results

[0290] Figure 4 Accelerated degradation profiles of OV1 to OV4 implants are shown. The degradation profiles indicate that the use of various monoacrylate polymers in the implant matrix increases the rate of degradation. Figure 5 Similar degradation profiles of OV2 and OV6 implants are shown, indicating that the use of another diacrylate, i.e. poly(ethylene glycol) dimethacrylate, does not have a beneficial effect in enhancing the degradation of the implants. Therefore, the use of monoacrylate polymers is responsible for increasing the rate of degradation of the implants. Figure 6It was shown that the use of mono-acrylates such as poly(ethylene glycol) methyl acrylate, PEGMA (OV2) or poly(ethylene glycol) methyl ether methacrylate, PEGMEMA (OV3) can increase the degradation rate of the implant while maintaining a drug release rate above the minimum therapeutic dose level for 56 days or more.

[0291] Example 3: Dexamethasone (DEX), molecular weight 392.46 Da

[0292] 3.1 Materials

[0293] Poly(ethylene glycol) diacrylate (Mn = 250 Da, PEGDA 700), 1 -[4-(2- hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1 -propanone (Irgacure 2959), phosphate buffered saline (PBS) solution tablets, poly(ethylene glycol) methyl acrylate (Mn = 360 Da, PEGMA) were purchased from Sigma (Dorset, UK). Poly(d,l-lactide-co-glycolide) (PLGA) (50:50, 75:25, 85:15, 90:10, 95:5, 99:1) were purchased from Corbion Purac Biomaterials (Hollinheim, Netherlands). Dexamethasone (DEX) was purchased from Alfa Aesar (Hitchin, UK). Silicone tubing (peroxide cured, internal diameter 0.3 mm, wall thickness 0.17 mm) was purchased from Polymer System Technology, UK.

[0294] 3.2 Preparation of DEX 1, DEX 2 and DEX 3 implants

[0295]

[0296] For each implant of 100 mg total mixture, 10 mg of DEX (Alfa Aesar, Hitchen, UK) was mixed with 5 mg of PLGA 75 / 25 (Corbion Purac Biomaterials, Hoorn, Netherlands) and added to (i) 84.5 mg of PEGDA250 (DEX 1) or (ii) 74.5 mg PEGDA250 and 10 mg PEGMA 360 (DEX 2) or (iii) 64.5 mg PEGDA250 and 20 mg PEGMA 360 (DEX 3). The mixture was stirred at 200 rpm for 24 hours (Multistirrer, Velp Scientifica™, Italy). Finally, 0.5 mg of Irgacure 2959 was added to each mixture and stirred for a further 10 minutes. The final mixture obtained was taken into a silicone tube (Polymer System Technology, UK) with an internal diameter (ID) of 0.300 mm and photo-crosslinked using UV light of 365 nm (Light 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 seconds (i.e. a total of 10 runs). The rod-shaped implants were cut at a length of every 5 mm.

[0297] 3.3 In vitro drug release set up

[0298] In vitro release was performed by placing four (4) DEX 1 implants into glass vials containing 4 mL of PBS (Phosphate Buffered Saline) and 0.05% w / w NaN3(pH 7.4 ± 0.2) as release medium. Similar in vitro release was performed for implants DEX 2 and DEX 3. All experiments were performed in triplicate. The glass vials containing the implants were placed in an incubator and incubated at 37°C and 40 rpm (SciQuip FL16-2 cold incubation shaker, SciQuip Ltd., Skelmersdale, UK). At the sampling time points of day 1 and every week thereafter (i.e. day 7, day 14, day 21, day 28, etc.), 1 mL of PBS was withdrawn and replaced with 1 mL of fresh PBS. The concentration of the released drug molecules in the PBS samples was analysed as described in the following section.

[0299] 3.4 In vitro degradation study set up

[0300] In vitro degradation studies were performed by placing four (4) DEX 1 implants into glass vials containing 4 mL of 50 mM NaOH as an accelerated degradation condition medium or 4 mL of PBS (Phosphate Buffered Saline) and 0.05% w / w NaN3(pH 7.4 ± 0.2) as an environmental condition degradation medium. Similar in vitro degradation was performed for DEX 2 and DEX 3 implants. All experiments were performed in triplicate. The glass vials containing the implants were placed in an incubator and incubated at 37°C and 40 rpm (SciQuip FL16-2 cold room incubator shaker, SciQuip Ltd., Cheshire, UK). Sampling was performed at each time point followed by complete replacement of the degradation medium. Accelerated condition degradation was performed for 16 days, while environmental condition degradation was performed simultaneously with in vitro drug release until release was complete. Samples were analysed for wet weight, dry weight, wet diameter and dry diameter of the implants after each time point.

[0301] 3.5 Sample analysis

[0302] Analysis of dexamethasone (DEX) in vitro release samples was performed using a VWD-HPLC (Agilent 1260 Infinity quaternary system, Agilent Ltd., UK) equipped with UV detection, using a Poroshell 120 EC-C18, 4pm (250 x 4.60 mm) analytical column and a refillable guard column (Agilent, UK). The mobile phase consisted of acetonitrile and water in a ratio of 40:60. The mobile phase was filtered under vacuum through a 0.45pm membrane filter (Whatman International, UK) and degassed prior to use. The flow rate of the mobile phase was 0.8 mL / min and the drug was detected at a wavelength of 245 nm. Chromatographic separation of DEX was achieved at ambient room temperature (24 ± 2°C).

[0303] 3.6 Results

[0304] Figure 7 Accelerated degradation profiles of DEX 1, DEX 2 and DEX 3 implants in 50 mM NaOH at 37°C and an oscillation speed of 40 rpm are shown. The degradation profiles indicate that the use of a monoacrylate polymer in the implant matrix increases the rate of degradation. Figure 8The daily DEX release rate (in pg) per implant is shown in comparison to the weight loss of the DEX1, DEX2 and DEX3 implants. This demonstrates that the use of the monoacrylate polymer is responsible for increasing the degradation rate of the implant while maintaining the drug release rate above the minimum therapeutic level for 56 days and beyond. (Nehmé A, Lobenhofer EK, Stamer WD, Edelman JL. Glucocorticoids with different chemical structures but similar glucocorticoid receptor potency regulate subsets of common and unique genes in human trabecular meshwork cells. BMC Med Genomics. 2009 Sep 10;2:58).

[0305] Example 4: Latanoprost (LP), molecular weight 432 Da

[0306] 4.1 Materials

[0307] Poly(ethylene glycol) diacrylate (Mn= 250 Da, PEGDA700), 1 -[4-(2- hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1 -propanone (Irgacure 2959), Phosphate buffered saline (PBS) solution tablets, Poly(ethylene glycol) methacrylate (Mn= 360 Da, PEGMA) were purchased from Sigma (Dorset, UK). Poly(d,l-lactide-co-glycolide) (PLGA 50:50, PLGA50 / 50), Poly(d,l-lactide-co-glycolide) (PDLG 75:25, PLGA75 / 25) were purchased from Corbion Purac Biomaterials (Hollindem, Netherlands). Latanoprost (LP) was purchased from Alfa Chemistry, New York, USA. Silicone tubing (peroxide cured, 0.3 mm internal diameter, 0.17 mm wall thickness) was purchased from Polymer System Technology, UK. Poly(ethylene glycol) diacrylate (Mn= 250 Da, PEGDA700), 1 -[4-(2- hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1 -propanone (Irgacure 2959), Phosphate buffered saline (PBS) solution tablets, Poly(ethylene glycol) methacrylate (Mn= 360 Da, PEGMA) were purchased from Sigma (Dorset, UK). Poly(d,l-lactide-co-glycolide) (PLGA 50:50, PLGA50 / 50), Poly(d,l-lactide-co-glycolide) (PDLG 75:25, PLGA75 / 25) were purchased from Corbion Purac Biomaterials (Hollindem, Netherlands). Latanoprost (LP) was purchased from Alfa Chemistry, New York, USA. Silicone tubing (peroxide cured, 0.3 mm internal diameter, 0.17 mm wall thickness) was purchased from Polymer System Technology, UK.

[0308] 4.2 Preparation of LP1, LP2 and LP3 implants

[0309]

[0310] Irgacure 2959 (Sigma Aldrich, Basingstoke, UK) was dissolved in acetonitrile to make solution A. 50 mg of latanoprost (LP) (Alfa Chemistry, USA, New York) was dissolved in 0.5 mL of acetonitrile to make solution B. For the preparation of 250 mg of LP-polymer mixture, (i) 186.25 mg of PEGDA250 and 12.5 mg of PLGA75 / 25 (Purac Biochem, Hollinheim, Netherlands) (LP1) or (ii) 161.25 mg of PEGDA250, 25 mg of PEGMA 360 and 12.5 mg of PLGA75 / 25 (Purac Biochem, Hollinheim, Netherlands) (LP2) or (iii) 136.2 mg of PEGDA250, 50 mg of PEGMA 360 and 12.5 mg of PLGA75 / 25 (Purac Biochem, Hollinheim, Netherlands) (LP3) were placed in a 2 mL Eppendorf tube, dissolved with 250 pL of acetonitrile to make solution C. Then 62.5 pL of solution A and 0.5 mL of solution B were added to solution C, followed by stirring at 250 rpm for 30 minutes (Multistirrer, Velp Scientifica™, Italy). Acetonitrile was then evaporated at a gauge pressure of -0.1 MPa at room temperature for 6 hours (OV-12 vacuum oven; JeioTech, Korea). The final mixture obtained was drawn into a silicone tube (Polymer System Technology, UK) with an inner diameter (ID) of 0.32 mm by using a 25G needle connected to a 1 mL syringe, and photo-crosslinking was performed using a UV light (Light 6,Heraeus Noblelight Fusion UV Inc.,USA, Gaithersburg, MD) at 365 nm. The intensity of the UV light was set to 100% and the silicone tube was exposed to the UV light for 30 seconds (i.e. a total of 10 runs). The rod-shaped implants were cut at a length of every 5 mm.

[0311] 4.3 In vitro drug release set up

[0312] In vitro release was performed by placing four (4) LP1 implants into glass vials containing 4 mL of PBS (Phosphate Buffered Saline) and 0.05% w / w NaN3(pH 7.4 ± 0.2) as release medium. Similar in vitro release was performed for implants LP2 and LP3. All experiments were performed in triplicate. The glass vials containing the implants were placed in an incubator and incubated at 37°C and 40 rpm (SciQuip FL16-2 cold incubation shaker, SciQuip Ltd. Shropshire, UK). At the sampling time points of day 1 and every week thereafter (i.e. day 7, day 14, day 21, day 28, etc.) 1 mL of PBS was withdrawn and replaced with 1 mL of fresh PBS. The PBS samples were analysed for the concentration of released drug molecules as described in the following section.

[0313] 4.4 In vitro degradation study set up

[0314] In vitro degradation studies were performed by placing four (4) LP1 implants into glass vials containing 4 mL of 50 mM NaOH as accelerated degradation condition medium or 4 mL of PBS (Phosphate Buffered Saline) and 0.05% w / w NaN3(pH 7.4 ± 0.2) as environmental condition degradation medium. Similar in vitro degradation was performed for LP2 and LP3 implants. All experiments were performed in triplicate. The glass vials containing the implants were placed in an incubator and incubated at 37°C and 40 rpm (SciQuip FL16-2 cold incubation shaker, SciQuip Ltd. Shropshire, UK). Sampling was performed at each time point and the degradation medium was then completely replaced. Accelerated condition degradation was performed for 16 days, whereas environmental condition degradation was performed simultaneously with in vitro drug release until release was complete. Samples were analysed for wet weight, dry weight, wet diameter and dry diameter of the implants after each time point.

[0315] 4.5 Sample analysis

[0316] Analysis of LP1, LP2 and LP3 samples was performed using an HPLC system with fluorescence detection (Agilent 1260 Infinity II Quaternary System) using a Poroshell 120 EC-C18 column (250 mm length, 4.6 mm internal diameter and 4 pm particle size). Samples were analysed in isocratic mode using acetonitrile: 0.1% v / v formic acid (60:40) mobile phase with an injection volume of 50 pL and a flow rate of 1 mL / min. The column temperature was maintained at 40°C. The fluorescence detector had an excitation wavelength of 265 nm and an emission wavelength of 285 nm.

[0317] 4.6 Results

[0318] Figure 9 Accelerated degradation curves of LP1, LP2 and LP3 implants in 50mM NaOH at 37°C and 40rpm shaking speed are shown. The degradation curves show that the use of a monoacrylate polymer in the implant matrix increases the degradation rate. Figure 10 The comparison of the daily LP release rate (in pg) per implant versus the implant weight loss of LP1, LP2 and LP3 implants is shown. This shows that the use of a monoacrylate polymer helps to increase the degradation rate of the implant while keeping the drug release rate above the minimum therapeutic level of 0.105 pg / day (Sharif, N. A., Kelly, C. R., Crider, J. Y.; Agonist activity of bimatoprost, travoprost, latanoprost, unoprostone isopropyl ester and other prostaglandin analogs at the cloned human ciliary body FP prostaglandin receptor; Journal of Ocular Pharmacology and Therapeutics, (2002); 18:313-324) for at least 35 days.

[0319] Example 5: Bevacizumab (BEZ), molecular weight 150 kDa

[0320] 5.1 Materials

[0321] Poly(ethylene glycol) diacrylate (Mn = 700 Da, PEGDA700), 1 -[4-(2- hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1 -propanone (Irgacure 2959), Phosphate buffered saline (PBS) solution tablets, Poly(ethylene glycol) methacrylate (Mn = 360 Da, PEGMA) were purchased from Sigma (Dorset, UK). Poly(d,l-lactide-co-glycolide) PDLG 7502,75:25, PLGA 75 / 25) were purchased from Corbion Purac Biomaterials (Hollindem, Netherlands). Bevacizumab (BEZ) Bevacizumab (BEZ) was purchased from a local pharmacy (Roche, Switzerland; 100 mg BEZ contained in each vial of 4 mL, i.e. 25 mg / ml). Silicone tubing (peroxide cured, inner diameter 0.635 mm, wall thickness 0.27 mm) was purchased from Polymer System Technology, UK.

[0322] 5.2 Preparation of F19, B6 and B7 implants

[0323]

[0324]

[0325] For the preparation of polymer mixtures, 50 mg of PLGA7502 (75 / 25) was dissolved in (i) 442.5 mg of PEGDA700 (F19) or (ii) 392.5 mg of PEGDA700 and 50 mg of PEGMA360 (B6) or (iii) 420.5 mg of PEGDA700 and 22.1 mg of PEGMA360 (B7) to make solution A. 6 mg of Irgacure 2559 was dissolved in 1 mL of PBS (0.01 M, pH 7.4) to make solution B. 62.5 μL of solution B was taken in a 2 mL Eppendorf tube. Subsequently, 25 mg of BEZ was added to the Eppendorf tube and stirred with a stir bar at 250 rpm for 30 seconds. The mixture so obtained was left for 30 minutes at 4-7 °C to dissolve and then centrifuged at 2000 rpm for 1 minute to remove air bubbles. To the mixture so obtained, 25 mg of solution A was added and then stirred at 250 rpm for 30 minutes. It was then centrifuged at 2000 rpm for 1 minute to remove air bubbles and then stirred again at 250 rpm for 10 minutes. The final mixture obtained was taken out into a silicone tube (ID: 0.635 mm) and crosslinked using a light hammer (Light Hammer® 6, Heraeus Noblelight Fusion UV Inc., Gaithersburg, MD, USA). The intensity of the UV light (365 nm) was set to 50% and the silicone tube was exposed to the UV light for 15 seconds (5 runs). The rod-shaped implant was taken out of the silicone tube and dried in vacuum at 25 °C for 4 hours. The dried implant was cut into 5 mm long. 6, Heraeus Noblelight Fusion UV Inc., Gaithersburg, MD, USA). The intensity of the UV light (365 nm) was set to 50% and the silicone tube was exposed to the UV light for 15 seconds (5 runs). The rod-shaped implant was taken out of the silicone tube and dried in vacuum at 25 °C for 4 hours. The dried implant was cut into 5 mm long.

[0326] 5.3 In vitro drug release study

[0327] For the drug release studies, one implant each of F19, B6 and B7 was placed in glass vials containing 1 ml of PBS (pH 7.4, 0.05% NaN3). The glass vials were placed in a static incubator at 37 °C. Sampling was done on day 1 and every week thereafter (i.e. 7thday, 14thday, 21stday, 28thday, etc.) followed by complete change of the PBS release medium. All experiments were performed in triplicate. The concentration of the released drug molecules in the PBS samples was analyzed as described below.

[0328] 5.4 SEC-HPLC analysis method for BEZ

[0329] SEC HPLC (Agilent 1260 Infinity Quad System) with fluorescence detection was used. BioZen TM SEC-2 column (length 150 mm, internal diameter 4.6 mm and particle size 1.8 pm) and BioZen TM SEC-20.46 mm Security Guard Ultra Cartridge (Phenomenex, Torrance, USA) was used for the analysis of bevacizumab (BEZ) released from B6 and F19 implants. BEZ samples were analysed in isocratic mode using 35 mM sodium phosphate buffer (pH 6.8, 300 mM NaCI) as mobile phase, with an injection volume of 10 pL and a flow rate of 0.5 mL / min. The column temperature was kept at 25 °C. The fluorescence detector was set at an excitation wavelength of 280 nm and an emission wavelength of 340 nm.

[0330] 5.5 BEZ Micro BCA analysis method

[0331] The analysis of bevacizumab (BEZ) released from B7 implants was performed using the Micro BCA Protein Assay Kit (Pierce Biotechnology, Thermofisher Scientific, USA). Briefly, 150 pL of sample was mixed with 150 pL of Micro BCA reagent mixture and incubated at 37 °C for 2 hours. The colour intensity due to the interaction between the protein and the Micro BCA reagent was measured at a wavelength of 562 nm.

[0332] 5.6 In vitro degradation study set up

[0333] In vitro degradation studies were performed by placing one F19 implant in a glass bottle containing 4 mL of 10 mM NaOH as accelerated degradation condition medium or 4 mL of PBS (Phosphate Buffered Saline) and 0.05% w / w NaN3(pH 7.4 ± 0.2) as environmental condition degradation medium. Similar in vitro degradation studies were performed for B6 and B7 implants. All experiments were performed in triplicate. The glass bottles containing the implants were placed in an incubator and incubated at 37 °C (MINI / 100 / F, Genlab Limited, Cheshire, UK). Sampling was performed at each time point and then the degradation medium was completely changed. Accelerated condition degradation was performed for 28 days, while environmental condition degradation was performed simultaneously with in vitro drug release until release was completed. Samples were analysed for wet weight, dry weight, wet diameter and dry diameter of the implants after each time point.

[0334] 5.7 Results

[0335] Figure 11Accelerated degradation curves of F19, B6 and B7 implants in 10 mM NaOH at 37 °C are shown. The degradation curves indicate that the use of a monoacrylate polymer in the implant matrix increases the rate of degradation. Figure 12 The daily BEZ release rate (in pg) per implant is shown in comparison to the weight loss of the implants for F19, B6 and B7 implants. This indicates that the use of a monoacrylate polymer is responsible for increasing the degradation rate of the implants while maintaining the drug release rate above the minimum target therapeutic level of 0.5 pg / day (approximately 5 times the IC50 value, Wang Y, Fei D, Vanderlaan M, Song A. Angiogenesis. 2004; 7: 335) for at least 56 days (for B6 implants).

[0336] Example 6: Ovalbumin (OVA, molecular weight 42.7 kDa)

[0337] 6.1 Materials

[0338] Poly(ethylene glycol) diacrylate (Mn = 700 Da, PEGDA700), l-[4-(2- hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-l-propanone (Irgacure 2959), phosphate buffered saline (PBS) solution tablets and poly(ethylene glycol) methacrylate (Mn = 360 Da, PEGMA) were purchased from Sigma (Dorset, UK). Poly(d,l-lactide-co-glycolide) PDLG 7502,75:25, PLGA 75 / 25) were purchased from Corbion Purac Biomaterials (Hollinheim, Netherlands). Albumin from chicken egg white, i.e. ovalbumin (OVA) was purchased from Sigma Aldrich (Basingstoke, UK). Silicone tubing (peroxide cured, internal diameter 0.6 mm, wall thickness 0.27 mm) was purchased from Polymer System Technology, UK.

[0339] 6.2 Preparation of B1, B2, B3 implants

[0340]

[0341]

[0342] 5 mg PLGA 7502, i.e. 75 / 25 (Corbion Purac Biomaterials, Hollinheim, Netherlands) was dissolved in a mixture of (i) 35.1 mg PEGDA 700 Da and 19.4 mg PEGMA 360 Da (B1) or (ii) 30.5 mg PEGDA 700 Da and 24 mg PEGMA 360 Da (B2) or (iii) 26.5 mg PEGDA 700 Da and 28 mg PEGMA 360 Da (B3) to make Solution A 5 mg Irgacure 2959 (Sigma Aldrich, Basingstoke, UK) was dissolved in 1 ml PBS to make Solution B Solution B 40 mg of albumin from chicken egg white, i.e. ovalbumin (Sigma Aldrich, Basingstoke, UK) was placed in 60 μL Solution C of PBS in an Eppendorf tube (Sarstedt, Numbrecht, Germany) to make Solution A Solution C was added to the Eppendorf tube. The Solution A slowly added to 6.3 In vitro drug release set up while continuously stirring at 600 rpm for 15 minutes. The final obtained mixture was taken out into a silicone tube with an inner diameter (ID) of 0.635 mm (Polymer System Technology, UK) and photo-crosslinked using UV light at 365 nm (Light 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 implant was then taken out of the silicone tube and dried in vacuum at 25 °C for 4 hours. The rod-shaped implant was cut in lengths of every 5 mm.

[0343] 6.4 In vitro degradation study set up

[0344] ​In vitro release was performed by placing two (2) B1 implants into glass vials containing 2 mL of PBS (Phosphate Buffered Saline) and 0.05% w / w NaN3(pH 7.4 ± 0.2) as release medium. Similar in vitro release was performed for implants B2 and B3. All experiments were performed in triplicate. The glass vials containing the implants were placed in an incubator and incubated at 37°C and 40 rpm (GFL shaking incubator; Gesellschaft fur Labortechnik mbH, Germany). Sampling was performed at day 1 and then every week (i.e. day 7, day 14, day 21, day 28, etc.) followed by complete exchange of the PBS medium. The concentration of released drug molecules in the PBS samples was analyzed as described in the following section.

[0345] 6.5 Sample analysis

[0346] In vitro degradation studies were performed by placing two (2) B1 implants into glass vials containing 4 mL of 10 mM NaOH as accelerated degradation condition medium or 4 mL of PBS (Phosphate Buffered Saline) and 0.05% w / w NaN3(pH 7.4 ± 0.2) as ambient condition degradation medium. Similar in vitro degradation was performed for implants B2 and B3 implants. All experiments were performed in triplicate. The glass vials containing the implants were placed in an incubator and incubated at 37°C and 40 rpm (GFL shaking incubator; Gesellschaft fur Labortechnik mbH, Germany). Sampling was performed at each time point followed by complete exchange of the degradation medium. Accelerated condition degradation was performed for 30 days, while ambient condition degradation was performed simultaneously with in vitro drug release until release was completed. Samples were analyzed for wet and dry weight of the implants after each time point.

[0347] 6.6 Results

[0348] Analysis of Ovalbumin (OVA) in vitro release samples was performed using SEC-HPLC with UV detector (Agilent 1260 Infinity quaternary system, Agilent Ltd., UK) using Biosep-SEC-S3000 column (length 300 mm, inner diameter 7.8 mm and particle size 5 pm) and Security Guard Cartridges GFC 3000 (4 x 3.0 mm ID) (Phenomenex, Torrance, USA). 20 pL of sample was eluted with 27 mM Phosphate buffer and 150 mM NaCl pH 6.35 at a flow rate of 1.0 ml / min for 14 min. Detection was performed by UV detector at 214 nm.

[0349] Figure 13

[0350] Figure 14 Accelerated degradation curves for B1, B2 and B3 implants are shown. The more PEGMA polymer content in the implant, the faster the implant degrades. ​ Daily OVA release rates and degradation curves for implants B1, B2 and B3 are shown. The higher PEGMA concentration in the B3 implant results in faster degradation of the implant (measured as percent loss of implant weight) while maintaining a release rate above the minimum therapeutic level for at least 75 days.

Claims

1. An ophthalmic composition comprising: a) at least 0.1% w / w of a therapeutic agent; b) 5-95% w / w of a photopolymerizable composition, wherein the photopolymerizable composition comprises 5-70% w / w of one or more compounds of Formula I: I wherein R1 is hydrogen or a linear or branched C1-C3 alkyl group; R2 is an acrylate or methacrylate group; n is 2 or 3 and m is equal to or greater than 1, the weight percent of the one or more compounds of Formula I being based on the total weight of the photopolymerizable composition, and the photopolymerizable composition further comprises a poly(ethylene glycol) diacrylate or a poly(ethylene glycol) dimethacrylate; c) 0.1-40% w / w of a biodegradable polymer selected from the group consisting of poly(lactide-co-glycolide), poly(L-lactide), polyhydroxyalkanoate, polyglycolic acid, polycaprolactone, poly(DL-lactide), poly(D-lactide), poly(lactide-co-caprolactone), poly-L-lactide-co-caprolactone and mixtures thereof, copolymers; and d) a photoinitiator.

2. The ophthalmic composition of claim 1, wherein the one or more compounds of Formula I are selected from the group consisting of poly(ethylene glycol) acrylate, poly(ethylene glycol) methacrylate, poly(ethylene glycol) methyl ether acrylate, poly(ethylene glycol) methyl ether methacrylate, ethylene glycol methyl ether acrylate, di(ethylene glycol) ethyl ether acrylate, ethylene glycol methyl ether methacrylate, di(ethylene glycol) ethyl ether methacrylate.

3. The ophthalmic composition of claim 2, wherein the compound of Formula I is poly(ethylene glycol) methacrylate.

4. The ophthalmic composition of any one of claims 1 to 3, wherein the photopolymerizable composition comprises 5-60% w / w of one or more compounds of Formula I.

5. The ophthalmic composition of any one of claims 1 to 3, comprising 40-75% w / w of the photopolymerizable composition.

6. The ophthalmic composition of any one of claims 1 to 3, wherein the biodegradable polymer is poly(lactide-co-glycolide), poly(L-lactide), poly(DL-lactide) and poly(lactide-co-caprolactone).

7. The ophthalmic composition of any one of claims 1 to 3, wherein the biodegradable polymer is poly(lactide-co-glycolide).

8. The ophthalmic composition of any one of claims 1 to 3, wherein the therapeutic agent is present in an amount of 20-70% w / w and the photopolymerizable composition is present in an amount of 20-75% w / w.

9. The ophthalmic composition of any one of claims 1 to 3, comprising a) 10-50% w / w of a therapeutic agent; b) 1-20% w / w of poly(lactide-co-glycolide); c) 30-88.99% w / w of a photopolymerizable composition consisting of poly(ethylene glycol) methacrylate and poly(ethylene glycol) diacrylate; d) 0.01-5% w / w of a photoinitiator selected from the group consisting of 1-[4-(2- hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propanone, phenyl-bis(2, 4,6- trimethylbenzoyl)-phosphine oxide and mixtures thereof, wherein the weight ratio of poly(ethylene glycol) diacrylate: poly(ethylene glycol) methacrylate is 0.5-20.

10. The ophthalmic composition according to claim 9, wherein the weight ratio of poly(ethylene glycol) diacrylate: poly(ethylene glycol) methacrylate is 0.5-15.

11. The ophthalmic composition according to claim 9, wherein the weight ratio of poly(ethylene glycol) diacrylate: poly(ethylene glycol) methacrylate is 1-15.

12. The ophthalmic composition according to claim 9, wherein the weight ratio of poly(ethylene glycol) diacrylate: poly(ethylene glycol) methacrylate is 1-10.

13. The ophthalmic composition according to claim 9, wherein the weight ratio of poly(ethylene glycol) diacrylate: poly(ethylene glycol) methacrylate is 2-5.

14. The ophthalmic composition according to any one of claims 1 to 3, wherein the therapeutic agent is ranibizumab, bevacizumab, latanoprost, dexamethasone or timolol maleate.

15. A method of manufacturing an ophthalmic implant, comprising the steps of: a) providing an ophthalmic composition according to any one of claims 1 to 14; and b) irradiating the ophthalmic composition with light having a wavelength of 200-550 nm for a period of 1 second to 60 minutes to form the ophthalmic implant.

16. An ophthalmic implant comprising at least 0.1% w / w of a therapeutic agent, 5-95% w / w of a crosslinked polymeric matrix and 0.1-40% w / w of a biodegradable polymer selected from the group consisting of poly(lactide-co-glycolide), poly(L-lactide), polyhydroxyalkanoate, polyglycolic acid, polycaprolactone, poly(DL-lactide), poly(D-lactide), poly(lactide-co-caprolactone), poly-L-lactide-co-caprolactone and mixtures thereof, characterized in that: a) the crosslinked polymeric matrix is obtained by crosslinking a photopolymerizable composition, wherein the photopolymerizable composition comprises 5-70% w / w of one or more compounds of formula I: I wherein R1 is hydrogen or a linear or branched C1-C3 alkyl group; R2 is an acrylate or methacrylate group; n is 2 or 3 and m is equal to or greater than 1, the weight percentage of the one or more compounds of formula I being based on the total weight of the photopolymerizable composition, and the photopolymerizable composition further comprises poly(ethylene glycol) diacrylate or poly(ethylene glycol) dimethacrylate; b) the therapeutic agent and the biodegradable polymer are embedded in the polymeric matrix.

17. The ophthalmic implant according to claim 16, comprising: a) 10-50% w / w of the therapeutic agent; b) 1-20% w / w of poly(lactide-co-glycolide); c) 30-89% w / w of the crosslinked polymer matrix obtained by crosslinking a photopolymerizable composition consisting of poly(ethylene glycol) methacrylate and poly(ethylene glycol) diacrylate, wherein the weight ratio of poly(ethylene glycol) diacrylate: poly(ethylene glycol) methacrylate is 0.5-20.

18. The ocular implant of claim 17, wherein the weight ratio of poly(ethylene glycol) diacrylate: poly(ethylene glycol) methacrylate is 0.5-15.

19. The ocular implant of claim 17, wherein the weight ratio of poly(ethylene glycol) diacrylate: poly(ethylene glycol) methacrylate is 1-15.

20. The ocular implant of claim 17, wherein the weight ratio of poly(ethylene glycol) diacrylate: poly(ethylene glycol) methacrylate is 1-10.

21. The ocular implant of claim 17, wherein the weight ratio of poly(ethylene glycol) diacrylate: poly(ethylene glycol) methacrylate is 2-5.

22. The ocular implant of claim 16, consisting of: a) 10-50% w / w of the therapeutic agent; b) 1-20% w / w of poly(lactide-co-glycolide); c) 30-89% w / w of the crosslinked polymer matrix obtained by crosslinking a photopolymerizable composition consisting of poly(ethylene glycol) methacrylate and poly(ethylene glycol) diacrylate, wherein the weight ratio of poly(ethylene glycol) diacrylate: poly(ethylene glycol) methacrylate is 0.5-20.

23. The ocular implant of claim 22, wherein the weight ratio of poly(ethylene glycol) diacrylate: poly(ethylene glycol) methacrylate is 0.5-15.

24. The ocular implant of claim 22, wherein the weight ratio of poly(ethylene glycol) diacrylate: poly(ethylene glycol) methacrylate is 1-15.

25. The ocular implant of claim 22, wherein the weight ratio of poly(ethylene glycol) diacrylate: poly(ethylene glycol) methacrylate is 1-10.

26. The ocular implant of claim 22, wherein the weight ratio of poly(ethylene glycol) diacrylate: poly(ethylene glycol) methacrylate is 2-5.

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