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; JPEG2023530173000014.jpg1485 wherein R1 is hydrogen or a straight or branched C1-C3 alkyl, R2 is an acrylate or methacrylate group, n is 2 or 3, and m is 1 or greater, and the weight percentage of the one or more compounds of Formula I is based on the total weight of the photopolymerizable composition; c) lactide / glycolide copolymers (including poly(lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA ), 0.1 to 40% w / w of a biodegradable polymer selected from the group consisting of polyhydroxyalkanoates, including polyhydroxybutyrate, polyglycolic acid (PGA), polycaprolactone (PCL), poly(DL-lactide) (PDL), poly(D-lactide), lactide / caprolactone copolymers, poly-L-lactide-co-caprolactone (PLC), and mixtures, copolymers, and block copolymers thereof; and 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 Art

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

[0003] Multiple approaches are used to deliver therapeutic agents to the PS of the eye, such as systemic, topical, periocular (or transscleral), and intravitreal. Topical (e.g., eye drops) and systemic (e.g., oral tablets) routes require administration of unnecessarily high concentrations of therapeutic agents, which cause therapeutic agent-related toxicity and result in low or sub-therapeutic drug levels due to multiple ocular barriers, leading to low therapeutic efficacy.

[0004] International Publication No. 2017081154 discloses ophthalmic compositions that can be administered to the eye in various forms to achieve controlled release of therapeutic agents. These compositions can be used to form ophthalmic implants by crosslinking the formulation in situ after injection into the patient's eye, or they can be pre-formed before injection into the eye.

[0005] An alternative system is needed for the ocular delivery of therapeutic agents. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] International Publication No. 2017081154 [Overview of the Initiative]

[0007] In a first aspect, the present invention relates to an ophthalmic composition that can be administered to the eye in various forms to achieve controlled release of a therapeutic agent. Such an ophthalmic composition is a) At least 0.1% w / w therapeutic agent, b) A photopolymerizable composition containing one or more compounds of formula I in 3-70% w / w amounts, with a w / w content of 5-95% w / w. In formula JPEG0007855531000001.jpg1485, R1 is hydrogen or a linear or branched C1-C3 alkyl group, R2 is an acrylate or methacrylate group, n is 2 or 3, m is 1 or more, and the weight percentage of one or more compounds of formula I is based on the total weight of the photopolymerizable composition. c) 0.1 to 40% w / w biodegradable polymers selected from the group consisting of lactide / glycolide copolymers (including poly(lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), polyhydroxyalkanoates including polyhydroxybutyrate, polyglycolic acid (PGA), polycaprolactone (PCL), poly(DL-lactide) (PDL), poly(D-lactide), lactide / caprolactone copolymers, poly-L-lactide-co-caprolactone (PLC), and mixtures thereof, copolymers, and block copolymers, and d) Contains a photoinitiator.

[0008] In a further embodiment, the present invention relates to the above-mentioned ophthalmic composition for use in the preparation of ophthalmic implants.

[0009] In further embodiments, the present invention relates to a method for preparing the above-mentioned ophthalmic composition, an implant based on the above-mentioned ophthalmic composition, and an ophthalmic implant obtained by such a method.

[0010] In a further embodiment, the present invention relates to an ophthalmic implant comprising, as defined above, at least 0.1% w / w therapeutic agent, 5 to 95% w / w crosslinked polymer matrix, and 0.1 to 40% w / w biodegradable polymer, characterized in that the crosslinked polymer matrix is ​​obtained by crosslinking the photopolymerizable composition as defined above.

[0011] The present invention provides ophthalmic compositions and implants that can be administered to the eye in various forms to achieve controlled release of therapeutic agents. The present invention allows for the administration of a variety of small and large therapeutic molecules, including proteins, peptides, and gene therapies, and enables the flexibility to maintain their activity for a controlled period.

[0012] The presence of one or more compounds of formula I in the photopolymerizable composition allows for optimized delivery and complete degradation of the implant after the release of the therapeutic compound has been stopped.

[0013] The disintegration of the implant according to this invention occurs along with drug release. The complete disintegration of the ejected implant also allows for the injection of additional implants if the treatment procedure must be continued. Even if the organ can partition two or more implants simultaneously, the co-existence time between the old and new implants should be kept as short as possible in all cases.

[0014] The compositions and implants of the present invention exhibit a delivery profile that allows for the release of therapeutically effective amounts of drug over a long period of time while being sufficiently degraded after the completion of drug release.

[0015] Furthermore, the implant according to the present invention maintains its physical structure during decomposition and therefore does not break down into multiple particles that could cause a series of undesirable mini-burst effects, particularly within organs. Thus, the formation of particle debris in the anterior and / or posterior parts of the eye, which carries the potential risk of clogging the trabecular network, is avoided, and proper drainage of aqueous humor from the eye is maintained. [Brief explanation of the drawing]

[0016] [Figure 1] This shows the in vitro accelerated degradation profiles of O1, O2, O3, and O4 implants in 10 mM NaOH at 37°C with a shaking rate of 40 rpm.

[0017] [Figure 2] This shows the daily OVA release (μg) profiles (Y1 axis) versus the percentage of implant weight (Y2 axis) for each of the O1, O2, O3, and O4 implants in PBS (pH 7.4) at 37°C and a shaking rate of 40 rpm.

[0018] [Figure 3] Scanning electron microscope (SEM) images of morphological changes in composition O1 and O4 implants during ambient condition decomposition in 10 mM PBS (pH 7.4) at 37°C and a shaking speed of 40 rpm are shown.

[0019] [Figure 4] Shows the in vitro accelerated degradation profiles of OV1, OV2, OV3 and OV4 in 10 mM NaOH at 37 °C with a shaking speed of 40 rpm.

[0020] [Figure 5] Shows the in vitro accelerated degradation profiles of OV2 and OV6 in 10 mM NaOH at 37 °C with a shaking speed of 40 rpm.

[0021] [Figure 6] Shows the daily OVA release (μg) profile (Y1 axis) vs. percentage of implant weight (Y2 axis) for each of the OV1, OV2, OV3, OV4 and OV6 implants in PBS (pH 7.4) at 37 °C and a shaking speed of 40 rpm.

[0022] [Figure 7] Shows the accelerated degradation profiles of the DEX1, DEX2 and DEX3 implants in 50 mM NaOH at 37 °C and a shaking speed of 40 rpm.

[0023] [Figure 8] Shows the daily DEX release (μg) profile (Y1 axis) vs. percentage of implant weight (Y2 axis) for each of the DEX1, DEX2 and DEX3 implants in PBS (pH 7.4) at 37 °C and a shaking speed of 40 rpm.

[0024] [Figure 9] Shows the accelerated degradation profiles of the LP1, LP2 and LP3 implants in 50 mM NaOH at 37 °C and a shaking speed of 40 rpm.

[0025] [Figure 10]This shows the daily LP release (μg / mL) profiles (Y1 axis) versus the percentage of implant weight (Y2 axis) for each LP1, LP2, and LP3 implant in PBS (pH 7.4) at 37°C and a shaking rate of 40 rpm.

[0026] [Figure 11] The accelerated degradation profiles of F19, B6, and B7 implants in 50 mM NaOH incubated in a static incubator at 37°C are shown.

[0027] [Figure 12] The BEZ release (μg / mL) profiles (Y1 axis) of each implant in PBS (pH 7.4) versus the weight percentage of the implant in 10 mM NaOH (Y2 axis) for F19, B6, and B7 implants incubated in a static incubator at 37°C are shown.

[0028] [Figure 13] This shows the in vitro accelerated degradation profiles of B1, B2, and B3 implants in 10 mM NaOH at 37°C with a shaking rate of 40 rpm.

[0029] [Figure 14] This shows the daily OVA release (μg) profiles (Y1 axis) versus the percentage of implant weight (Y2 axis) for each of the B1, B2, and B3 implants in PBS (pH 7.4) at 37°C and a shaking rate of 40 rpm. [Modes for carrying out the invention]

[0030] Where used herein, unless otherwise specified, the term "%w / w" means, in some cases, the weight percentage of a given component relative to the total weight of a copolymer, composition, or implant containing such component.

[0031] As used herein, “biodegradable” means chemical degradation by biological means. In some embodiments, biodegradation is the degradation of one or more of a composition, monomer, oligomer, fragment, polymer, photoinitiator, solvent, cosolvent, or coinitiator by 100%, 98%, 90%, 85%, 80%, 60%, 50%, or 45%.

[0032] As used herein, “copolymer” is a mixture of two or more different types of monomer units. As used herein, “block copolymer” is a mixture of two or more homopolymer subunits.

[0033] The therapeutic agents of the present invention can be selected from a wide range of small and large molecules. Exemplary therapeutic agents include, but are not limited to, polypeptides, nucleic acids such as DNA, RNA and siRNA, growth factors, steroids, antibody therapies including bispecific antibodies, antibacterial agents, antibiotics, antiretroviral therapeutic agents, anti-inflammatory compounds, antitumor agents, anti-angiogenic agents, anti-VEGF (vascular endothelial growth factor) agents, chemotherapeutic agents, various ophthalmic agents, mydriatics, ophthalmic anesthetics, ophthalmic anti-infectives, ophthalmic anti-inflammatory agents, ophthalmic antihistamines and decongestants, ophthalmic diagnostic agents, ophthalmic glaucoma agents, ophthalmic lubricants and irrigators, ophthalmic steroids, ophthalmic steroids including anti-infectives, ophthalmic surgical agents, and tyrosine kinase inhibitors.

[0034] In some other embodiments, the molecular weight of the therapeutic agent is greater than 200kDa, 500kDa, 1000kDa, 10kDa, 30kDa, 50kDa, 75kDa, 100kDa, 150kDa, 200kDa, and 250kDa.

[0035] In one embodiment, the therapeutic agent of the present invention includes ketrolac, naphazoline, lidocaine, bevacizumab, aflibercept, brolucizumab, pegaptanib, brimonidine tartrate, dorzolamide, bromfenac sodium, azithromycin, rapamycin, bepotastine besylate, diclofenac, becifloxacin, cysteamine hydrochloride, fluocinolone acetonide, difluprenate, tasimerteon, ocliplasmin, enoxaparin sodium, ranibizumab, latanoprost, timolol maleate, bimatoprost, ofloxacin, cefazolin, Examples include phenylephrine, dexamethasone, triamcinolone acetonide, levofloxacin, cyclophosphamide, melphalancyclosporine, 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.

[0036] In another embodiment, the therapeutic agent of the present invention is dexamethasone, timolol maleate, brimonidine tartrate, triamcinolone acetonide, bromfenac sodium, latanoprost, or a mixture thereof.

[0037] In one embodiment, the composition or implant of the present invention can deliver a bioactive agent, a high molecular weight therapeutic agent, such as aflibercept, pegaptanib, or an antibody therapeutic agent, such as ranibizumab, bevacizumab, trastuzumab, rituximab, gentuzumab, osagamicin, brolucizumab, cetuximab, falisimab, convercept, or a biosimilar thereof.

[0038] In one embodiment, the therapeutic agent of the present invention is ranibizumab, bevacizumab, latanoprost, dexamethasone, or timolol maleate.

[0039] According to other embodiments of the present invention, the therapeutic agent is present in amounts 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.

[0040] The therapeutic agent can be used as is, or in the form of a solution in which a certain amount of the therapeutic agent is dissolved in a suitable solvent. The therapeutic agent can also be freeze-dried or spray-dried before use in the preparation of the ophthalmic composition of the present invention to facilitate the incorporation of high concentrations of the therapeutic agent into implants. The amount of therapeutic agent to be dissolved depends on the final load that the ophthalmic composition or implant should have. The choice of solvent depends on the polarity of the therapeutic agent.

[0041] According to embodiments of the present invention, the solvent can be selected from water, dimethyl sulfoxide, decyl methyl sulfoxide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, N-vinyl-pyrrolidine, N-methyl-2-pyrrolidone, N-ethyl-pyrrolidone, glycerol formal, glycerol, polyethylene glycol, propylene glycol, benzyl alcohol, benzyl benzoate, ethyl benzoate, triacetin, triethyl citrate, dimethylformamide, dimethylacetamide, and tetrahydrofuran.

[0042] In one embodiment, a cosolvent may be used, which can be selected from dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, acetic acid, methanol, ethanol, isopropanol, glycoflore, or butanol.

[0043] In the case of hydrophilic therapeutic agents, the solvent may be water or an aqueous solvent such as phosphate-buffered saline (PBS) solution.

[0044] According to another embodiment, the solvent may be selected from dimethyl sulfoxide, decyl methyl sulfoxide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, N-methyl-2-pyrrolidone, and glycerol formal.

[0045] Furthermore, the solvents and co-solvents described herein can be used in combination with any of the other photopolymerizable compositions, biodegradable polymers, photoinitiators, pore-forming agents, and co-initiators described herein to prepare any of the compositions and implants of the present invention.

[0046] The photopolymerizable fragments or monomers of the present invention can be used in any of the compositions and implants of the present invention in combination with any other biodegradable polymers, therapeutic agents, photoinitiators, solvents, cosolvents, drug modifiers, and coinitiators described herein or known in the common general knowledge.

[0047] In one embodiment, complete biodegradation occurs over a period of 1 to 4 times the total drug release time of the implant. As an example of this embodiment, an implant of the present invention that delivers a drug over a period of 3 months should completely degrade within 3 to 12 months after injection into the organ.

[0048] As used herein, the term “photopolymerizable composition” refers to a composition that can form a crosslinked polymer network when exposed to light, particularly UV light. As used herein, a photopolymerizable composition includes photopolymerizable monomers and oligomers (e.g., dimers, trimers, and tetramers). The terms “oligomer” and “fragment” can be used interchangeably to mean between 2 and 20 monomers, optionally between 2 and 10 monomers, even more optionally between 2 and 5 monomers, or between 2 and 4 monomers. A “photopolymerizable monomer” is a single unit of a photopolymerizable polymer that can be chemically bonded to other monomers to form a polymer.

[0049] The photopolymerizable composition of the present invention can be crosslinked with UV radiation to form a crosslinked polymer matrix for the ophthalmic implant of the present invention.

[0050] In one embodiment, R1 of one or more compounds of formula I is independently selected from hydrogen and methyl. In yet another embodiment, n in formula I is equal to 2.

[0051] According to further embodiments of the present invention, 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, one or more compounds of formula I are poly(ethylene glycol) methacrylate (PEGMA).

[0052] In one embodiment of the present invention, the photopolymerizable composition comprises one or more compounds of formula I in amounts of 5-60% w / w, 5-45% w / w, 5-20% w / w, or 10-15% w / w, where the weight percentage is based on the total weight of the photopolymerizable composition.

[0053] According to another embodiment, the photopolymerizable composition further comprises poly(alkylene glycol) diacrylate, poly(alkylene glycol) dimethacrylate, their monomers, oligomers, mixtures, copolymers, and block copolymers.

[0054] In one embodiment, the photopolymerizable composition includes monomers incorporating diacrylate-terminated units such as 3-armed, 4-armed, or 8-armed PEG acrylates.

[0055] 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, and 1,6-hexanediol dimethacrylate.

[0056] In one embodiment of the present invention, the weight ratios between one or more such disubstituted acrylate or methacrylate compounds and one or more compounds of formula I are 0.5 to 20, 0.5 to 15, 1 to 15, 1 to 10, and 2 to 5.

[0057] In another embodiment, one or more disubstituted acrylate or methacrylate compounds of the photopolymerizable composition are polyethylene glycol diacrylate (PEGDA) or polyethylene glycol dimethacrylate (PEGDMA).

[0058] In yet another embodiment, one or more disubstituted acrylate or methacrylate compounds in the photopolymerizable composition are polyethylene glycol diacrylate (PEGDA).

[0059] In yet another embodiment, the photopolymerizable composition further comprises polyethylene glycol diacrylate (PEGDA).

[0060] In yet another embodiment, the weight ratio of PEGDA:PEGMA is 0.5-20, 0.5-15, 1-15, 1-10, and 2-5.

[0061] PEGMA and PEGDA are synthetic polymers available in different molecular weights. They are highly adaptable to mechanical, structural, and chemical modifications, resulting in hydrogels with diverse properties for drug delivery and other biomedical applications. PEGMA and PEGDA are formed by the functionalization of one or both ends of each PEG molecule, each containing an acrylate group. PEGMA and PEGDA are non-toxic and induce only minimal immunogenic responses. PEGMA and PEGDA have double-bond-containing acrylate-terminated groups that exhibit rapid polymerization upon exposure to light in the presence of a suitable initiator, generating a hydrogel network.

[0062] The average molecular weight of the photopolymerizable composition of the present invention is typically 100-300,000 Da, 200-100,000 Da, 200-50,000 Da, 200-20,000 Da, 200-10,000 Da, 200-8,000 Da, 200-5,000 Da, or 200-1,000 Da.

[0063] The photopolymerizable compositions of the present invention typically have a viscosity of 0.1 to 7 dL / g, 0.2 to 5 dL / g, or 0.5 to 2 dL / g.

[0064] In the embodiment, the photopolymerizable composition is present in amounts of 10-75% w / w, 20-75% w / w, 30-75% w / w, 40-75% w / w, and 45-75% w / w of the total weight of the ophthalmic composition.

[0065] The biodegradable polymers of the present invention can be used in combination with any of the other photopolymerizable compositions, therapeutic agents, photoinitiators, solvents, cosolvents, therapeutic agent release regulators, and coinitiators described herein or known in the common general knowledge in any of the compositions and implants of the present invention.

[0066] The biodegradable polymer of the present invention is biodegradable, but not photopolymerizable.

[0067] In one embodiment of the present invention, the biodegradable polymer is an aliphatic polyester polyurethane, polylactide, polycaprolactone, polyorthoester, or a mixture thereof, copolymer, or block copolymer.

[0068] In another embodiment of the present invention, the biodegradable polymer is chitosan, poly(propylene fumarate), lactide / glycolide copolymer (PLGA), poly(L-lactide) (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), lactide / caprolactone copolymer (PLC), polyhydroxybutyrate, natural biodegradable polymers such as collagen and hyaluronic acid, or mixtures thereof, copolymers or block copolymers.

[0069] In another embodiment, the biodegradable polymer is selected from the group consisting of lactide / glycolide copolymers (including poly(lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), polyhydroxyalkanoates, such as polyhydroxybutyrate, polyglycolic acid (PGA), polycaprolactone (PCL), poly(DL-lactide) (PDL), poly(D-lactide), lactide / caprolactone copolymers, poly-L-lactide-co-caprolactone (PLC), and mixtures thereof, copolymers, and block copolymers.

[0070] In one embodiment, the biodegradable polymers include lactide / glycolide copolymers (containing poly(L-lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), poly(DL-lactide) (PDL), and lactide / caprolactone copolymers (PLC).

[0071] In certain embodiments, the biodegradable polymer is poly(lactide-co-glycolide) (PLGA).

[0072] PLGA is typically prepared by polymerization of lactic acid and glycolic acid monomers. The glass transition temperature (Tg) of PLGA copolymers is higher than the physiological temperature of 37°C, imparting a moderately rigid chain structure and thus mechanical strength at ambient temperature. Using PLGA with different lactide (LA) to glycolide (GA) ratios and molecular weights allows for different drug release profiles. In one embodiment, the molar ratios of lactic acid to glycolic acid in PLGA are 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.

[0073] In another embodiment, the biodegradable polymer is PCL, PLC, PLA, or a mixture, copolymer, or block copolymer thereof.

[0074] In the embodiment, the biodegradable polymer is present in amounts 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, and 1-5% w / w of the total weight of the ophthalmic composition.

[0075] The photoinitiators described herein can be used in combination with any of the other photopolymerizable compositions, biodegradable polymers, therapeutic agents, photoinitiators, solvents, co-solvents, and co-initiators described herein in any of the compositions and implants of the present invention.

[0076] In certain embodiments, the photoinitiator is designed to act using light in the 200–550 nm range. In some embodiments, the photoinitiator is designed to act using UV light in the 200–500 nm range. In other embodiments, the photoinitiator is designed to act using UV light in the 200–425 nm range.

[0077] In certain embodiments, the light source can allow for differences in the wavelength and / or intensity of the light. Useful light sources in the present invention include, but are not limited to, laser diodes and lamps. Light can be transmitted using optical fiber devices.

[0078] In another embodiment, the photoinitiator may be selected from hydroxyketone photoinitiators, aminoketone photoinitiators, hydroxyketone / benzophenone photoinitiators, benzyldimethylketal photoinitiators, phenylglyoxylate photoinitiators, acylphosphine oxide photoinitiators, acylphosphine oxide / alphahydroxyketone photoinitiators, benzophenone photoinitiators, ribitylisoaloxazine photoinitiators, peroxide photoinitiators, persulfate photoinitiators, or phenylglyoxylate photoinitiators, or any combination thereof. Optionally, the photoinitiator is 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone, 1-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propanone, 2,2-dimethoxy-2-phenylacetophenone (DMPA), diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide (DPPO), or riboflavin. In another embodiment, the photoinitiator is benzoyl peroxide, 2,2''-azobisisobutyronitrile, dicumyl peroxide, lauroyl peroxide, and / or camphorquinone.

[0079] In one embodiment, the photoinitiator is 1-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propanone (Irgacure 2959), phenyl-bis(2,4,6-trimethylbenzoyl)-phosphine oxide (Irgacure 819), or a mixture thereof.

[0080] In one embodiment, the photoinitiator is present in an amount that varies from 0.1 to 5% w / w of the total weight of the ophthalmic composition.

[0081] In one embodiment, the composition of the present invention further comprises a co-initiator. In one embodiment, the co-initiator is triethanolamine, dimethylaminobenzoic acid (DMAB), trimethylolpropane, or L-arginine.

[0082] In another embodiment, the photoinitiator is riboflavin and the coinitiator is L-arginine.

[0083] According to another embodiment of the present invention, the ophthalmic composition is a) 10-50% w / w of the therapeutic agent b) 1-20% w / w of poly(lactide-co-glycolide) (PLGA) c) A photopolymerizable composition comprising poly(ethylene glycol) methacrylate (PEGMA) and poly(ethylene glycol) diacrylate (PEGDA) with a concentration of 30-88.99% w / w. d) comprising or consisting of 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, The weight ratios of PEGDA:PEGMA are 0.5-20, 0.5-15, 1-15, 1-10, and 2-5.

[0084] According to yet another embodiment of the present invention, an ophthalmic composition, a) 20-50% w / w therapeutic agent b) 5-20% w / w of poly(lactide-co-glycolide) (PLGA) c) A photopolymerizable composition comprising poly(ethylene glycol) methacrylate (PEGMA) and poly(ethylene glycol) diacrylate (PEGDA) with a concentration of 30-74.99% w / w. d) comprising or consisting of 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, The weight ratio PEGDA:PEGMA is 0.5-20, 0.5-15, 1-15, 1-10, or 2-5.

[0085] In one embodiment, the therapeutic agent is ranibizumab, bevacizumab, latanoprost, dexamethasone, or timolol maleate.

[0086] In one embodiment, the composition of the present invention includes a release regulator. A suitable release regulator may be selected considering the composition of the particular therapeutic agent and implant, as well as the desired dissolution profile or release rate. The release regulator may be a naturally occurring drug or polymer, or a synthetic drug or polymer.

[0087] All release regulators described herein can be used in combination with any of the other photopolymerizable compositions, biodegradable polymers, therapeutic agents, photoinitiators, solvents, co-solvents, and co-initiators described herein in any of the implants and compositions of the present invention.

[0088] Release regulators may be present in amounts of 0.1-40% w / w, 1-30% w / w, 1-20% w / w, 1-10% w / w, and 5-10% w / w.

[0089] Optionally, a release regulator alters the water absorption into the implant matrix, thereby controlling the release rate of the therapeutic agent and the degradation of the implant. In embodiments, suitable water absorption regulators are one or more polysaccharides, e.g., chitosan and cellulosic materials, e.g., hydroxypropyl methylcellulose (HPMC); hyaluronic acid; poloxamer; polyethers similar to polyethylene glycol, e.g., gelatin; polyvinylpyrrolidone; polyvinyl alcohol and mixtures thereof. In one embodiment, suitable water absorption regulators are hydroxypropyl methylcellulose (HPMC) and polyethylene glycol (PEG).

[0090] In one embodiment, the release regulator is a pore-forming agent and / or a stability enhancer. Optionally, these are lactose, maltose, glucose, mannitol, sodium chloride, magnesium carbonate, magnesium hydroxide, potassium chloride, sodium bicarbonate, ammonium bicarbonate, potassium bicarbonate, agarose, or sucrose.

[0091] In another embodiment, the release regulator is a mixture of two or more of the above-mentioned regulators for imparting two or more functions to the ophthalmic composition or implant of the present invention. Optionally, the release regulator is polyethylene glycol, hydroxypropyl methylcellulose (HPMC), or a mixture thereof.

[0092] Optionally, the porosity of the implant can be adjusted by preparing the implant in the presence of dispersed water-soluble porosinogen, which can then be removed by washing with water, leaving an interconnected network structure (i.e., a porous hydrogel). The pore size of the hydrogel prepared by the porosinogen technique depends on the size of the porosinogen.

[0093] In another embodiment of the present invention, the ophthalmic composition does not contain a release regulator.

[0094] Another aspect of the present invention is to provide the above-described ophthalmic composition for use in the preparation of ophthalmic implants. Alternatively, the ophthalmic composition of the present invention may be used to coat ophthalmic implants or supports for ophthalmic implants.

[0095] A further aspect of the present invention is a method for preparing the above-described ophthalmic composition. This method comprises the steps of: dissolving a therapeutic agent in a solvent / co-solvent to obtain a solution or suspension; and subsequently mixing the therapeutic agent solution thus obtained with a polymerizable composition, a biodegradable polymer, a photoinitiator, and optionally a release regulator, 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, a photoinitiator, and optionally a release regulator, 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, a photoinitiator, and optionally a release regulator.

[0096] The choice of solvent that can be used according to the present invention depends on the polarity of the therapeutic agent.

[0097] Optionally, the solvent can be selected from water, dimethyl sulfoxide, decyl methyl sulfoxide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, N-vinyl-pyrrolidine, N-methyl-2-pyrrolidone, N-ethyl-pyrrolidone, glycerol formal, glycerol, polyethylene glycol, propylene glycol, benzyl alcohol, benzyl benzoate, ethyl benzoate, triacetin, triethyl citrate, dimethylformamide, dimethylacetamide, acetonitrile, dichloromethane, and tetrahydrofuran.

[0098] In one embodiment, a cosolvent may be used, which can be selected from dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, acetic acid, methanol, ethanol, isopropanol, glycoflore, or butanol.

[0099] In the case of hydrophilic therapeutic agents, the solvent may be water or an aqueous solvent such as phosphate-buffered saline (PBS) solution.

[0100] According to another embodiment, the solvent may be selected from dimethyl sulfoxide, decyl methyl sulfoxide, acetonitrile, 2-pyrrolidone, 1-methyl-2-pyrrolidone, N-methyl-2-pyrrolidone, and glycerol formal.

[0101] Alternatively, the therapeutic agent may not be dissolved in the solvent before being mixed with other components. Therefore, the therapeutic agent, polymerizable composition, biodegradable polymer, photoinitiator, and optionally release regulator may be mixed together in any order of addition. Alternatively, the therapeutic agent may be first mixed with a portion of the photopolymerizable composition, and another portion of the photopolymerizable composition may be mixed with the biodegradable polymer, photoinitiator, and optionally release regulator.

[0102] A further aspect of the present invention is a method for producing an ophthalmic implant of the present invention, comprising the steps of: preparing an ophthalmic composition of the present invention; and subsequently irradiating the ophthalmic composition with light of wavelengths of 200-550 nm, 200-500 nm, 200-490 nm, or 200-425 nm for periods of 1 second to 60 minutes, 30 seconds to 30 minutes, 2.5 minutes to 20 minutes, or 5 minutes to 10 minutes. In one embodiment, the crosslinking period is 3 seconds, 6 seconds, 9 seconds, 15 seconds, 30 seconds, 1 minute, 2.5 minutes, 5 minutes, 10 minutes, 20 minutes, or 30 minutes.

[0103] A further aspect of the present invention is an ophthalmic implant that can be obtained by the method described above.

[0104] In one embodiment, the rate and degree of drug release can be controlled by changing the polymer molecular weight, type and copolymer ratio, drug type and load, implant size, UV crosslinking time and degree, photoinitiator, release regulator, solvent and / or co-solvent amount and type. These changes in factors result in compositions of the present invention that can be easily adjusted to produce a desired drug release period to address specific clinical / patient needs in the treatment of various eye diseases.

[0105] The ophthalmic composition of the present invention is i) After injection into the eye, UV light is briefly irradiated to induce photocrosslinking in the situ, resulting in the formation of an implant called an in-situ photocrosslinked implant (ISPcI). ii) The implant may be photocrosslinked before application to the eye to form an implant of a desired shape and size (e.g., a film, rod, or nano / microparticles), which may then be administered intraocularly to provide a desired drug delivery period, known as a pre-formed photocrosslinked implant (PPcI).

[0106] Alternatively, the compositions of the present invention can be used to coat ophthalmic devices, including both in-situ and pre-molded ophthalmic devices.

[0107] The implants of the present invention may be any desired shape, but are not limited to rectangular, square, spherical, cylindrical, circular, elliptical, film, dumbbell, rod, and bead.

[0108] The implant of the present invention can have any desired size, which may be, for example, in the range of macro, micro, or nanoparticle sizes.

[0109] In one embodiment, the ophthalmic implant is an implant having one dimension less than 10 mm, less than 5 mm, or less than 3 mm. In one embodiment, the implant is a rectangular implant with dimensions of 10 × 5 × 0.5 mm. In one embodiment, the implant (ISPcI) is a spherical implant with a diameter of less than 10 mm, less than 5 mm, or less than 3 mm. In one embodiment, the ophthalmic implant is a nanoparticle or microparticle.

[0110] In one embodiment, the nanoparticle ophthalmic implant has a size of less than 1,000 nm, less than 900 nm, less than 750 nm, less than 500 nm, or less than 100 nm.

[0111] In one embodiment, the microparticle ophthalmic implant is less than 1,000 μm, less than 900 μm, less than 750 μm, less than 500 μm, or less than 25 μm.

[0112] Optionally, the implant is an ophthalmic implant formed in situ. Alternatively, the implant is a pre-formed ophthalmic implant.

[0113] The in-situ photocrosslinking implants (ISPcIs) according to the present invention are designed to take up and form a final local structure once inserted into the body. One of their advantages is that ISPcIs can fill irregular defects. The ISPcIs of the present invention also have additional advantages, including site-specific action due to relatively easy and less invasive application, local delivery to specific tissues, extended delivery time, reduced side effects associated with systemic delivery, and excellent patient comfort and compliance. A further advantage of the ISPcIs of the present invention is that they do not require extreme pH conditions or high temperatures during processing, which can cause problems when working with temperature or pH unstable drugs such as proteins, peptides, or genetic material. Furthermore, rapid crosslinking at physiological temperatures can rapidly capture drug molecules, resulting in ISPcIs that lead to long-term controlled drug release. Photocrosslinking is also beneficial compared to spontaneous crosslinking (e.g., enzymatic, self-assembly, Michael addition) because the process is initiated only when exposed to a light source, and therefore, premature gelation is not an issue, resulting in excellent control over material formation. Furthermore, since UV light is clinically used for corneal crosslinking, short-term application of UV light is considered safe for ocular use and does not cause any safety issues. Importantly, this method of administration allows for the injection of relatively low-viscosity materials into the body, which then solidifies by phase inversion, forming a semi-solid depot, which, at the time of photocrosslinking, controls drug delivery to produce short- or long-term therapeutic effects.

[0114] In one embodiment, ISPcI is formed by injecting the ophthalmic composition of the present invention into a subject requiring it and then crosslinking it 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.

[0115] In the case of ISPcI of the present invention, the molecular weight of the photopolymerizable composition is typically 100 to 6,000 Da, 200 to 3,000 Da, or 200 to 1,000 Da.

[0116] The pre-formed photocrosslinked implants (PPcIs) of the present invention can be inserted into the eye, for example, in the fornix, subconjunctival, anterior chamber, intrastromal / intracorneal, transscleral / periorbital, intrascleral or intravitreous, or subretinal, to treat diseases of the anterior or posterior part of the eye. PPcIs can be manufactured in a variety of shapes, including but not limited to rods, films, cylindrical or circular, and in sizes including micro or nanoparticle forms.

[0117] In one embodiment, PPcI nanoparticles and microparticles are obtained by sonicating a mixture of a therapeutic agent, a photopolymerizable composition, a biodegradable polymer, a photoinitiator, and optionally a release regulator in an aqueous medium. In one embodiment, the aqueous medium is a combination of water and phosphate-buffered saline (PBS). Irradiation can be applied during sonication, i.e., sonicating the mixture under UV light, or it can be performed after the sonication process.

[0118] The PPCI of the present invention has the advantage of a high crosslink density and / or a tight polymer network structure, which can be configured to control drug release and / or eliminate any burst release.

[0119] The PPCI of the present invention can be manufactured to have a single layer and / or multilayer structure that allows loading of two or more drugs or the same drug with different release profiles or release rates.

[0120] Furthermore, the rate of implant disintegration can be made slower with PPCI than with ISPCI according to the present invention, and can be controlled in terms of the function of the specific disease or disorder being treated.

[0121] In the case of PPCI of the present invention, the average molecular weight of the photopolymerizable polymer is typically 100-300,000 Da, 200-100,000 Da, 200-50,000 Da, 200-20,000 Da, or 200-10,000 Da.

[0122] In one embodiment, the present invention is PLGA / PEGDA / PEGMA PPcI. In another embodiment, the present invention is PLGA / PEGDA / PEGMA ISPcI.

[0123] In one embodiment, polymers of a photopolymerizable composition, such as PEGDA and PEGMA, can act as a solvent before they are crosslinked in situ to form ISPcI. The polymers of the photopolymerizable composition also help prevent the dispersion of different components of the composition within the organ after injection and before they are immobilized at the time of crosslinking.

[0124] In one embodiment, the biodegradable polymer is essentially contained within the matrix of the photopolymerizable composition. Optionally, the biodegradable polymer is essentially contained within the matrix of the photopolymerizable composition that forms a gel upon mixing. In one embodiment, the photopolymerizable polymer is crosslinked in the presence of a photoinitiator, as well as the biodegradable polymer and the therapeutic agent. In one embodiment, the biodegradable polymer is essentially hydrophobic, and the photopolymerizable polymer is essentially hydrophilic. In one embodiment, the degree of crosslinking of the composite implant governs the release rate and extent of the therapeutic agent.

[0125] Another aspect of the present invention is an ophthalmic implant comprising at least 0.1% w / w of a therapeutic agent, 5 to 95% w / w of a crosslinked polymer matrix, and 0.1 to 40% w / w of a biodegradable polymer selected from the group consisting of lactide / glycolide copolymers (including poly(lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), polyhydroxyalkanoates including polyhydroxybutyrate, polyglycolic acid (PGA), polycaprolactone (PCL), poly(DL-lactide) (PDL), poly(D-lactide), lactide / caprolactone copolymers, poly-L-lactide-co-caprolactone (PLC) and mixtures thereof, copolymers and block copolymers, a) The crosslinked polymer matrix is ​​obtained by crosslinking a photopolymerizable composition containing one or more compounds of formula I in an amount of 3-70% w / w. In formula JPEG0007855531000002.jpg1485, R1 is hydrogen or a linear or branched C1-C3 alkyl group, R2 is an acrylate or methacrylate group, n=2 or 3, m is 1 or more, and the weight percentage of one or more compounds of formula I is based on the total weight of the photopolymerizable composition. b) The therapeutic agent and biodegradable polymer are embedded in a polymer matrix in an ophthalmic implant.

[0126] As used herein, “embedded” means that the therapeutic agent is essentially captured within a crosslinked polymer matrix and is uniformly dispersed or dissolved in the crosslinked polymer matrix and / or biodegradable polymer.

[0127] In the compositions and implants of the present invention, the rate and duration of drug release can be controlled by varying the UV crosslinking time. In some embodiments, increasing the UV crosslinking time results in a decrease in drug release. Furthermore, the rate and duration of drug release can be controlled by varying the concentration of the photoinitiator. Moreover, the rate and duration of drug release can be controlled by varying both the UV crosslinking time and the concentration of the photoinitiator. In one embodiment, the addition of a pore-forming agent (e.g., MgCO3) increases the drug release rate. In one embodiment, a higher UV crosslinking time and a higher concentration of photoinitiator can sustain drug release for a longer period. In one embodiment, drug release can last for a period exceeding 1 day, 2 days, 1 week, 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months.

[0128] In some embodiments, the controlled degradation rates of ISPCI and PPCI of the present invention result in the protection of sensitive molecules such as peptides and proteins.

[0129] In some embodiments, burst release can be eliminated or controlled by changing the UV crosslinking time and the formulation composition and implant volume.

[0130] In one embodiment, the present invention is a PPcI with no or low burst release. In one embodiment, the present invention is a PPcI having a high crosslinking density that significantly slows drug diffusion.

[0131] Any implants and compositions described herein are suitable for use in any method of the present invention as described herein.

[0132] In one embodiment, the present invention is a method for treating an eye disease or disorder of a subject requiring such treatment, comprising administering a composition or implant of the present invention to a region of the eye of the subject.

[0133] In one embodiment, the present invention is a composition or implant for use in the treatment of eye diseases or disorders of a subject requiring such treatment.

[0134] As used herein, “region of the eye” refers to the medial, lateral, or adjacent regions of the eye in question. In one embodiment, the region of the eye is the sclera (intrascleral), episcleral (transscleral), vitreous humor, choroid, cornea, interstitial tissue, anterior chamber, aqueous humor, lens, limbus, or optic nerve.

[0135] In one embodiment, the composition and implant can be administered onto the cornea by injection, including intravitreous, subconjunctival, periocular, sub-Tenon's capsule, or retroocular injection.

[0136] In some embodiments, the implant is administered via a surgical procedure. In some embodiments, the implant is secured in place via adhesive or sutures after surgical implantation.

[0137] The term “subject” refers to animals (e.g., birds such as chickens, quail, or turkeys, or mammals), specifically “mammals” including non-primates (e.g., cattle, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (e.g., monkeys, chimpanzees, and humans), and more specifically humans. In one embodiment, the subject is a non-human animal such as livestock (e.g., horses, cattle, pigs, or sheep) or pets (e.g., dogs, cats, guinea pigs, or rabbits). In another embodiment, the subject is “human.”

[0138] As used herein, the terms “to treat,” “to treat,” and “treating” include, but are not limited to, a therapeutic treatment that includes a reduction or improvement in the progression, severity, and / or duration of a disease, disorder, or condition resulting from the administration of a composition or implant of the present invention, or an improvement in one or more symptoms (specifically, one or more identifiable symptoms) of the disease, disorder, or condition. In certain embodiments, a therapeutic treatment includes an improvement in at least one measurable physical parameter of the disease, disorder, or condition. In other embodiments, a therapeutic treatment includes inhibition of the progression of the condition by means of physical, for example, stabilization of an identifiable symptom; by physiological, for example, stabilization of a physical parameter; or both. In other embodiments, a therapeutic treatment includes alleviation or stabilization of the disease, disorder, or condition.

[0139] In one embodiment, the disease or disorder is pain, inflammation, infection, cataract, allergy, age-related macular degeneration (AMD), diabetic retinopathy (DR), macular edema, diabetic macular edema (DME), cytomegalovirus (CMV), retinitis, retinitis pigmentosa, uveitis, dry eye syndrome, keratitis, glaucoma, blepharitis, palpebral conjunctivitis, palpebral conjunctivitis, elevated intraocular pressure, conjunctivitis, cystinosis, vitreomacular adhesion, corneal neovascularization, corneal ulcer, and postoperative ocular inflammation / wound healing.

[0140] The following is a list of numbered items that are embodiments of the present invention.

[0141] 1. An ophthalmic composition, a) At least 0.1% w / w therapeutic agent, b) A photopolymerizable composition containing one or more compounds of formula I in 3-70% w / w amounts, with a w / w content of 5-95% w / w. In formula JPEG0007855531000003.jpg1485, R1 is hydrogen or a linear or branched C1-C3 alkyl group, R2 is an acrylate or methacrylate group, n is 2 or 3, m is 1 or more, and the weight percentage of one or more compounds of formula I is based on the total weight of the photopolymerizable composition. c) 0.1 to 40% w / w biodegradable polymers selected from the group consisting of lactide / glycolide copolymers (including poly(lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), polyhydroxyalkanoates including polyhydroxybutyrate, polyglycolic acid (PGA), polycaprolactone (PCL), poly(DL-lactide) (PDL), poly(D-lactide), lactide / caprolactone copolymers, poly-L-lactide-co-caprolactone (PLC), and mixtures thereof, copolymers, and block copolymers, and d) An ophthalmic composition comprising a photoinitiator.

[0142] 2. The ophthalmic composition described in item 1, wherein R1 is hydrogen or methyl.

[0143] 3. An ophthalmic composition according to item 1 or 2, wherein n is 2.

[0144] 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.

[0145] 5. The ophthalmic composition according to item 4, wherein the compound of formula I is poly(ethylene glycol) methacrylate (PEGMA).

[0146] 6. An ophthalmic composition according to any one of items 1 to 5, wherein the photopolymerizable composition contains one or more compounds of formula I in an amount of 5 to 60% w / w.

[0147] 7. The ophthalmic composition according to item 6, wherein the photopolymerizable composition contains one or more compounds of formula I in an amount of 5-45% w / w.

[0148] 8. The ophthalmic composition according to item 7, wherein the photopolymerizable composition contains one or more compounds of formula I in an amount of 5-20% w / w.

[0149] 9. The ophthalmic composition according to item 8, wherein the photopolymerizable composition contains one or more compounds of formula I in an amount of 10-15% w / w.

[0150] 10. An ophthalmic composition according to any one of items 1 to 9, further comprising poly(alkylene glycol) diacrylate, poly(alkylene glycol) dimethacrylate, monomers, oligomers, mixtures, copolymers and block copolymers thereof.

[0151] 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 dimethacrylate, di(propylene glycol) dimethacrylate, poly(propylene glycol) dimethacrylate, and 1,6-hexanediol dimethacrylate.

[0152] 12. The ophthalmic composition according to item 11, wherein one or more disubstituted acrylate or methacrylate compounds are poly(ethylene glycol) diacrylate (PEGDA).

[0153] 13. An ophthalmic composition according to item 11 or 12, wherein the weight ratio between one or more disubstituted acrylate or methacrylate compounds and 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.

[0154] An ophthalmic composition according to any of items 1 to 13, comprising a photopolymerizable composition of 14.40-75% w / w.

[0155] 15. An ophthalmic composition according to any one of items 1 to 14, wherein the biodegradable polymer is lactide / glycolide copolymer (containing poly(L-lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), poly(DL-lactide) (PDL), and lactide / caprolactone copolymer (PLC).

[0156] 16. The ophthalmic composition according to item 15, wherein the biodegradable polymer is poly(lactide-co-glycolide) (PLGA).

[0157] 17. An ophthalmic composition according to any of items 1 to 16, wherein the therapeutic agent is present in an amount of 10-70% w / w.

[0158] 18. An ophthalmic composition as described in item 17, wherein the therapeutic agent is present in an amount of 20-70 w / w.

[0159] 19. An ophthalmic composition as described in item 17, wherein the therapeutic agent is present in an amount of 10-60% w / w.

[0160] 20. An ophthalmic composition according to item 17, 18, or 19, wherein the therapeutic agent is present in an amount of 20-50% w / w.

[0161] 21. An ophthalmic composition as described in item 20, wherein the therapeutic agent is present in an amount of 30-50% w / w.

[0162] 22. An ophthalmic composition according to any one of items 1 to 21, wherein a biodegradable polymer is present in an amount of 1 to 20% w / w.

[0163] 23. The ophthalmic composition described in item 22, wherein a biodegradable polymer is present in an amount of 5-20% w / w.

[0164] 24. An ophthalmic composition according to any of items 1 to 23, wherein the photoinitiator is selected from hydroxyketone photoinitiators, aminoketone photoinitiators, hydroxyketone / benzophenone photoinitiators, benzyldimethylketal photoinitiators, phenylglyoxylate photoinitiators, acylphosphine oxide photoinitiators, acylphosphine oxide / α-hydroxyketone photoinitiators, benzophenone photoinitiators, ribitylisoaloxazine photoinitiators, peroxide photoinitiators, persulfate photoinitiators, or phenylglyoxylate photoinitiators, or any combination thereof. Optionally, the photoinitiator is 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone, 1-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propanone, 2,2-dimethoxy-2-phenylacetophenone (DMPA), diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide (DPPO), or riboflavin. In another embodiment, the photoinitiator is benzoyl peroxide, 2,2''-azobisisobutyronitrile, dicumyl peroxide, lauroyl peroxide, and / or camphorquinone.

[0165] 25. The photoinitiator is 1-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propanone, phenyl-bis(2,4,6-trimethylbenzoyl)-phosphine oxide, or a mixture thereof, as described in item 24 for ophthalmic compositions.

[0166] 26. An ophthalmic composition according to any of items 1 to 25, wherein the photoinitiator is present in an amount that varies from 0.1 to 5% w / w.

[0167] 27. a) 10-50% w / w of the therapeutic agent b) 1-20% w / w of poly(lactide-co-glycolide) (PLGA) c) A photopolymerizable composition of 30-88.99 w / w consisting of poly(ethylene glycol) methacrylate (PEGMA) and poly(ethylene glycol) diacrylate (PEGDA). d) comprising or consisting of 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, An ophthalmic composition according to any of items 1 to 26, wherein the weight ratio of PEGDA:PEGMA is 0.5 to 20, 0.5 to 15, 1 to 15, 1 to 10, or 2 to 5.

[0168] 28. a) 20-50% w / w therapeutic agent b) 5-20% w / w of poly(lactide-co-glycolide) (PLGA) c) A photopolymerizable composition comprising poly(ethylene glycol) methacrylate (PEGMA) and poly(ethylene glycol) diacrylate (PEGDA) with a concentration of 30-74.99% w / w. d) comprising or consisting of 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, An ophthalmic composition according to any of items 1 to 26, wherein the weight ratio of PEGDA:PEGMA is 0.5 to 20, 0.5 to 15, 1 to 15, 1 to 10, or 2 to 5.

[0169] 29. An ophthalmic composition according to item 27 or 28, wherein the therapeutic agent is ranibizumab, bevacizumab, latanoprost, dexamethasone, or timolol maleate.

[0170] 30. An ophthalmic composition according to any one of items 1 to 29, further comprising a release regulator.

[0171] 31. The ophthalmic composition according to item 30, wherein the release regulator is selected from polysaccharides, e.g., chitosan and cellulosic materials, e.g., hydroxypropyl methylcellulose (HPMC); hyaluronic acid; poloxamer; polyethers containing 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.

[0172] 32. The ophthalmic composition according to item 31, wherein the release regulator is polyethylene glycol (PEG), hydroxypropyl methylcellulose (HPMC), or a mixture thereof.

[0173] 33. An ophthalmic composition according to any of items 1 to 29, which does not contain a release regulator.

[0174] 34. An ophthalmic composition according to any one of items 1 to 33, for use in the preparation of ophthalmic implants.

[0175] 35. A method for preparing an ophthalmic composition described in any of items 1 to 34, a) A step of dissolving the therapeutic agent in a solvent to obtain a solution or suspension, b) A method comprising the step of mixing the solution obtained under step a) with a polymerizable composition, a biodegradable polymer, a photoinitiator, and optionally an emission regulator.

[0176] 36. The method according to item 35, wherein the solvent is an aqueous solvent.

[0177] 37. A method for fabricating an ophthalmic implant, a) A step of preparing an ophthalmic composition as described in any of items 1 to 34, and b) A method comprising the step of irradiating an ophthalmic composition with light of a wavelength of 200 to 550 nm for a period of 1 second to 60 minutes in order to form an ophthalmic implant.

[0178] 38. The method according to item 37, wherein the ophthalmic composition prepared under step a) is administered to the eye area of ​​interest before being irradiated according to step b).

[0179] 39. The method of item 37, wherein the ophthalmic implant formed under step b) is administered to the ocular region of interest.

[0180] 40. Ocular implants that can be obtained by the methods described in items 35-39.

[0181] 41. An ophthalmic implant comprising at least 0.1% w / w therapeutic agent, 5-95% w / w crosslinked polymer matrix, and 0.1-40% w / w biodegradable polymer selected from the group consisting of lactide / glycolide copolymers (including poly(lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), polyhydroxyalkanoates including polyhydroxybutyrate, polyglycolic acid (PGA), polycaprolactone (PCL), poly(DL-lactide) (PDL), poly(D-lactide), lactide / caprolactone copolymer, poly-L-lactide-co-caprolactone (PLC) and mixtures thereof, copolymers and block copolymers, a) The crosslinked polymer matrix is ​​obtained by crosslinking a photopolymerizable composition containing one or more compounds of formula I in an amount of 3-70% w / w. In formula JPEG0007855531000004.jpg1485, R1 is hydrogen or a linear or branched C1-C3 alkyl group, R2 is an acrylate or methacrylate group, n is 2 or 3, m is 1 or more, and the weight percentage of one or more compounds of formula I is based on the total weight of the photopolymerizable composition. b) An ophthalmic implant characterized in that the therapeutic agent and biodegradable polymer are embedded in a polymer matrix.

[0182] 42. An ophthalmic implant as described in item 41, wherein R1 is hydrogen or methyl.

[0183] 43. An ophthalmic implant as described in item 41 or 42, where n is 2.

[0184] 44. An ophthalmic 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.

[0185] 45. An ophthalmic implant as described in item 44, wherein the compound of formula I is poly(ethylene glycol) methacrylate (PEGMA).

[0186] 46. ​​An ophthalmic implant according to any of items 41 to 45, wherein the photopolymerizable composition comprises one or more compounds of formula I in an amount of 5 to 45% w / w.

[0187] 47. An ophthalmic implant according to item 46, wherein the photopolymerizable composition comprises one or more compounds of formula I in an amount of 5-20% w / w.

[0188] 48. An ophthalmic implant according to item 47, wherein the photopolymerizable composition comprises one or more compounds of formula I in an amount of 10-15% w / w.

[0189] 49. An ophthalmic implant according to any of items 41-48, further comprising poly(alkylene glycol) diacrylate, poly(alkylene glycol) dimethacrylate, monomers, oligomers, mixtures, copolymers and block copolymers thereof.

[0190] 50. The ophthalmic implant according to item 49, wherein the photopolymerizable composition further comprises one or more disubstituted acrylate or methacrylate compounds 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, and 1,6-hexanediol dimethacrylate.

[0191] 51. An ophthalmic implant according to item 50, wherein one or more disubstituted acrylate or methacrylate compounds are poly(ethylene glycol) diacrylate (PEGDA).

[0192] 52. An ophthalmic implant according to item 50 or 51, wherein the weight ratio between one or more disubstituted acrylate or methacrylate compounds and one or more compounds of formula I is 0.5-20, 0.5-15, 1-15, 1-10, and 2-5.

[0193] 53. An ophthalmic implant according to any one of items 41 to 52, wherein the biodegradable polymer is lactide / glycolide copolymer (containing poly(L-lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), poly(DL-lactide) (PDL), and lactide / caprolactone copolymer (PLC).

[0194] 54. An ophthalmic implant as described in item 53, wherein the biodegradable polymer is poly(lactide-co-glycolide) (PLGA).

[0195] 55. An ophthalmic implant described in any of items 41-54, in which the therapeutic agent is present in an amount of 10-70% w / w.

[0196] 56. An ophthalmic implant as described in item 55, in which the therapeutic agent is present in an amount of 20-70% w / w.

[0197] 57. An ophthalmic implant as described in item 55, in which the therapeutic agent is present in an amount of 10-60% w / w.

[0198] 58. An ophthalmic implant as described in item 56 or 57, in which the therapeutic agent is present in an amount of 20-50% w / w.

[0199] 59. An ophthalmic implant as described in item 58, in which the therapeutic agent is present in an amount of 30-50% w / w.

[0200] 60. An ophthalmic implant as described in any of items 40-59, containing a biodegradable polymer in an amount of 1-20% w / w.

[0201] 61. An ophthalmic implant as described in any of item 60, containing a biodegradable polymer in an amount of 5-20% w / w.

[0202] 62. a) 10-50% w / w of the therapeutic agent b) 1-20% w / w of poly(lactide-co-glycolide) (PLGA) c) An ophthalmic implant according to item 41, comprising or comprising a crosslinked polymer matrix of 30-89% w / w obtained by crosslinking a photopolymerizable composition comprising 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.

[0203] 63. a) 20-50% w / w therapeutic agent b) 5-20% w / w of poly(lactide-co-glycolide) (PLGA) c) An ophthalmic implant according to item 62, comprising or comprising a crosslinked polymer matrix of 30-75% w / w obtained by crosslinking a photopolymerizable composition comprising 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.

[0204] 64. An ophthalmic implant as described in any of items 41-63, wherein the therapeutic agent is ranibizumab, bevacizumab, latanoprost, dexamethasone, or timolol maleate.

[0205] 65. An ophthalmic implant according to any of items 41-64, further comprising a release regulator.

[0206] 66. An ophthalmic implant according to item 65, wherein the release regulator is selected from polysaccharides, e.g., chitosan and cellulosic materials, e.g., hydroxypropyl methylcellulose (HPMC); hyaluronic acid; poloxamer; polyethers containing 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.

[0207] 67. An ophthalmic implant according to item 66, wherein the release regulator is polyethylene glycol (PEG), hydroxypropyl methylcellulose (HPMC), or a mixture thereof.

[0208] 68. An ophthalmic implant according to any of items 41 to 64, wherein the composition does not contain any release regulator.

[0209] 69. An ophthalmic implant described in any of items 40-68, which is macro, micro, or nanoparticle. [Examples]

[0210] Example 1: Ovalbumin (OVA, molecular weight 42.7 kDa) 1.1 Materials Poly(ethylene glycol) diacrylate (Mn=700Da, PEGDA 700), 1-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propanone (Irgacure 2959), phosphate-buffered saline (PBS) solution tablets, and poly(ethylene glycol) methacrylate (Mn=360Da, PEGMA) were purchased from Sigma (Dorset, UK). Poly(lactide-co-glycolide) (PURASORB® PDLG 7502, 75:25, PLGA 75 / 25) was obtained from Corbion Purac Biomaterials (Gorinchem, Netherlands). Chicken egg white-derived albumin, i.e., ovalbumin (OVA), was purchased from Sigma Aldrich (Buzzingstoke, UK). The silicone tubing (peroxide cured, inner diameter 0.6mm, wall thickness 0.27mm) was purchased from Polymer System Technology, UK.

[0211] 1.2 Preparation of O1, O2, O3, and O4 implants JPEG0007855531000005.jpg34161

[0212] Solution A was prepared by dissolving 5 mg of PLGA 7502, i.e., 75 / 25 (Corbion Purac Biomaterials, Gorinchem, Netherlands), in one of the following mixtures: (i) 64.7 mg of PEGDA 700Da (O1), (ii) 58.2 mg of PEGDA 700Da and 6.5 mg of PEGMA 360Da (O2), (iii) 51.8 mg of PEGDA 700Da and 12.9 mg of PEGMA 360Da (O3), or (iv) 45.3 mg of PEGDA 700Da and 19.4 mg of PEGMA 360Da (O4). Solution B was prepared by dissolving 5 mg of Irgacure 2559 (Sigma Aldrich, Basingstoke, UK) in 1 ml of PBS. Solution C was prepared by adding 30 mg of chicken egg white albumin (Sigma Aldrich, Basingstoke, UK) to 60 μL of Solution B in an Eppendorf tube (Sarstedt, Numbrechtt, Germany). Solution A was then added to the Eppendorf tube. Solution C was slowly added to Solution A through the wall of the Eppendorf tube while continuously stirring at 900 rpm for 15 minutes. The final mixture was transferred into a 0.635 mm inner diameter (ID) silicone tube (Polymer Systems Technology, UK) and photocrosslinked using 365 nm UV light (Light Hammer® 6, Heraeus Noblelight Fusion UV Inc., Gaithersburg, Maryland, 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 under vacuum at 25°C for 4 hours. Each rod-shaped implant was cut to a length of 7.5 mm.

[0213] 1.3 In vitro drug release settings In vitro release was performed by placing two O1 implants in a glass vial containing 2 mL of PBS (phosphate-buffered saline) with 0.05% w / w NaN3 (pH 7.4 ± 0.2) as the 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 FL 16-2 refrigerated incubation shaker, SciQuip Ltd., Shropshire, UK). Sampling and subsequent complete replacement of the PBS medium were performed on day 1 and then weekly thereafter, i.e., on days 7, 14, 21, 28, etc. The concentrations of the released drug molecules in the PBS samples were analyzed as described in the following sections.

[0214] 1.4 In Vitro Degradation Study Setup In vitro degradation studies were performed by placing two O1 implants in glass vials containing either 4 mL of 10 mM NaOH as the accelerated degradation medium, or 4 mL of PBS (phosphate-buffered saline) containing 0.05% w / w NaN2 (pH 7.4 ± 0.2) as the ambient degradation medium. Similar in vitro degradation 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 FL 16-2 refrigerated incubation shaker, SciQuip Ltd., Shropshire, UK). Sampling and subsequent complete replacement of the degradation medium were performed at each time point. Accelerated degradation was performed for 30 days, and ambient degradation was performed in parallel with in vitro drug release until release was complete. After each time point, the samples were analyzed for the wet and dry weights of the implants.

[0215] 1.5 Analysis of the sample Ovalbumin (OVA) in vitro release samples were analyzed using SEC-HPLC (Agilent 1260 Infinity Quaternary System, Agilent Ltd, UK) with UV detection using a Phenomenex® Biosep-SEC-S3000 column (length 300 mm, inner diameter 7.8 mm, particle size 5 μm) and Phenomenex® SecurityGuard Cartridges GFC 3000 (4 × 3.0 mm, ID) (Phenomenex, Torrance, USA). 20 μL of sample was eluted for 14 minutes at a flow rate of 1.0 ml / min with 27 mM phosphate buffer and 150 mM NaCl, pH 6.35. Detection was performed using a UV detector at 214 nm.

[0216] 1.6 Results Figure 1 shows the accelerated degradation profiles of O1, O2, O3, and O4 implants. The higher the PEGMA polymer content of the implant, the faster the implant degrades. The SEM image in Figure 3 shows that O4 degrades faster than O1 (decrease in diameter) and shows signs of surface erosion and pore formation, but its physical structure remains intact during the degradation process. This allows for the avoidance of fragmentation in the anterior and / or posterior parts of the eye, which carries the potential risk of clogging the trabecular network and hindering proper drainage of aqueous humor from the eye. Furthermore, maintaining the physical structure during degradation prevents the occurrence of second and third burst effects and therefore allows for more sustained and predictable drug release over time, while preventing harmful overdoses, especially in the case of very potent drugs.

[0217] Figure 2 shows the daily OVA release rate and the degradation profiles of implant O1, O2, O3, and O4. The minimum therapeutic level of 0.5 μg / day shown in Figure 2 is the IC for ranibizumab (LUCENTIS®). 50This value is five times the minimum inhibitory concentration ((Genentech Inc. Prescribing Information for Lucentis(registered trademark)(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). Ranibizumab has a molecular weight close to that of ovalbumin. Implant O4 degrades faster than implant O1. Nevertheless, it releases OVA at a therapeutically acceptable rate for more than four months.

[0218] Example 2: Ovalbumin (OVA), molecular weight 42.7 kDa 2.1 Materials Poly(ethylene glycol) diacrylate (Mn=700Da, PEGDA 700), 1-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propanone (Irgacure 2959), phosphate-buffered saline (PBS) solution tablets, poly(ethylene glycol) methacrylate (Mn=360Da, PEGMA), poly(ethylene glycol) methyl ether methacrylate (PEGMEMA, Mn 500Da), poly(ethylene glycol) methyl ether acrylate (PEGMEA, Mn 480Da), and poly(ethylene glycol) dimethacrylate (PEGDMA, Mn 750Da) were purchased from Sigma (Dorset, UK). Poly(lactide-coglycolide) (PURASORB® PDLG 7502, 75:25, PLGA 75 / 25) was obtained from Corbion Purac Biomaterials (Gorinchem, Netherlands). Ovalbumin (OVA), derived from chicken egg white, was purchased from Sigma Aldrich (Buzzingstoke, UK). Silicone tubing (peroxide cured, inner diameter 0.6 mm, wall thickness 0.27 mm) was purchased from Polymer System Technology, UK.

[0219] 2.2 Preparation of OV1, OV2, OV3, OV4 and OV6 implants JPEG0007855531000006.jpg46161

[0220] 1 mg of PLGA 7502, i.e., 75 / 25 (Corbion Purac Biomaterials, Gorinchem, Netherlands) and 0.5 mg of Irgacure 2959 (Sigma Aldrich, Basingstoke, UK), (i) 68.5 mg of PEGDA 700Da (OV1) or (ii) 49.1 mg of PEGDA 700Da and 19.4 mg of PEGMA 360Da (OV2) or (iii) 49.1 mg of PEGDA 700Da and 19.4 mg of PEGMEMA 500Da (OV3) or (iv) 49.1 mg of PEGDA 700Da and 19.4 mg of PEGMEA 480Da (OV4) or (v) 49.1 mg of PEGDMA 750Da and 19.4 mg of PEGMA Solution A was prepared by dissolving 360Da(OV6) in one of the mixtures. Solution B was prepared by adding 30 mg of chicken egg white albumin (Sigma Aldrich, Basingstoke, UK) to 45 μL of ultrapure water in an Eppendorf tube (Sarstedt, Numbrechtt, Germany). Solution A was added to the Eppendorf tube, and Solution B was slowly added to Solution A through the wall of the Eppendorf tube while continuously stirring at 600 rpm for 10 minutes, followed by stirring at 300 rpm for a further 30 minutes. The resulting mixture was transferred into a silicone tube with an inner diameter (ID) of 0.635 mm (Polymer Systems Technology, UK) and photocrosslinked using 365 nm UV light (Light Hammer® 6, Heraeus Noblelight Fusion UV Inc., Gaithersburg, Maryland, 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 under vacuum at 25°C for 4 hours. Each rod-shaped implant was cut to a length of 5 mm.

[0221] 2.3 In vitro drug release settings In vitro release was performed by placing two OV1 implants in a glass vial containing 2 mL of PBS (phosphate-buffered saline) with 0.05% w / w NaN3 (pH 7.4 ± 0.2) as the release medium. Similar in vitro releases were performed for implants OV2, OV3, OV4, and OV6. 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 orbital shaking incubator; Gesellschaft fur LabortechnikmbH, Germany). Sampling and subsequent complete replacement of the PBS medium were performed on day 1 and then weekly thereafter, i.e., on days 7, 14, 21, 28, etc. The concentrations of the released drug molecules in the PBS samples were analyzed as described in the following sections.

[0222] 2.4 In Vitro Degradation Study Setup In vitro degradation studies were performed by placing two OV1 implants in glass vials containing either 4 mL of 10 mM NaOH as the accelerated degradation medium, or 4 mL of PBS (phosphate-buffered saline) containing 0.05% w / w NaN3 (pH 7.4 ± 0.2) as the ambient degradation medium. Similar in vitro degradation was performed for implants OV2, OV3, OV4, and OV6. All experiments were performed in triplicate. Glass vials containing implants were placed in an incubator and incubated at 37°C and 40 rpm (GFL orbital shaking incubator; Gesellschaft fur LabortechnikmbH, Germany). Sampling and subsequent complete replacement of the degradation medium were performed at each time point. Accelerated degradation was performed for 30 days, and ambient degradation was performed in parallel with in vitro drug release until release was complete. After each time point, samples were analyzed for the weight of the wet portion, the weight of the dry portion, the diameter of the wet portion, and the diameter of the dry portion of the implant.

[0223] 2.5 Analysis of the sample Ovalbumin (OVA) in vitro release samples were analyzed using SEC-HPLC (Agilent 1260 Infinity Quaternary System, Agilent Ltd, UK) with UV detection using a Phenomenex® Biosep-SEC-S3000 column (length 300 mm, inner diameter 7.8 mm, particle size 5 μm) and Phenomenex® SecurityGuard Cartridges GFC 3000 (4 × 3.0 mm, ID) (Phenomenex, Torrance, USA). 20 μL of sample was eluted for 14 minutes at a flow rate of 1.0 ml / min with 27 mM phosphate buffer and 150 mM NaCl, pH 6.35. Detection was performed using a UV detector at 214 nm.

[0224] 2.6 Results Figure 4 shows the accelerated degradation profiles of OV1-OV4 implants. The degradation profiles indicate that the use of various monoacrylate polymers in the implant matrix increases the degradation rate. Figure 5 shows similar degradation profiles for OV2 and OV6 implants, indicating that the use of another diacrylate, namely poly(ethylene glycol) dimethacrylate, does not have a beneficial effect in enhancing implant degradation. Therefore, the use of monoacrylate polymers is involved in improving the degradation rate of implants. Figure 6 shows that the use of monoacrylates such as poly(ethylene glycol) methacrylate, PEGMA (OV2) or poly(ethylene glycol) methyl ether methacrylate, PEGMEMA (OV3) increases the degradation rate of implants while maintaining a drug release rate above the minimum therapeutic level for 56 days or beyond.

[0225] Example 3: Dexamethasone (DEX), molecular weight 392.46 Da 3.1 Materials Poly(ethylene glycol) diacrylate (Mn=250Da, PEGDA 700), 1-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propanone (Irgacure 2959), phosphate-buffered saline (PBS) solution tablets, and poly(ethylene glycol) methacrylate (Mn=360Da, PEGMA) were purchased from Sigma (Dorset, UK). Poly(lactide-co-glycolide) (PURASORB® PDLG 7502, 75:25, PLGA 75 / 25) was obtained from Corbion Purac Biomaterials (Gorinchem, Netherlands). Dexamethasone (DEX) was purchased from Alfa Aesar (Heysham, UK). Silicone tubing (peroxide cured, inner diameter 0.3 mm, wall thickness 0.17 mm) was purchased from Polymer System Technology, UK.

[0226] 3.2 Preparation of DEX1, DEX2, and DEX3 implants JPEG0007855531000007.jpg30161

[0227] For every 100 mg of the total mixture per implant, 10 mg of DEX (Alfa Aesar, Heysham, UK) was mixed with 5 mg of PLGA 75 / 25 (Corbion Purac Biomaterials, Gorinchem, Netherlands), and either (i) 84.5 mg of PEGDA 250 (DEX1), or (ii) 74.5 mg of PEGDA 250 and 10 mg of PEGMA 360 (DEX2), or (iii) 64.5 mg of PEGDA 250 and 20 mg of PEGMA 360 (DEX3) were added. The mixtures were stirred at 200 rpm for 24 hours (Multisterer, Velp Scientifica trademark, Italy). Finally, 0.5 mg of Irgacure 2959 was added to each mixture and stirred for a further 10 minutes. The final mixture was transferred into a 0.300 mm inner diameter (ID) silicone tube (Polymer Systems Technology, UK) and photocrosslinked using 365 nm UV light (Light Hammer® 6, Heraeus Noblelight Fusion UV Inc., Gaithersburg, Maryland, USA). The UV light intensity was set to 100%, and the silicone tube was exposed to UV light for 30 seconds (i.e., a total of 10 runs). The rod-shaped implants were each cut to a length of 5 mm.

[0228] 3.3 In vitro drug release settings In vitro release was performed by placing four DEX1 implants in a glass vial containing 4 mL of PBS (phosphate-buffered saline) with 0.05% w / w NaN3 (pH 7.4 ± 0.2) as the release medium. Similar in vitro releases were performed for implants DEX2 and DEX3. 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 FL 16-2 refrigerated incubation shaker, SciQuip Ltd., Shropshire, UK). At day 1 and subsequent weekly sampling points, i.e., days 7, 14, 21, 28, etc., 1 mL of PBS was removed and replaced with 1 mL of fresh PBS. The concentration of the released drug molecules in the PBS samples was analyzed as described in the following sections.

[0229] 3.4 In Vitro Degradation Study Setup In vitro degradation studies were performed by placing four DEX1 implants in glass vials containing either 4 mL of 50 mM NaOH as the accelerated degradation medium, or 4 mL of PBS (phosphate-buffered saline) containing 0.05% w / w NaN3 (pH 7.4 ± 0.2) as the ambient degradation medium. Similar in vitro degradation was performed for DEX2 and DEX3 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 FL 16-2 refrigerated incubation shaker, SciQuip Ltd., Shropshire, UK). Sampling and subsequent complete replacement of the degradation medium were performed at each time point. Accelerated degradation was performed for 16 days, and ambient degradation was performed in parallel with in vitro drug release until release was complete. After each time point, the samples were analyzed for the weight of the wet portion, the weight of the dry portion, the diameter of the wet portion, and the diameter of the dry portion of the implants.

[0230] 3.5 Analysis of the sample Analysis of in vitro release samples of dexamethasone (DEX) was performed using VWD-HPLC with UV detection (Agilent 1260 Infinity Quaternary System, Agilent Ltd, UK) on a Poroshell 120 EC-C18, 4 μm (250 × 4.60 mm) analytical column with a refillable guard column (Agilent, UK). The mobile phase consisted of acetonitrile and water in a 40:60 ratio. The mobile phase was filtered under vacuum through a 0.45 μm membrane filter (Whatman International, UK) and degassed before use. The mobile phase flow rate was 0.8 mL / min, and the eluted drug was detected at a wavelength of 245 nm. Chromatographic separation of DEX was achieved at ambient room temperature (24 ± 2 °C).

[0231] 3.6 Results Figure 7 shows the accelerated degradation profiles of DEX1, DEX2, and DEX3 implants in 50 mM NaOH at 37°C and a shaking rate of 40 rpm. The degradation profiles indicate that the use of monoacrylate polymers in the implant matrix increases the degradation rate. Figure 8 shows the daily DEX release rate (μg) of each implant relative to the weight loss of the implant from DEX1, DEX2, and DEX3 implants. This indicates that the use of monoacrylate polymers is responsible for the increased degradation rate of the implants while maintaining drug release rates above the minimum therapeutic level for 56 days and beyond. (Nehme 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).

[0232] Example 4: Latanoprost (LP), molecular weight 432Da 4.1 Materials Poly(ethylene glycol) diacrylate (Mn=250Da, PEGDA 700), 1-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propanone (Irgacure 2959), phosphate-buffered saline (PBS) solution tablets, and poly(ethylene glycol) methacrylate (Mn=360Da, PEGMA) were purchased from Sigma (Dorset, UK). Poly(lactide-co-glycolide) (PURASORB® PDLG 7502, 75:25, PLGA 75 / 25) was obtained from Corbion Purac Biomaterials (Gorinchem, Netherlands). Latanoprost (LP) was purchased from Alfa Chemistry, New York, USA. Silicone tubing (peroxide cured, inner diameter 0.3 mm, wall thickness 0.17 mm) was purchased from Polymer System Technology, UK.

[0233] 4.2 Preparation of LP1, LP2, and LP3 implants JPEG0007855531000008.jpg30161

[0234] Solution A was prepared by dissolving 20 mg of Irgacure 2959 (Sigma Aldrich, Basingstoke, UK) in acetonitrile. Solution B was prepared by dissolving 50 mg of latanoprost (LP) (Alfa Chemistry, New York, USA) in 0.5 mL of acetonitrile. To prepare a 250 mg LP polymer mixture, (i) 186.25 mg of PEGDA 250 and 12.5 mg of PLGA 75 / 25 (Purac Biochem, Golinkem, Netherlands) (LP1), or (ii) 161.25 mg of PEGDA 250, 25 mg of PEGMA 360, and 12.5 mg of PLGA 75 / 25 (Purac Biochem, Golinkem, Netherlands) (LP2), or (iii) 136.25 mg of PEGDA 250, 50 mg of PEGMA 360, and 12.5 mg of PLGA 75 / 25 (Purac Biochem, Golinkem, Netherlands) (LP3) were placed in a 2 mL Eppendorf tube and dissolved in 250 μL of acetonitrile to prepare solution C. Next, 62.5 μL of solution A and 0.5 mL of solution B were added to solution C and stirred at 250 rpm for 30 minutes (Multisterer, Velp Scientifica trademark, Italy). Then, acetonitrile was evaporated at room temperature for 6 hours under a gauge pressure of -0.1 MPa (OV-12 vacuum oven; JeioTech, South Korea). The final mixture was withdrawn into a silicone tube with an inner diameter (ID) of 0.32 mm (Polymer Systems Technology, UK) using a 25 G needle attached to a 1 mL syringe and photocrosslinked using 365 nm UV light (Light Hammer® 6, Heraeus Noblelight Fusion UV Inc, Gaithersburg, MD, USA). The UV light intensity was set to 100%, and the silicone tube was exposed to UV light for 30 seconds (i.e., a total of 10 runs). The rod-shaped implants were each cut to a length of 5 mm.

[0235] 4.3 In vitro drug release settings In vitro release was performed by placing four LP1 implants in a glass vial containing 4 mL of PBS (phosphate-buffered saline) with 0.05% w / w NaN3 (pH 7.4 ± 0.2) as the release medium. Similar in vitro releases were 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 FL 16-2 refrigerated incubation shaker, SciQuip Ltd., Shropshire, UK). At day 1 and subsequent weekly sampling points, i.e., days 7, 14, 21, 28, etc., 1 mL of PBS was removed and replaced with 1 mL of fresh PBS. The concentration of the released drug molecules in the PBS samples was analyzed as described in the following sections.

[0236] 4.4 In Vitro Degradation Study Setup In vitro degradation studies were performed by placing four LP1 implants in glass vials containing either 4 mL of 50 mM NaOH as the accelerated degradation medium, or 4 mL of PBS (phosphate-buffered saline) containing 0.05% w / w NaN3 (pH 7.4 ± 0.2) as the ambient 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 FL 16-2 refrigerated incubation shaker, SciQuip Ltd., Shropshire, UK). Sampling and subsequent complete replacement of the degradation medium were performed at each time point. Accelerated degradation was performed for 16 days, and ambient degradation was performed in parallel with in vitro drug release until release was complete. After each time point, the samples were analyzed for the weight of the wet portion, the weight of the dry portion, the diameter of the wet portion, and the diameter of the dry portion of the implants.

[0237] 4.5 Analysis of the sample The LP1, LP2, and LP3 samples were analyzed using an HPLC system (Agilent 1260 Infinity II Quaternary System) with fluorescence detection using a Poroshell 120 EC-C18 column (length 250 mm, inner diameter 4.6 mm, and particle size 4 μm). Samples were analyzed in isocratic mode using a mobile phase of acetonitrile:0.1% v / v formic acid (60:40) at an injection volume of 50 μL and a flow rate of 1 mL / min. The column temperature was maintained at 40°C. The fluorescence detector was set to an excitation wavelength of 265 nm and an emission wavelength of 285 nm.

[0238] 4.6 Results Figure 9 shows the accelerated degradation profiles of LP1, LP2, and LP3 implants in 50 mM NaOH at 37°C and a shaking rate of 40 rpm. The degradation profiles indicate that the use of monoacrylate polymers in the implant matrix increases the degradation rate. Figure 10 shows the daily LP release rate (μg) of each implant relative to the weight loss of the implants from LP1, LP2, and LP3 implants. This indicates that the use of monoacrylate polymers plays a role in improving the rate of implant degradation while maintaining a drug release rate above the minimum therapeutic level of 0.105 μg / day (Sharif, NA, Kelly, CR, Crider, JY; Agonist activity of bimato-prost, 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.

[0239] Example 5: Bevacizumab (BEZ), molecular weight 150 kDa 5.1 Materials Poly(ethylene glycol) diacrylate (Mn=700Da, PEGDA 700), 1-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propanone (Irgacure 2959), phosphate-buffered saline (PBS) solution tablets, and poly(ethylene glycol) methacrylate (Mn=360Da, PEGMA) were purchased from Sigma (Dorset, UK). Poly(lactide-coglycolide) (PURASORB® PDLG 7502, 75:25, PLGA 75 / 25) was obtained from Corbion Purac Biomaterials (Gorinchem, Netherlands). Bevacizumab (BEZ) (Avastin®) was purchased from a local pharmacy (Roche, Switzerland; each vial contains 100 mg of BEZ in 4 mL, i.e., 25 mg / ml). The silicone tubing (peroxide cured, inner diameter 0.635mm, wall thickness 0.27mm) was purchased from Polymer System Technology, UK.

[0240] 5.2 Preparation of F19, B6, and B7 implants JPEG0007855531000009.jpg30161

[0241] To prepare the polymer mixture, Solution A was prepared by dissolving 50 mg of PLGA 7502 (75 / 25) in either (i) 442.5 mg of PEGDA 700 (F19), (ii) 392.5 mg of PEGDA 700 and 50 mg of PEGMA 360 (B6), or (iii) 420.5 mg of PEGDA 700 and 22.1 mg of PEGMA 360 (B7). Solution B was prepared by dissolving 6 mg of Irgacure 2559 in 1 mL of PBS (0.01 M, pH 7.4). 62.5 μL of Solution B was placed in a 2 mL Eppendorf tube. Subsequently, 25 mg of BEZ was added to the Eppendorf tube, and the mixture was stirred at 250 rpm for 30 seconds using a stirrer bar. The resulting mixture was allowed to stand at 4-7°C for 30 minutes to dissolve, and then centrifuged at 2000 rpm for 1 minute to remove air bubbles. 25 mg of solution A was added to the mixture obtained in this way, and then stirred at 250 rpm for 30 minutes. Next, this was centrifuged at 2000 rpm for 1 minute to remove air bubbles, and then stirred for another 10 minutes at 250 rpm. The final mixture was transferred into a silicone tube (inner diameter: 0.635 mm) and crosslinked using a light hammer (Light Hammer® 6, Heraeus Noblelight Fusion UV Inc., Gaithersburg, MD, USA). The UV light intensity (365 nm) was set to 50%, and the silicone tube was exposed to UV light for 15 seconds (5 times). The rod-shaped implant was removed from the silicone tube and vacuum-dried at 25°C for 4 hours. The dried implant was cut to a length of 5 mm.

[0242] 5.3 In vitro drug release studies For drug release studies, one implant each of F19, B6, and B7 was placed in a glass vial containing 1 ml of PBS (pH 7.4, 0.05% NaN3). The glass vials were placed in a static incubator at 37°C. Sampling and subsequent complete replacement of the PBS release medium were performed on day 1 and then weekly thereafter, i.e., on days 7, 14, 21, 28, etc. All experiments were performed in triplicate. The concentrations of released drug molecules in the PBS samples were analyzed as described below.

[0243] 5.4 SEC-HPLC analysis method for BEZ Analysis of bevacizumab (BEZ) released from implants B6 and F19 was performed using SEC-HPLC (Agilent 1260 Infinity Quaternary System) with fluorescence detection using a Phenomenex® BioZen® SEC-2 column (150 mm length, 4.6 mm inner diameter, 1.8 μm particle size) and a Phenomenex® BioZen® SEC-2 0.46 mm SecurityGuard Ultra Cartridge (Phenomenex, Torrance, USA). BEZ samples were analyzed in isocratic mode with a mobile phase of 35 mM sodium phosphate buffer (pH 6.8, 300 mM NaCl) at an injection volume of 10 μL and a flow rate of 0.5 mL / min. The column temperature was maintained at 25°C. The fluorescence detector was set to an excitation wavelength of 280 nm and an emission wavelength of 340 nm.

[0244] 5.5 Micro-BCA Analysis Method for BEZ Analysis of bevacizumab (BEZ) released from a B7 implant using the MicroBCA Protein Assay Kit (Pierce Biotechnology, Thermofisher Scientific, USA). Briefly, 150 μL of sample was mixed with 150 μL of MicroBCA reagent mixture and incubated at 37°C for 2 hours. The intensity of the color development resulting from the interaction between the protein and the MicroBCA reagent was measured at a wavelength of 562 nm.

[0245] 5.6 In Vitro Degradation Study Setup In vitro degradation studies were performed by placing one F19 implant in a glass vial containing either 4 mL of 10 mM NaOH as the accelerated degradation medium, or 4 mL of PBS (phosphate-buffered saline) containing 0.05% w / w NaN3 (pH 7.4 ± 0.2) as the ambient degradation medium. Similar in vitro degradation was performed for B6 and B7 implants. All experiments were performed in triplicate. The glass vials containing the implants were placed in a static incubator and incubated at 37°C (MINI / 100 / F, Genlab Limited, Cheshire, UK). Sampling and subsequent complete replacement of the degradation medium were performed at each time point. Accelerated degradation was performed for 28 days, and ambient degradation was performed in parallel with in vitro drug release until release was complete. After each time point, the samples were analyzed for the weight of the wet portion, the weight of the dry portion, the diameter of the wet portion, and the diameter of the dry portion of the implant.

[0246] 5.7 Results Figure 11 shows the accelerated degradation profiles of F19, B6, and B7 implants in 10 mM NaOH at 37°C. The degradation profiles indicate that the use of monoacrylate polymers in the implant matrix increases the degradation rate. Figure 12 shows the daily BEZ release rate (μg) of each implant relative to the weight loss of the implant from F19, B6, and B7 implants. This indicates that the use of monoacrylate polymers plays a role in improving the degradation rate of the implant while maintaining the drug release rate above the minimum target therapeutic level of 0.5 μg / 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 the B6 implant).

[0247] Example 6: Ovalbumin (OVA, molecular weight 42.7 kDa) 6.1 Materials Poly(ethylene glycol) diacrylate (Mn=700Da, PEGDA 700), 1-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propanone (Irgacure 2959), phosphate-buffered saline (PBS) solution tablets, and poly(ethylene glycol) methacrylate (Mn=360Da, PEGMA) were purchased from Sigma (Dorset, UK). Poly(lactide-co-glycolide) (PURASORB® PDLG 7502, 75:25, PLGA 75 / 25) was obtained from Corbion Purac Biomaterials (Gorinchem, Netherlands). Chicken egg white-derived albumin, i.e., ovalbumin (OVA), was purchased from Sigma Aldrich (Buzzingstoke, UK). The silicone tubing (peroxide cured, inner diameter 0.6mm, wall thickness 0.27mm) was purchased from Polymer System Technology, UK.

[0248] 6.2 Preparation of B1, B2, and B3 implants JPEG0007855531000010.jpg29161

[0249] Solution A was prepared by dissolving 5 mg of PLGA 7502, i.e., 75 / 25 (Corbion Purac Biomaterials, Gorinchem, Netherlands), in one of the following mixtures: (i) 35.1 mg of PEGDA 700Da and 19.4 mg of PEGMA 360Da (B1), (ii) 30.5 mg of PEGDA 700Da and 24 mg of PEGMA 360Da (B2), or (iii) 26.5 mg of PEGDA 700Da and 28 mg of PEGMA 360Da (B3). Solution B was prepared by dissolving 5 mg of Irgacure 2559 (Sigma Aldrich, Basingstoke, UK) in 1 ml of PBS. Solution C was prepared by adding 40 mg of chicken egg white albumin (Sigma Aldrich, Basingstoke, UK) to 60 μL of Solution B in an Eppendorf tube (Sarstedt, Numbrechtt, Germany). Solution A was then added to the Eppendorf tube. Solution C was slowly added to Solution A through the wall of the Eppendorf tube while continuously stirring at 600 rpm for 15 minutes. The final mixture was transferred into a silicone tube with an inner diameter (ID) of 0.635 mm (Polymer Systems Technology, UK) and photocrosslinked using 365 nm UV light (Light Hammer® 6, Heraeus Noblelight Fusion UV Inc., Gaithersburg, Maryland, 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 under vacuum at 25°C for 4 hours. Each rod-shaped implant was cut to a length of 5 mm.

[0250] 6.3 In vitro drug release settings In vitro release was performed by placing two implants B1 in a glass vial containing 2 mL of PBS (phosphate-buffered saline) with 0.05% w / w NaN3 (pH 7.4 ± 0.2) as the 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 orbital shaking incubator; Gesellschaft fur LabortechnikmbH, Germany). Sampling and subsequent complete replacement of the PBS medium were performed on day 1 and then weekly thereafter, i.e., on days 7, 14, 21, 28, etc. The concentration of the released drug molecules in the PBS samples was analyzed as described in the following section.

[0251] 6.4 In Vitro Degradation Study Setup In vitro degradation studies were performed by placing two implants B1 in glass vials containing either 4 mL of 10 mM NaOH as an accelerated degradation medium or 4 mL of PBS (phosphate-buffered saline) containing 0.05% w / w NaN3 (pH 7.4 ± 0.2) as an ambient degradation medium. Similar in vitro degradation 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 orbital shaking incubator; Gesellschaft fur LabortechnikmbH, Germany). Sampling and subsequent complete replacement of the degradation medium were performed at each time point. Accelerated degradation was performed for 30 days, and ambient degradation was performed in parallel with in vitro drug release until release was complete. After each time point, the samples were analyzed for the wet and dry weights of the implants.

[0252] 6.5 Analysis of the sample Ovalbumin (OVA) in vitro release samples were analyzed using SEC-HPLC (Agilent 1260 Infinity Quaternary System, Agilent Ltd, UK) with UV detection using a Phenomenex® Biosep-SEC-S3000 column (length 300 mm, inner diameter 7.8 mm, particle size 5 μm) and Phenomenex® SecurityGuard Cartridges GFC 3000 (4 × 3.0 mm, ID) (Phenomenex, Torrance, USA). 20 μL of sample was eluted for 14 minutes at a flow rate of 1.0 ml / min with 27 mM phosphate buffer and 150 mM NaCl, pH 6.35. Detection was performed using a UV detector at 214 nm.

[0253] 6.6 Results Figure 13 shows the accelerated degradation profiles of implants B1, B2, and B3. The higher the PEGMA polymer content of the implant, the faster the implant degrades. Figure 14 shows the daily OVA release rate and the degradation profiles of implants B1, B2, and B3. The higher PEGMA concentration in implant B3 results in faster implant degradation, measured as a percentage of implant weight loss, while maintaining a release rate above the minimum therapeutic level for at least 75 days.

Claims

1. An ophthalmic composition, a) At least 0.1% w / w therapeutic agent, b) A photopolymerizable composition containing 3 to 70% w / w of one or more compounds of formula I, In the formula, R １ This refers to hydrogen or linear or branched C １ -C ３ It is alkyl, R ２ is an acrylate or methacrylate group, n is 2 or 3, m is 1 or more, and the weight percentage of the one or more compounds of formula I is based on the total weight of the photopolymerizable composition. c) 0.1 to 40% w / w of biodegradable polymers selected from the group consisting of lactide / glycolide copolymers (including poly(lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), polyhydroxyalkanoates including polyhydroxybutyrate, polyglycolic acid (PGA), polycaprolactone (PCL), poly(DL-lactide) (PDL), poly(D-lactide), lactide / caprolactone copolymers, poly-L-lactide-co-caprolactone (PLC), and mixtures, copolymers, and block copolymers thereof, and d) Containing a photoinitiator, The photopolymerizable composition further comprises one or more substituted 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, and 1,6-hexanediol dimethacrylate. Ophthalmic composition.

2. The ophthalmic composition according to claim 1, 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.

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

4. The ophthalmic composition according to any one of claims 1 to 3, wherein the photopolymerizable composition contains one or more compounds of formula I in an amount of 5 to 60% w / w.

5. The ophthalmic composition according to claim 1, wherein the one or more disubstituted acrylate or methacrylate compounds are poly(ethylene glycol) diacrylate (PEGDA).

6. An ophthalmic composition according to any one of claims 1 to 5, comprising 40 to 75% w / w of the photopolymerizable composition.

7. The ophthalmic composition according to any one of claims 1 to 6, wherein the biodegradable polymer is lactide / glycolide copolymer (containing poly(L-lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), poly(DL-lactide) (PDL), and lactide / caprolactone copolymer (PLC).

8. The ophthalmic composition according to claim 7, wherein the biodegradable polymer is poly(lactide-co-glycolide) (PLGA).

9. The ophthalmic composition according to any one of claims 1 to 8, wherein the therapeutic agent is present in an amount of 20 to 70% w / w.

10. a) The therapeutic agent in a concentration of 10-50% w / w b) 1-20% w / w poly(lactide-co-glycolide) (PLGA) c) The photopolymerizable composition comprising poly(ethylene glycol) methacrylate (PEGMA) and poly(ethylene glycol) diacrylate (PEGDA) in an amount of 30 to 88.99% w / w, d) comprising 0.01 to 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, The ophthalmic composition according to any one of claims 1 to 9, wherein the weight ratio of PEGDA:PEGMA is 0.5 to 20.

11. The ophthalmic composition according to any one of claims 1 to 10, wherein the therapeutic agent is ranibizumab, bevacizumab, latanoprost, dexamethasone, or timolol maleate.

12. An ophthalmic implant comprising at least 0.1% w / w therapeutic agent, 5–95% w / w crosslinked polymer matrix, and 0.1–40% w / w biodegradable polymer selected from the group consisting of lactide / glycolide copolymers (including poly(lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), polyhydroxyalkanoates including polyhydroxybutyrate, polyglycolic acid (PGA), polycaprolactone (PCL), poly(DL-lactide) (PDL), poly(D-lactide), lactide / caprolactone copolymer, poly-L-lactide-co-caprolactone (PLC) and mixtures, copolymers and block copolymers thereof, a) The crosslinked polymer matrix is ​​obtained by crosslinking a photopolymerizable composition containing one or more compounds of formula I in an amount of 3 to 70% w / w. In the formula, R １ This refers to hydrogen or linear or branched C １ ~C ３ It is alkyl, R ２ is an acrylate or methacrylate group, n is 2 or 3, m is 1 or more, and the weight percentage of the one or more compounds of formula I is based on the total weight of the photopolymerizable composition. b) The therapeutic agent and the biodegradable polymer are embedded in the polymer matrix, and c) The photopolymerizable composition is characterized by further comprising one or more substituted 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, and 1,6-hexanediol dimethacrylate. Eye implants.

13. a) The therapeutic agent in an amount of 10-50% w / w, b) 1-20% w / w poly(lactide-co-glycolide) (PLGA), c) The ophthalmic implant according to claim 12, comprising or consisting of a crosslinked polymer matrix obtained by crosslinking a photopolymerizable composition comprising 30-89% w / w of poly(ethylene glycol) methacrylate (PEGMA) and poly(ethylene glycol) diacrylate (PEGDA), wherein the weight ratio of PEGDA:PEGMA is 0.5-20.

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