Ocular compositions

Abstract

To provide ocular compositions for the controlled release of a therapeutic agent.SOLUTION: The ocular composition comprises at least 20% w / w of a therapeutic agent; 5 to 75% w / w of a photopolymerizable composition selected from the group consisting of fragments or monomers of polyalkylene glycol mono-acrylate, polyalkylene glycol diacrylate, polyalkylene glycol methacrylate and polyalkylene glycol dimethacrylate, and mixtures, copolymers, and block copolymers thereof; 0.1 to 40% w / w of a biodegradable polymer selected from the group consisting of lactide / glycolide copolymer (including poly(lactide-co-glycolide), poly (L-lactide), polyhydroxyalkanoates including polyhydroxybutyrate, polyglycolic acid, polycaprolactone, poly (DL-lactide), poly (D-lactide), lactide / caprolactone copolymer, poly-L-lactide-co-caprolactone and mixtures, copolymers, and block copolymers thereof; and a photoinitiator.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to ophthalmic compositions and ophthalmic implants for the controlled release of therapeutic agents. [Background technology]

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

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

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

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

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

[0007] In a first aspect, the present invention relates to ophthalmic compositions that can be administered to the eye in a variety of forms to achieve controlled release of a therapeutic agent. Such ophthalmic compositions include (a) at least 20 w / w% of a therapeutic agent; and (b) 5 to 75 w / w% of a photopolymerizable composition selected from the group consisting of polyalkylene glycol monoacrylates, polyalkylene glycol diacrylates, polyalkylene glycol methacrylates, polyalkylene glycol dimethacrylate fragments or monomers, and mixtures, copolymers, and block copolymers thereof; and (c) 0.1 to 40 w / w % of a biodegradable polymer selected from the group consisting of lactide / glycolide copolymers (including poly(lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), polyhydroxyalkanoates including polyhydroxybutyrate, polyglycolic acid (PGA), polycaprolactone (PCL), poly(DL-lactide) (PDL), poly(D-lactide), lactide / caprolactone copolymers, poly-L-lactide-co-caprolactone (PLC), and mixtures, copolymers, and block copolymers thereof; and (d) a photoinitiator; and Includes.

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

[0009] In a still further aspect, the present invention relates to an ophthalmic composition as described above for use in the preparation of an ocular implant.

[0010] In a still further aspect, the present invention relates to methods of making such ocular implants.

[0011] In a still further aspect, the present invention relates to an ocular implant obtainable by such a method.

[0012] In yet a further aspect, the present invention relates to an ocular implant comprising at least 20 w / w% therapeutic agent, 5-75 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 copolymers, 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 selected from the group consisting of polyalkylene glycol monoacrylates, polyalkylene glycol diacrylates, polyalkylene glycol methacrylates, polyalkylene glycol dimethacrylate fragments or monomers, and mixtures, copolymers, and block copolymers thereof; and (b) the therapeutic agent and the biodegradable polymer are embedded in a crosslinked polymer matrix.

[0013] The present invention provides ophthalmic compositions and implants that can be administered to the eye in a variety of forms to achieve controlled release of therapeutic agents. The present invention allows the flexibility to administer a wide range of small and large therapeutic molecules, including proteins, peptides and gene therapy agents, and maintain their activity for controlled periods of time.

[0014] The ophthalmic compositions and implants of the present invention allow for inclusion of therapeutic agents in amounts of 20 w / w% or more, thus allowing for the manufacture of high-load therapeutic delivery implants without encountering unacceptable burst release. Furthermore, the overall size of the implants of the present invention can be substantially reduced without compromising the effectiveness of the therapeutic agent release profile over time. Given the reduced size, patient acceptance, tolerance, and comfort are generally improved overall.

[0015] The high concentration of therapeutic agent in the ophthalmic compositions and implants of the present invention also allows for increased bioavailability of the therapeutic agent itself, thus ensuring efficacy of the treatment over the entire period.

[0016] Furthermore, implants with reduced dimensions and high drug loading allow for administration through small gauge needles, causing less ocular tissue trauma. [Brief description of the drawings]

[0017] [Figure 1] FIG. 1 shows the in vitro release of BEZ from implants F18 and F19, expressed as cumulative release percentage (mean±standard deviation, n=3). [Diagram 2] Figure 2 shows the in vitro release of BEZ from implant F18, with [Diagram 3] FIG. 3 shows the in vitro release of BEZ from implant F19, expressed as μg released per day (mean±standard deviation, n=3). [Figure 4]FIG. 4 shows the in vitro release of BEZ from implant F7, expressed as cumulative release percentage (mean±standard deviation, n=3). [Diagram 5] FIG. 5 shows the in vitro release of BEZ from implant F7, expressed as μg released per day (mean±standard deviation, n=3). [Figure 6] FIG. 6 shows the in vitro release of BEZ from implants B1 and B4, expressed as cumulative release percentage (mean±standard deviation, n=3). [Figure 7] FIG. 7 shows the in vitro release of BEZ from implants B1 and B4, expressed as μg released per day (mean±standard deviation, n=3). [Figure 8] FIG. 8 shows the in vitro release of OVA from implants O1, O2 and O4, expressed as cumulative release percentage (mean±standard deviation, n=3). [Figure 9] FIG. 9 shows the in vitro release of BEZ from implants B1, BL1, and BS4, expressed as cumulative release percentage (mean±standard deviation, n=3). [Figure 10] FIG. 10 shows the in vitro release of BEZ from implants B1, BL1, and BS4, expressed as μg released per day (mean±standard deviation, n=3). [Figure 11] FIG. 11 shows the in vitro release of BEZ from implants B1, BL1, and FN4, expressed as cumulative release percentage (mean±standard deviation, n=3). [Figure 12] FIG. 12 shows the in vitro release of BEZ from implants B1, BL1, and FN4, expressed as μg released per day (mean±standard deviation, n=3). [Figure 13] FIG. 13 shows the in vitro release of BEZ from implants FN2 and FN5, expressed as cumulative release percentage (mean±standard deviation, n=3). [Figure 14] FIG. 14 shows the in vitro release of OVA from implants O3 and O7, expressed as cumulative release percentage (mean±standard deviation, n=3). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] As used herein, the term "w / w %" refers to the percentage by weight of a given component relative to the total weight of the copolymer, composition, or implant containing such component, as the case may be.

[0019] As used herein, "biodegradable" is chemical degradation by biological means. In some embodiments, biodegradation is 100%, 98%, 90%, 85%, 80%, 60%, 50%, or 45% degradation of one or more of the composition, monomers, oligomers, fragments, polymers, photoinitiators, solvents, co-solvents, or coinitiators.

[0020] As used herein, a "copolymer" is a mixture of two or more different types of monomer units. As used herein, a "block copolymer" is a mixture of two or more homopolymer subunits.

[0021] The therapeutic agents of the compositions of the invention can be selected from a wide range of small and large molecules. Exemplary therapeutic agents include, but are not limited to, polypeptides, nucleic acids, such as DNA, RNA and siRNA, growth factors, steroids, antibody therapy, antibacterial agents, antibiotics, antiretroviral therapy, anti-inflammatory compounds, anti-tumor agents, anti-angiogeneic agents, anti-VEGF (vascular endothelial growth factor) agents, and chemotherapeutic agents.

[0022] In one embodiment, the therapeutic agents of the present invention include ketorolac, naphazoline, lidocaine, bevacizumab, aflibercept, pegaptanib, brimonidine tartrate, dorzolamide, bromfenac sodium, azithromycin, rapamycin, bepotastine besylate, diclofenac, besifloxacin, cysteamine hydrochloride, fluocinolone acetonide, difluprednate, tasimelteon, ocriplasmin, enoxaparin sodium, ranibizumab, latanoprost, timolol maleate, bimatoprost, ofloxacin, cefazolin, phenylephrine, dexamethasone, cyclosporine ... These include, but are not limited to, samethasone, triamcinolone acetonide, levofloxacin, cyclophosphamide, melphalan cyclosporine, methotrexate, azathioprine, travoprost, verteporfin, tafluprost, ketotifen fumarate, foscarnet, amphotericin B, fluconazole, voriconazole, ganciclovir, acyclovir, gatifloxacin, mitomycin C, prednisolone, prednisone, vitamins (vitamin A, vitamin C, and vitamin E), zinc, copper, lutein, zeaxanthin, or combinations thereof.

[0023] 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.

[0024] In one embodiment, the compositions or implants of the invention can deliver a bioactive agent, a large molecular weight therapeutic agent, such as aflibercept, pegaptanib, or an antibody therapeutic agent, such as ranibizumab, bevacizumab, trastuzumab, rituximab, gentuzumab, ozagamycin, brolucizumab, or cetuximab.

[0025] In some embodiments, the molecular weight of the therapeutic agent is greater than 200 Da, 500 Da, 1000 Da, 10 kDa, 30 kDa, 50 kDa, 75 kDa, 100 kDa, 150 kDa, 200 kDa, and 250 kDa.

[0026] According to other embodiments of the invention, the therapeutic agent is present in an amount of between 20-70 w / w%, between 30-70 w / w%, between 40-70 w / w%, and between 50-70 w / w% of the total weight of the ophthalmic composition.

[0027] The therapeutic agent can be used as is or in the form of a solution in which a certain amount of the therapeutic agent is dissolved in a suitable solvent. The therapeutic agent can also be freeze-dried or spray-dried prior to use in the preparation of the ophthalmic composition of the present invention to facilitate the incorporation of high concentrations of the therapeutic agent into the implant. The amount of the therapeutic agent dissolved depends on the final loading that the ophthalmic composition or implant is to have. The choice of solvent depends on the polarity of the therapeutic agent.

[0028] According to one embodiment of the present invention, the solvent may be selected from water, dimethyl sulfoxide, decyl methyl sulfoxide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, N-vinyl-pyrrolidine, N-methyl-2-pyrrolidone, N-ethyl-pyrrolidone, glycerol formal, glycerol, polyethylene glycol, propylene glycol, benzyl alcohol, benzyl benzoate, ethyl benzoate, triacetin, triethyl citrate, dimethylformamide, dimethylacetamide, and tetrahydrofuran.

[0029] In one embodiment, a co-solvent may be used, which may be selected from dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, acetic acid, methanol, ethanol, isopropanol, glycofurol, or butanol.

[0030] For hydrophilic therapeutic agents, the solvent can be an aqueous solvent such as water or a phosphate buffered saline (PBS) solution.

[0031] 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.

[0032] Additionally, the above solvents and co-solvents can be used in combination with any of the other photopolymerizable compositions, biodegradable polymers, photoinitiators, pore formers, and co-initiators described herein in the preparation of any of the compositions and implants of the present invention.

[0033] In one embodiment, when the biodegradable polymer is PLGA, PCL, PLC and / or PLA, a solvent is used. In one embodiment, when the biodegradable polymer is PLGA, PCL, PLC and / or PLA, the solvent is N-methyl-2-pyrrolidone and N-vinyl-2-pyrrolidine. In another embodiment, when the photopolymerizable composition is PEGDA, a solvent is used.

[0034] The photopolymerizable fragments or monomers of the present invention can be used in any of the compositions and implants of the present invention in combination with any of the other biodegradable polymers, therapeutic agents, photoinitiators, solvents, cosolvents, drug modifiers, and coinitiators described herein or known in the common general knowledge.

[0035] In one embodiment, the photopolymerizable composition of the present invention can be biodegradable. In some embodiments, biodegradation occurs over 1 minute, 10 minutes, 20 minutes, 2 hours, 6 hours, 12 hours, 24 hours, 2 days, 5 days, 1 week, 1 month, 2 months, 5 months, 6 months, 8 months, or 12 months. In some embodiments, biodegradation occurs between 1 month and 12 months, between 6 months and 12 months, or between 8 months and 12 months.

[0036] As used herein, the term "photopolymerizable composition" is a composition that can form a crosslinked polymer network upon exposure to light, particularly UV light. As used herein, photopolymerizable compositions include photopolymerizable monomers and oligomers (e.g., dimers, trimers, and tetramers). The terms "oligomer" and "fragment" can be used interchangeably to mean 2-20 monomers, optionally 2-10 monomers, further optionally 2-5 monomers, or 2-4 monomers. A "photopolymerizable monomer" is a single unit of a photopolymerizable polymer that can be chemically bonded to other monomers to form a polymer.

[0037] The photopolymerizable compositions of the present invention can be crosslinked with UV radiation to form the crosslinked polymer matrix of the ocular implants of the present invention.

[0038] In one embodiment, the photopolymerizable composition is selected from the group consisting of polyalkylene glycol monoacrylates, polyalkylene glycol diacrylates, polyalkylene glycol methacrylates, polyalkylene glycol dimethacrylate fragments or monomers, and mixtures, copolymers, and block copolymers thereof.

[0039] In one embodiment, the photopolymerizable composition is a polyalkylene glycol diacrylate fragment or monomer incorporating diacrylate terminal units selected from the group including polyether fragments or monomers, polyester fragments or monomers, polycarbonate fragments or monomers, or mixtures, copolymers or block copolymers thereof.

[0040] In one embodiment, the photopolymerizable composition includes monomers incorporating diacrylate terminal units, such as 4-arm or 8-arm PEG acrylate.

[0041] In another embodiment, the photopolymerizable composition is polyethylene glycol diacrylate, diethylene glycol diacrylate, polyethylene glycol dimethacrylate, diethylene glycol dimethacrylate, polypropylene glycol diacrylate, dipropylene glycol diacrylate, dipropylene glycol dimethacrylate, and polypropylene glycol dimethacrylate, or mixtures, copolymers, or block copolymers thereof.

[0042] In another embodiment, the photopolymerizable composition is polyethylene glycol diacrylate (PEGDA), polyethylene glycol monoacrylate (PEGMoA), or polyethylene glycol dimethacrylate (PEGDMA).

[0043] In yet another embodiment, the photopolymerizable composition is polyethylene glycol diacrylate (PEGDA).

[0044] In yet another embodiment, the photopolymerizable composition is polyethylene glycol methacrylate (PEGMA) or a mixture of PEGMA with other polyalkylene glycol monoacrylates, diacrylates, methacrylates and / or dimethacrylates, hi one embodiment, the polymerizable composition is a mixture of PEGDA, PEGMoA, and / or PEGMA.

[0045] PEGDA is a synthetic polymer available in a variety of molecular weights. PEGDA is highly amenable to mechanical, structural, and chemical modification, resulting in hydrogels with a variety of properties for drug delivery and other biomedical applications. PEGDA is formed by end-functionalization of each PEG molecule with an acrylate group. PEGDA is also non-toxic and induces minimal immunogenic responses. PEGDA has double bond-containing acrylate end groups that exhibit rapid polymerization when exposed to light in the presence of a suitable initiator to produce a hydrogel network.

[0046] The average molecular weight of the photopolymerizable composition of the present invention is typically 100 to 300,000 Da, 200 to 100,000 Da, 200 to 50,000 Da, 200 to 20,000 Da, 200 to 10,000 Da, 200 to 8,000 Da, 200 to 5,000 Da, or 200 to 1,000 Da.

[0047] For the compositions and implants of the present invention, it has been found that an increase in the molecular weight of the photopolymerizable composition results in an increase in the therapeutic agent release rate. Without wishing to be bound by theory, it is believed that photopolymerizable compositions having a lower molecular weight have a higher crosslink density and therefore a slower therapeutic agent release rate.

[0048] The photopolymerizable composition of the present invention typically has a viscosity of 0.1 to 7 dL / g, 0.2 to 5 dL / g, or 0.5 to 2 dL / g.

[0049] In one embodiment, the photopolymerizable composition is present in an amount of 10-75 w / w%, 20-75 w / w%, 30-75 w / w%, 40-75 w / w%, and 45-75 w / w%.

[0050] The biodegradable polymers of the present invention can be used in any of the compositions and implants of the present invention in combination with any of the other photopolymerizable compositions, therapeutic agents, photoinitiators, solvents, cosolvents, therapeutic agent release modifiers, and co-initiators described herein or known in the common general knowledge.

[0051] The biodegradable polymers of the present invention are biodegradable but not photopolymerizable.

[0052] In one embodiment of the present invention, the biodegradable polymer is an aliphatic polyester-based polyurethane, a polylactide, a polycaprolactone, a polyorthoester, or a mixture, copolymer, or block copolymer thereof.

[0053] In another embodiment of the 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, copolymers or block copolymers thereof.

[0054] In another embodiment, the biodegradable polymer is selected from the group consisting of lactide / glycolide copolymers (including poly(lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), polyhydroxyalkanoates, including polyhydroxybutyrate, polyglycolic acid (PGA), polycaprolactone (PCL), poly(DL-lactide) (PDL), poly(D-lactide), lactide / caprolactone copolymers, poly-L-lactide-co-caprolactone (PLC), and mixtures, copolymers, and block copolymers thereof.

[0055] In one embodiment, the biodegradable polymer is lactide / glycolide copolymers (including poly(L-lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), poly(DL-lactide) (PDL), and lactide / caprolactone copolymers (PLC).

[0056] In certain embodiments, the biodegradable polymer is poly(lactide-co-glycolide) (PLGA).

[0057] PLGA is typically prepared by polymerization of lactic and glycolic acid monomers. The glass transition temperature (Tg) of PLGA copolymers is higher than the physiological temperature of 37°C, resulting in a moderately rigid chain configuration and thus imparting mechanical strength at ambient temperatures. The use of PLGA with different lactide (LA) to glycolide (GA) ratios and molecular weights allows for different drug release profiles. Increasing the GA content increases the water uptake of PLGA, thus resulting in more rapid degradation. The degradation of PLGA with LA / GA 50 / 50 is typically 1-3 months. In one embodiment, the molar ratio of lactic acid to glycolic acid in the PLGA is 90% lactic acid to 10% glycolic acid, 85% lactic acid to 15% glycolic acid, 75% lactic acid to 25% glycolic acid, 65% lactic acid to 35% glycolic acid, 50% lactic acid to 50% glycolic acid, 35% lactic acid to 65% glycolic acid, 25% lactic acid to 75% glycolic acid, 15% lactic acid to 85% glycolic acid, and 10% lactic acid to 90% glycolic acid.

[0058] In another embodiment, the biodegradable polymer is PCL, PLC, PLA, or a mixture, copolymer, or block copolymer thereof.

[0059] In one embodiment, the biodegradable polymer is present in an amount of 1-40 w / w%, 1-30 w / w%, 1-20 w / w%, 2-10 w / w%, 5-10 w / w%.

[0060] The photoinitiators described herein can be used in any of the compositions and implants of the invention in combination with any of the other photopolymerizable compositions, biodegradable polymers, therapeutic agents, photoinitiators, solvents, co-solvents, and co-initiators described herein.

[0061] In certain embodiments, the photoinitiator is designed to work with light between 200 and 550 nm. In some embodiments, the photoinitiator is designed to work with UV light between 200 and 500 nm. In other embodiments, the photoinitiator is designed to work with UV light between 200 and 425 nm.

[0062] In certain embodiments, the light source can allow for the variation of the wavelength and / or intensity of light. Light sources useful in the present invention include, but are not limited to, laser diodes and lamps. Fiber optic devices can be used to transmit light.

[0063] In one embodiment, the photoinitiator is a ketone (i.e., RCOR'). In one embodiment, the compound is an azo compound (i.e., a compound having a -N=N- group). In one embodiment, the photoinitiator is an acylphosphine oxide. In one embodiment, the photoinitiator is a sulfur-containing compound. In one embodiment, the initiator is a quinone. In certain embodiments, a combination of photoinitiators is used.

[0064] In another embodiment, the photoinitiator may be selected from a hydroxyketone photoinitiator, an aminoketone photoinitiator, a hydroxyketone / benzophenone photoinitiator, a benzyl dimethyl ketal photoinitiator, a phenylglyoxylate photoinitiator, an acylphosphine oxide photoinitiator, an acylphosphine oxide / alphahydroxyketone photoinitiator, a benzophenone photoinitiator, a ribitylisoalloxazine photoinitiator, a peroxide photoinitiator, a persulfate photoinitiator, or a phenylglyoxylate photoinitiator, or any combination thereof. Optionally, the photoinitiator is 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone, 1-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propanone, 2,2-dimethoxy-2-phenylacetophenone (DMPA), diphenyl(2,4,6 trimethylbenzoyl)phosphine oxide (DPPO), or riboflavin. In another embodiment, the photoinitiator is benzoyl peroxide, 2,2″-azobisisobutyronitrile, dicumyl peroxide, lauroyl peroxide, and / or camphorquinone.

[0065] In one embodiment, the composition of the present invention further comprises a coinitiator. In one embodiment, the coinitiator is eosin Y, triethanolamine, camphorquinone, 1-vinyl-2 pyrrolidinone (NVP), eosin, dimethylaminobenzoic acid (DMAB), Irgacure® D-2959 (Sigma Aldrich, Basingstoke, UK), Irgacure® 907 (Sigma Aldrich, Basingstoke, UK), Irgacure® 651 (Sigma Aldrich, Basingstoke, UK), diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide (DPPO / Darocur TPO) (Sigma Aldrich, Basingstoke, UK), or ethyl-4-N,N-dimethylaminobenzoate (4EDMAB). Optionally, the photoinitiator is riboflavin and the coinitiator is L-arginine.

[0066] In one embodiment, the composition of the present invention comprises a release modifier. The appropriate release modifier can be selected taking into consideration the specific therapeutic agent and the composition of the implant, as well as the desired elution profile or release rate. The release modifier can be a naturally occurring drug or polymer, or a synthetic drug or polymer.

[0067] All of the release modifiers described herein can be used in any of the implants and compositions of the present invention in combination with any of the other photopolymerizable compositions, biodegradable polymers, therapeutic agents, photoinitiators, solvents, co-solvents, and co-initiators described herein.

[0068] The release modifier may be present in an amount of 0.1-40 w / w%, 1-30 w / w%, 1-20 w / w%, 1-10 w / w%, 5-10 w / w%.

[0069] In some cases, the release regulator alters water absorption into the implant matrix, thus controlling the release rate of the therapeutic agent and the implant degradation. In one embodiment, suitable water absorption regulators are one or more polysaccharides, such as, for example, cellulosic materials including chitosan and hydroxypropyl methylcellulose (HPMC); hyaluronic acid; poloxamer; polyethers, such as polyethylene glycol; gelatin; polyvinylpyrrolidone; polyvinyl alcohol, and mixtures thereof. In one embodiment, suitable water absorption regulators are hydroxypropyl methylcellulose (HPMC) and polyethylene glycol (PEG).

[0070] In one embodiment, the release modifier is a pore-forming agent and / or a stability enhancer, optionally lactose, maltose, glucose, mannitol, sodium chloride, magnesium carbonate, magnesium hydroxide, potassium chloride, sodium bicarbonate, ammonium bicarbonate, potassium bicarbonate, agarose, or sucrose.

[0071] In another embodiment, the release modifier is a mixture of two or more modifiers as described above to provide two or more functionalities to the ophthalmic compositions or implants of the present invention.Optionally, the release modifier is polyethylene glycol, hydroxypropyl methylcellulose (HPMC), or a mixture thereof.

[0072] Optionally, the porosity of the implant can be adjusted by preparing the implant in the presence of dispersed water-soluble porosinogens, which can be subsequently removed by washing with water to leave an interconnected network (i.e., a porous hydrogel). The pore size of hydrogels prepared by porosinogen techniques depends on the size of the porosinogens.

[0073] In another embodiment of the present invention, the ophthalmic composition does not contain a release modifier.

[0074] Another aspect of the invention is a method of making the above ophthalmic composition. The method includes dissolving a therapeutic agent in a solvent / co-solvent to obtain a solution, followed by mixing the therapeutic agent solution thus obtained with a polymerizable composition, a biodegradable polymer, a photoinitiator, and optionally a release modifier, in any order of addition. Optionally, the therapeutic agent is first mixed with the photopolymerizable composition, and the mixture thus obtained is mixed with the biodegradable polymer, the photoinitiator, and optionally a release modifier, in any order of addition. Alternatively, the therapeutic agent is first mixed with a portion of the photopolymerizable composition, and another portion of the photopolymerizable composition is mixed with the biodegradable polymer, the photoinitiator, and optionally a release modifier.

[0075] The choice of solvent that can be used in accordance with the present invention depends on the polarity of the therapeutic agent.

[0076] Optionally, the solvent may be selected from water, dimethyl sulfoxide, decyl methyl sulfoxide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, N-vinyl-pyrrolidine, N-methyl-2-pyrrolidone, N-ethyl-pyrrolidone, glycerol formal, glycerol, polyethylene glycol, propylene glycol, benzyl alcohol, benzyl benzoate, ethyl benzoate, triacetin, triethyl citrate, dimethylformamide, dimethylacetamide, acetonitrile, dichloromethane and tetrahydrofuran.

[0077] In one embodiment, a co-solvent may be used, which may be selected from dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, acetic acid, methanol, ethanol, isopropanol, glycofurol, or butanol.

[0078] In the case of hydrophilic therapeutic agents, the solvent can be an aqueous solvent such as water or a phosphate buffered saline (PBS) solution.

[0079] 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.

[0080] Alternatively, the therapeutic agent is not dissolved in a solvent prior to mixing with the other components. Thus, the therapeutic agent, polymerizable composition, biodegradable polymer, photoinitiator, and optionally release controlling agent are mixed together in any order of addition. Alternatively, the therapeutic agent is first mixed with a portion of the photopolymerizable composition, and another portion of the photopolymerizable composition is mixed with the biodegradable polymer, photoinitiator, and optionally release controlling agent.

[0081] Another aspect of the present invention is to provide an ophthalmic composition as described above for use in preparing an ophthalmic implant. Alternatively, the ophthalmic composition of the present invention is used to coat an ophthalmic implant or an ophthalmic implant support.

[0082] A further aspect of the invention is a method of making an ocular implant of the invention, comprising the steps of providing an ocular composition of the invention, and subsequently irradiating the ocular composition with light having a wavelength of 200-550 nm, 200-500 nm, 200-490 nm, or 200-425 nm for 1 second to 60 minutes, 30 seconds to 30 minutes, 2.5 minutes to 20 minutes, or 5 minutes to 10 minutes. In one embodiment, crosslinking is for 3 seconds, 6 seconds, 9 seconds, 15 seconds, 30 seconds, 1 minute, 2.5 minutes, 5 minutes, 10 minutes, 20 minutes, or 30 minutes.

[0083] A further aspect of the present invention is an ocular implant obtainable by the method described above.

[0084] In one embodiment, the rate and extent of drug release can be controlled by varying polymer molecular weight, type and copolymer ratio, drug type and loading, implant size, time and extent of UV crosslinking, amount and type of photoinitiator, release modifier, solvent and / or co-solvent. Variation of these factors provides compositions of the invention that can be easily tailored to provide desired drug release periods to address specific clinical / patient needs in the treatment of various ocular diseases.

[0085] The ophthalmic composition of the present invention comprises (i) injecting the material into the eye and then irradiating it with a brief period of UV light to induce in situ photocrosslinking, resulting in the formation of an implant called an In Situ Photocrosslinked Implant (ISPcI); and (ii) They can be photocrosslinked prior to application to the eye to form implants (e.g., films, rods, or nano / microparticles) of desired shape and size, which can be administered intraocularly to provide the desired drug delivery period, referred to as Preformed Photocrosslinked Implants (PPcIs).

[0086] Alternatively, the compositions of the present invention may be used to coat ophthalmic devices, including both in situ and preformed ophthalmic devices.

[0087] The implants of the present invention may be of any desired shape, including, but not limited to, rectangular, square, spherical, cylindrical, circular, oval, film, dumbbell, rod, and bead.

[0088] The implants of the present invention can be of any desired size, for example, in the macro, micro, or nanoparticle size range.

[0089] In one embodiment of the invention, the ocular implant is an implant with one of its dimensions being less than 10 mm, or less than 5 mm, or less than 3 mm. In one embodiment, the implant is a rectangular implant with dimensions 10x5x0.5 mm. In one embodiment, the implant (ISPcI) is a spherical implant with a diameter of less than 10 mm, or less than 5 mm, or less than 3 mm. In one embodiment of the invention, the ocular implant is a nanoparticle or microparticle.

[0090] In one embodiment, the nanoparticle ocular implant is less than 1,000 nm, less than 900 nm, less than 750 nm, less than 500 nm, or less than 100 nm.

[0091] In one embodiment, the particulate ocular implant is less than 1,000 μm, less than 900 μm, less than 750 μm, less than 500 μm, or less than 25 μm.

[0092] Optionally, the implant is an in situ formed ocular implant. Alternatively, the implant is a preformed ocular implant.

[0093] The in situ photocrosslinking implants (ISPcIs) of the present invention form and seal the final local structure when inserted into the body. The ability of ISPcIs to fill irregular defects is one of these advantages. The ISPcIs of the present invention also have additional advantages, including site-specific action with relatively easy and minimally invasive application, localized delivery to specific tissues, extended delivery times, reduced side effects associated with systemic delivery, and also 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 labile drugs such as proteins, peptides or genetic materials. Furthermore, rapid crosslinking at physiological temperatures can result in ISPcIs that can quickly capture drug molecules and provide long-term controlled drug release. Photocrosslinking is also beneficial compared to spontaneous crosslinking (e.g., enzymatic, self-assembly, Michael addition) since the initiation of the process is triggered only upon exposure to a light source, and therefore premature gelation is not an issue resulting in superior control of material formation. Furthermore, because UV light is used clinically for corneal crosslinking, short-term application of UV light is considered safe for ocular use and therefore does not pose safety concerns. Importantly, administration by this method allows for the injection into the body of a relatively low viscosity material which then solidifies by phase inversion to form a semi-solid depot that controls drug delivery upon crosslinking to provide short- or long-term therapeutic action.

[0094] In one embodiment, the ISPcI is formed by injecting the ophthalmic composition of the present invention into a subject in need thereof, followed by crosslinking with an external source of UV light, which causes the formation of a solid implant that controls drug release over a desired period of time.

[0095] In the case of the ISPcI of the present invention, the molecular weight of the photopolymerizable composition is typically from 100 to 6,000 Da, from 200 to 3,000 Da, or from 200 to 1,000 Da.

[0096] The preformed photocrosslinkable implants (PPcIs) of the present invention can be inserted into the eye, for example, into the fornix, subconjunctivally, intracamerally, intrastromally / intracorneally, transscleral / periocularly, intrasclerally, or intravitreally, subretinaly, to treat diseases of the anterior or posterior parts of the eye. PPcIs can be manufactured in a variety of shapes, including, but not limited to, rods, films, cylindrical or round shapes, and sizes, including micro- or nanoparticle forms.

[0097] In one embodiment, PPcI nanoparticles and microparticles are obtained by sonicating a mixture of therapeutic agent, photopolymerizable composition, biodegradable polymer, photoinitiator, and optionally release modifier in an aqueous medium. In one embodiment, the aqueous medium is a combination of water and phosphate buffered saline (PBS). Irradiation can be applied during sonication, i.e. while sonicating the mixture under UV light, or it can be performed after the sonication step.

[0098] The PPcIs of the present invention have the advantage of high crosslink density and / or tight polymer network structure, which can be configured to control drug release and / or eliminate burst release.

[0099] The PPcIs of the present invention can be fabricated to have single and / or multiple layers that allow the loading of two or more drugs or the same drug with different release profiles or release rates.

[0100] Furthermore, the rate of degradation of the implant can be slower for the PPcIs than for the ISPcIs of the present invention and can be controlled in function of the particular disease or disorder being treated.

[0101] In the case of the PPcI of the present invention, the average molecular weight of the photopolymerizable polymer is typically from 100 to 300,000 Da, from 200 to 100,000 Da, from 200 to 50,000 Da, from 200 to 20,000 Da, or from 200 to 10,000 Da.

[0102] In one embodiment, the invention is a PLGA / PEGDA PPcI. In another embodiment, the invention is a PLGA / PEGDA ISPcI.

[0103] In one embodiment, the biodegradable polymer is essentially contained within the matrix of the photopolymerizable composition. Optionally, the biodegradable polymer is essentially contained within the matrix of the photopolymerizable composition that forms a gel upon mixing. In one embodiment, the photopolymerizable polymer is crosslinked in the presence of a photoinitiator and the biodegradable polymer and the therapeutic agent(s). In one embodiment, the biodegradable polymer is hydrophobic in nature and the photopolymerizable polymer is hydrophilic in nature. In one embodiment, the degree of crosslinking of the composite implant governs the rate and extent of release of the therapeutic agent.

[0104] Another aspect of the invention relates to an ocular implant comprising at least 20 w / w% therapeutic agent and 5-75 w / w% crosslinked polymer matrix, wherein 0.1-40 w / w% of the biodegradable polymer is selected from the group consisting of lactide / glycolide copolymers (including poly(lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), polyhydroxyalkanoates including polyhydroxybutyrate, polyglycolic acid (PGA), polycaprolactone (PCL), poly(DL-lactide) (PDL), poly(D-lactide), lactide / caprolactone copolymers, poly-L-lactide-co-caprolactone (PLC), and mixtures, copolymers and block copolymers thereof; (a) the crosslinked polymer matrix is ​​obtained by crosslinking a photopolymerizable composition selected from the group consisting of polyalkylene glycol monoacrylates, polyalkylene glycol diacrylates, polyalkylene glycol methacrylates, and polyalkylene glycol dimethacrylate fragments or monomers, and mixtures, copolymers, and block copolymers thereof; and (b) the therapeutic agent and the biodegradable polymer are embedded in a polymer matrix.

[0105] As used herein, "embedded" means that the therapeutic agent is essentially entrapped within the crosslinked polymer matrix, uniformly dispersed or dissolved throughout the crosslinked polymer matrix and / or the biodegradable polymer.

[0106] 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 causes a decrease in drug release. Furthermore, the rate and duration of drug release can be controlled by varying the concentration of photoinitiator. Furthermore, the rate and duration of drug release can be controlled by varying both the UV crosslinking time and the concentration of photoinitiator. In one embodiment, decreasing the concentration of biodegradable polymer (such as PLGA) increases the drug release rate. In one embodiment, adding a pore-forming agent (e.g., MgCO3) increases the drug release rate. In one embodiment, longer UV crosslinking time and higher concentration of photoinitiator can sustain drug release for a longer period of time. In one embodiment, drug release can be sustained for more than 1 day, 2 days, 1 week, 1 month, 2 months, 3 months, 6 months, or 9 months.

[0107] In some embodiments, sensitive molecules such as peptides and proteins are protected due to the slow degradation rate of the ISPcIs and PPcIs of the present invention.

[0108] In some embodiments, the burst release can be eliminated or controlled by varying the UV crosslinking time, varying the formulation composition, implant volume.

[0109] In one embodiment, the present invention is a PPcI with no or low burst release.In one embodiment, the present invention is a PPcI with high crosslink density that significantly slows drug diffusion.

[0110] In one embodiment, the ocular implant of the present invention has a concentration of 200 μg to 2000 μg / μm 3 , 1000μg~2000μg / μm 3, 1200μg~1800μg / μm 3 , 1200μg~1500μg / μm 3 The therapeutic agent is present in a concentration of

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

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

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

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

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

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

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

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

[0119] In one embodiment, the disease or disorder is pain, inflammation, 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, blephariconjunctivtis, ocular hypertension, conjunctivitis, cystinosis, vitreomacular adhesion, corneal neovascularization, corneal ulcer, and post-operative ocular inflammation / wound healing.

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

[0121] 1. An ophthalmic composition comprising: (a) at least 20 w / w% of a therapeutic agent; and (b) 5 to 75 w / w% of a photopolymerizable composition selected from the group consisting of polyalkylene glycol monoacrylates, polyalkylene glycol diacrylates, polyalkylene glycol methacrylates, polyalkylene glycol dimethacrylate fragments or monomers, and mixtures, copolymers, and block copolymers thereof; and (c) 0.1-40 w / w% of the biodegradable polymer is selected from the group consisting of lactide / glycolide copolymers (including poly(lactide-co-glycolide) (PLGA)), poly(L-lactide) (PLA), polyhydroxyalkanoates including polyhydroxybutyrate, polyglycolic acid (PGA), polycaprolactone (PCL), poly(DL-lactide) (PDL), poly(D-lactide), lactide / caprolactone copolymers, poly-L-lactide-co-caprolactone (PLC), and mixtures, copolymers, and block copolymers thereof; and (d) a photoinitiator; and 1. An ophthalmic composition comprising:

[0122] 2. The ophthalmic composition of embodiment 1, wherein the therapeutic agent is present in an amount of 20-70 w / w %.

[0123] 3. The ophthalmic composition of embodiment 2, wherein the therapeutic agent is present in an amount of 40-70 w / w %.

[0124] 4. The ophthalmic composition of embodiment 3, wherein the therapeutic agent is present in an amount of 50-70 w / w %.

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

[0126] 6. The ophthalmic composition of any one of embodiments 1 to 5, wherein the photopolymerizable composition is selected from the group consisting of polyethylene glycol diacrylate, diethylene glycol diacrylate, polyethylene glycol dimethacrylate, diethylene glycol dimethacrylate, polypropylene glycol diacrylate, dipropylene glycol diacrylate, dipropylene glycol dimethacrylate, and polypropylene glycol dimethacrylate, or mixtures, copolymers, or block copolymers thereof.

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

[0128] 8. The ophthalmic composition of any one of embodiments 1 to 7, wherein the biodegradable polymer is present in an amount of 5 to 10 w / w %.

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

[0130] 10. The ophthalmic composition of embodiment 9, wherein the biodegradable polymer is poly(lactide-co-glycolide) (PLGA).

[0131] 11. The ophthalmic composition of any one of embodiments 1-10, wherein the photoinitiator is a hydroxyketone photoinitiator, an aminoketone photoinitiator, a hydroxyketone / benzophenone photoinitiator, a benzyl dimethyl ketal photoinitiator, a phenylglyoxylate photoinitiator, an acylphosphine oxide photoinitiator, an acylphosphine oxide / alpha hydroxyketone photoinitiator, a benzophenone photoinitiator, a ribitylisoalloxazine photoinitiator, or a phenylglyoxylate photoinitiator, or any combination thereof.

[0132] 12. The ophthalmic composition of embodiment 11, wherein the photoinitiator is 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.

[0133] 13. The ophthalmic composition of any one of embodiments 1 to 12, further comprising a release modifier.

[0134] 14. The ophthalmic composition of embodiment 13, wherein the release modifier is selected from polysaccharides including chitosan and cellulosic materials including hydroxypropyl methylcellulose (HPMC); hyaluronic acid; poloxamers; polyethers including polyethylene glycol (PEG); gelatin; polyvinylpyrrolidone; polyvinyl alcohol, lactose, maltose, glucose, mannitol, sodium chloride, magnesium carbonate, magnesium hydroxide, potassium chloride, sodium bicarbonate, ammonium bicarbonate, potassium bicarbonate, agarose, sucrose, and mixtures thereof.

[0135] 15. The ophthalmic composition of embodiment 14, wherein the release modifier is polyethylene glycol (PEG), hydroxypropyl methylcellulose (HPMC), or a mixture thereof.

[0136] 16. The ophthalmic composition of any one of embodiments 1-12, wherein the composition does not contain any release modifier.

[0137] 17. An ophthalmic composition according to any one of embodiments 1 to 16 for use in the preparation of an ophthalmic implant.

[0138] 18. (a) dissolving the therapeutic agent in a solvent to obtain a solution; (b) mixing the solution obtained in step (a) with the polymerizable composition, the biodegradable polymer, the photoinitiator, and optionally the release modifier.

[0139] 19. The method of embodiment 18, wherein the solvent is an aqueous solvent.

[0140] 20. A method of making an ocular implant, comprising: (a) providing an ophthalmic composition according to any one of claims 1 to 17; and (b) irradiating the ophthalmic composition with light having a wavelength of 200 to 550 nm for a period of 1 second to 60 minutes to form the ophthalmic implant.

[0141] 21. The method of embodiment 20, wherein the ophthalmic composition provided in step (a) is administered to an ocular region of a subject prior to irradiating it according to step (b).

[0142] 22. The method of embodiment 20, wherein the ocular implant formed in step (b) is administered to an ocular region of a subject.

[0143] 23. An ocular implant obtainable by the method according to any one of embodiments 20 to 22.

[0144] 24. An ocular implant comprising at least 20 w / w% therapeutic agent; 5-75 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 copolymers, 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 selected from the group consisting of polyalkylene glycol monoacrylates, polyalkylene glycol diacrylates, polyalkylene glycol methacrylates, polyalkylene glycol dimethacrylate fragments or monomers, and mixtures, copolymers, and block copolymers thereof; and (b) an ocular implant, wherein a therapeutic agent and a biodegradable polymer are embedded in a polymer matrix.

[0145] 25. An ocular implant according to embodiment 23 or 24, which is a macro-, micro- or nanoparticle.

[0146] 26. The therapeutic agent is an ocular implant of 1 μm 3 26. The ocular implant of any one of embodiments 23-25, wherein the ocular implant is present in a concentration of 200 μg to 2000 μg per unit area. EXAMPLES

[0147] Example 1: Bevacizumab (BEZ), molecular weight 150 kDa 1.1 Materials Poly(ethylene glycol) diacrylate (Mn=750, PEGDA 700), Irgacure 2959 (1-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propanone), phosphate-buffered saline (PBS) solution tablets, and hydroxypropyl methylcellulose (HPMC, 10,000 Da) were purchased from Sigma (Dorset, UK). Poly(lactide-co-glycolide) (PURASORB® PDLG 7502A, 75:25, PLGA 75 / 25) was obtained from Corbion Purac Biomaterials (Gorinchem, The Netherlands).

[0148] Bevacizumab (BEZ) (Avastin®) was purchased from a local pharmacy (Roche, Switzerland; each vial contained 100 mg of BEZ in 4 mL, i.e., 25 mg / mL).

[0149] 1.2 Preparation of BEZ-loaded implants 1.2.1 Preparation of PPcI implant F18 (30 w / w% BEZ and 30 w / w% HPMC) Solution A was prepared by dissolving 50 mg of PLGA 7502 (75 / 25) in 650 mg of PEGDA 700. Solution B was prepared by dissolving 6 mg of Irgacure 2559 in 1 mL of PBS (0.01 M, pH 7.4). Solution C was prepared by dissolving 50 mg of HPMC 10,000 Da in 1 mL of solution B. 52.5 mg of solution C was placed in a 2 mL Eppendorf tube. Subsequently, 15 mg of BEZ was added to the Eppendorf tube and stirred at 250 rpm for 30 seconds using a stir bar. The mixture thus obtained was left to dissolve at 4-7 °C for 30 minutes, followed by centrifugation at 2000 rpm for 1 minute to remove air bubbles. To the mixture thus obtained, 32.5 mg of solution A and 10 μL of solution B were added, followed by stirring at 250 rpm for 30 minutes. It was then centrifuged at 2000 rpm for 1 min to remove air bubbles, followed by stirring at 250 rpm for another 10 min. The final mixture was taken into a silicon tube (inner diameter: 0.635 mm) and crosslinked using a light hammer (LightHammer® 6, Heraeus Noblelight Fusion UV Inc., Gaithersburg, MD, USA). The intensity of the UV light (365 nm) was set to 50%, and the silicone tube was exposed to the UV light for 15 seconds (5 times). The rod-shaped implant was taken out of the silicon tube and vacuum dried at 25° C. for 4 hours. The dried implant was cut into 5 mm lengths.

[0150] The resulting implants had an average diameter of 0.5 mm and a length of 5 mm.

[0151] 1.2.2 Preparation of PPcI implant F19 (50 w / w% BEZ) Solution A was prepared by dissolving 50 mg of PLGA 7502 (75 / 25) in 450 mg of PEGDA 700. 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. Then, 25 mg of BEZ was added to the Eppendorf tube and stirred with a stir bar at 250 rpm for 30 seconds. The mixture thus obtained was left to dissolve at 4-7 °C for 30 minutes, and then centrifuged at 2000 rpm for 1 minute to remove air bubbles. To the mixture thus obtained, 25 mg of solution A was added, followed by stirring at 250 rpm for 30 minutes. This was then centrifuged at 2000 rpm for 1 minute to remove air bubbles, followed by stirring at 250 rpm for another 10 minutes. The final mixture was taken into a silicon tube (inner diameter: 0.635 mm) and crosslinked using a light hammer (LightHammer® 6, Heraeus Noblelight Fusion UV Inc., Gaithersburg, MD, USA). The intensity of the UV light (365 nm) was set to 50%, and the silicone tube was exposed to the UV light for 15 seconds (5 times). The rod-shaped implant was taken out of the silicon tube and dried in vacuum at 25° C. for 4 hours. The dried implant was cut into a length of 5 mm. The diameter of the resulting implant was 0.4997+ / -0.002 mm and the length was 5 mm.

[0152] 1.2.3 Preparation of PPcI implant F7 (6 w / w% BEZ and 4 w / w% HPMC) Solution A was prepared by dissolving 20 mg of PLGA 7502 (75 / 25) in 160 mg of PEGDA 700. Solution B was prepared by dissolving 6 mg of Irgacure 2559 in 1 mL of PBS (0.1 M, pH 7.4). Solution C was prepared by dissolving 80 mg of HPMC 10,000 Da in 1 mL of solution B.

[0153] 27.5 mg of solution C was placed in a 2 mL Eppendorf tube. 3 mg of BEZ was then added to the Eppendorf tube and stirred with a stir bar at 250 rpm for 30 seconds. The mixture thus obtained was left to dissolve at 4-7°C for 30 minutes, and then centrifuged at 2000 rpm for 1 minute to remove air bubbles. 45.0 mg of solution A was added to the mixture thus obtained, and then stirred at 250 rpm for 30 minutes. This was then centrifuged at 2000 rpm for 1 minute to remove air bubbles, and then stirred at 250 rpm for another 10 minutes. The final mixture was taken out into a silicon tube (inner diameter: 0.635 mm) and crosslinked using a light hammer (LightHammer® 6, Heraeus Noblelight Fusion UV Inc., Gaithersburg, MD, USA). The intensity of the UV light (365 nm) was set to 50%, and the silicone tube was exposed to the UV light for 15 seconds (5 times). The rod-shaped implants were removed from the silicon tubes and dried in vacuum for 4 hours at 25° C. The dried implants were cut into 10 mm lengths.

[0154] The resulting implants had a mean diameter of 0.5 mm and a length of 10 mm.

[0155] 1.3 In vitro drug release study (PPcI implants F7, F18, F19) For drug release studies, each PPcI implant F7, F18 and F19 was placed in a glass vial containing 2 mL of PBS (pH 7.4, 0.05% NaN3). The glass vials were placed in a static incubator at 37°C. Sampling followed by complete replacement of the PBS release medium was performed on day 1 and every week thereafter, i.e., on days 7, 14, 21 and 28 etc. All experiments were performed in triplicate. The concentration of released drug molecules in the PBS samples was analyzed as described below.

[0156] 1.4 SEC-HPLC method for BEZ Analysis of bevacizumab (BEZ) samples was performed using SEC-HPLC (Agilent 1260 Infinity Quaternary System) with fluorescence detection using a Phenomenex® BioZen™ SEC-2 column (length 150 mm, internal diameter 4.6 mm, and particle size 1.8 μm) 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 at an excitation wavelength of 280 nm and an emission wavelength of 340 nm.

[0157] 1.5 BEZ ELISA method The bioactivity of released BEZ was determined using a sandwich ELISA technique. The washing buffer was 0.01 M PBS containing 0.05 w / w% Tween 20. The blocking buffer consisted of 0.01 M PBS, 0.05 w / w% Tween 20, and 1 w / w% BSA.

[0158] The primary coating antibody, recombinant human vascular endothelial growth factor (VEGF165), was diluted 1:5000 in 0.1 M bicarbonate buffer (pH 9.6). An aliquot (100 μL) of this recombinant human VEGF165 was dispensed into each well of a 96-well plate. The plate was covered with Parafilm® and incubated at 4°C for 16 hours. The plate was then washed three times with wash buffer (200 μL / well) to remove unbound antibody. 200 μL of blocking buffer was then added to each well and the plate was incubated at 25°C for 2 hours. After this, the plate was washed three times with wash buffer (200 μL / well) and a volume of 100 μL of BEZ sample was dispensed into each well, each sample was analyzed in triplicate, and a freshly prepared standard concentration curve was plated (5-400 ng / mL) and incubated at 25°C for 1.5 hours. The plate was then washed three times with washing buffer (200 μL / well). Following this, 100 μL of secondary antibody (biotinylated BEGF165 antibody diluted 1:10,000 in blocking buffer) was added to each well and incubated for 1 hour at 25° C. The plate was then washed three times with washing buffer (200 μL / well). 100 μL of streptavidin conjugated with horseradish peroxidase (Strep-HRP) diluted 1:5000 in PBS was dispensed into each well and the plate was incubated at 25° C. in the dark for 30 minutes. The plate was washed three times with washing buffer (200 μL / well). To detect antibody binding, 100 μL of the substrate TMB (3,3',5,5'-tetramethylbenzidine) was added to each well and incubated for 45 min in the dark at 25°C, and the reaction was stopped by adding 100 μL of 4.0 M hydrochloric acid to each well. Optical density was measured at 450 nm using a FLUOstar® Omega multimode microplate reader (BMG LABTECH, Offenburg, Germany).

[0159] The following table summarizes the parameters of implants F7, F18 and F19.

[0160] JPEG2024167337000002.jpg47156*The values ​​in brackets represent the percentage emission of BEZ on day 1.

[0161] The therapeutically relevant concentration of BEZ has been reported to be 50ng / mL (Yu Y, Lau LCM, Lo AC, Chau Y, Injectable Chemically Crosslinked Hydrogel for the Controlled Release of Bevacizumab in Vitreous: A 6 Month In Vivo Study., Transl Vis Sci Technol. (2015), Vol. 4, No. 2, p. 5, Doi:10.1167 / tvst.4.2.5). Considering a volume of 4mL for human vitreous humor, the therapeutic level of BEZ in the human eye is 0.2μg. The upper limit for BEZ is 1.25 mg or 1250 μg per eye (Edith Poku, John Rathbone, Emma Everson-Hock, Munira Essat, Ruth Wong, Abdullah Pandor, Allan Wailoo, Bevacizumab In Eye Conditions: Issues Related To Quality, Use, Efficacy and Safety, School of Health and Related Research, University of Sheffield, August 2012).

[0162] Figures 1-3 show that implants F18 and F19 according to the invention are capable of delivering therapeutically acceptable doses of therapeutic agents over an extended period (84 days). Implants F18 and F19 are 50% shorter in length than comparative implant F7 (5mm vs. 10mm), thus allowing for increased patient acceptance, tolerance and comfort. Furthermore, BEZ released from F18 implant maintained more than 85% of its bioactivity over 84 days as estimated by ELISA.

[0163] Example 2: Bevacizumab implants with different loadings

[0164] JPEG2024167337000003.jpg23156

[0165] 2.1 Preparation of B1 and B4 implants Solution A was prepared by dissolving 25 mg (B1) or 50 mg (B4) of PLGA 7502 (75 / 25) in 425 mg (B1) or 450 mg (B4) of PEGDA 700 (Sigma Aldrich, Basingstoke, UK). Solution B was prepared by dissolving 6 mg of Irgacure 2959 (Sigma Aldrich, Basingstoke, UK) in 1 mL of PBS (0.01 M, pH 7.4).

[0166] 25 μL of solution B was placed in a 2 mL Eppendorf tube. 5 mg (B1) or 25 mg (B4) of BEZ was then added to the Eppendorf tube and stirred with a stir bar at 250 rpm for 30 seconds. The mixture thus obtained was left to dissolve at 4-7°C for 30 minutes, and then centrifuged at 2000 rpm for 1 minute to remove air bubbles. 45 mg (B1) or 25 mg (B4) of solution A was added to the mixture obtained, and then stirred at 250 rpm for 30 minutes. This was then centrifuged at 2000 rpm for 1 minute to remove air bubbles, and then stirred at 250 rpm for another 10 minutes. The final mixture obtained was taken out into a silicon tube (inner diameter: 0.635 mm, Polymer System Technology, UK) and crosslinked using a light hammer (LightHammer® 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 implants were removed from the silicone tubes and dried under vacuum at 25° C. for 4 hours. The dried implants were cut into 6.5 mm lengths.

[0167] 2.2 In vitro drug release setting The in vitro release was performed by placing one implant of B1 (1) in an Eppendorf tube containing 1 mL of PBS (phosphate buffered saline) with 0.05% NaN2 (pH 7.4 ± 0.2) as the release medium. The same in vitro release was performed for implant B4. All experiments were performed in triplicate. The Eppendorf tube containing the implant was placed in an incubator and incubated at 37°C and 0 rpm (MINI / 100 / F oven, Genlab Ltd., UK). Sampling followed by complete replacement of the PBS medium was performed on days 1, 3 and every week thereafter, i.e., days 7, 14, 21, and 28 etc. The concentration of released drug molecules in the PBS samples was analyzed as described in the following section.

[0168] 2.3 Sample analysis The assay of bevacizumab was performed on an Agilent HPLC infinity II system consisting of a quaternary pump, autosampler, variable wavelength detector (VWD), and fluorescence detector (Agilent, UK). Separation was achieved on a Phenomenex® bioZen™ SEC-2 column (1.8 μm, 4.6×150 mm) (Phenomenex, UK). Chromatographic conditions included an aqueous mobile phase composed of 35 mM sodium phosphate buffer and 300 mM sodium chloride (pH 6.8) and were run at a flow rate of 0.5 mL / min, with the fluorescence detector set at excitation and emission wavelengths of 280 and 340 nm, respectively.

[0169] Figures 6 and 7 show the in vitro release of B1 and B4, expressed as cumulative percentage and daily release in μg, respectively, and as can be seen, implant B4 according to the invention allows sustained release of a therapeutically acceptable dose over at least 56 days without causing unacceptable burst effects immediately after the start of release.

[0170] Example 3 Ovalbumin, molecular weight 42.7kDa

[0171] JPEG2024167337000004.jpg35156

[0172] 3.1 Preparation of O1, O2, O3 and O4 implants Solution A was prepared by dissolving 5 mg of PLGA 7502, i.e. 75 / 25 (Corbion Purac Biomaterials, Gorinchem, The Netherlands), in 85 mg (O1) or 75 mg (O2) or 65 mg (O3) or 45 mg (O4) of PEGDA 700Da (Sigma Aldrich, Basingstoke, UK). Solution B was prepared by dissolving 5 mg of Irgacure 2559 (Sigma Aldrich, Basingstoke, UK) in 1 mL of PBS. Solution C was prepared by placing 10 mg (O1) or 20 mg (O2) or 30 mg (O3) or 40 mg (O4) of albumin from chicken egg white, i.e. Ovalbumin (Sigma Aldrich, Basingstoke, UK) in 60 μL of solution B in an Eppendorf tube. 90 mg (O1) or 80 mg (O2) or 70 mg (O3) or 50 mg (O4) of solution A was added to an Eppendorf tube. 60 μL of solution C was slowly added to the mixture through the Eppendorf tube wall with continuous stirring at 900 rpm for 15 min. The final mixture was taken out into a silicone tube with an inner diameter of 0.635 mm (Polymer System Technology, UK) and crosslinked using UV light (LightHammer® 6, Heraeus Noblelight Fusion UV Inc., Gaithersburg, MD, USA). The intensity of the UV light was set to 50% and the silicone tube was exposed to the UV light for 15 seconds (i.e., a total of 5 runs). The implants were then taken out of the silicone tube and dried under vacuum at 25° C. for 4 hours. Rod-shaped implants were cut into lengths of 7.5 mm each.

[0173] 3.2 In vitro drug release setting The in vitro release was carried out by placing two implants of O1 (2) in a glass vial containing 2 mL of PBS (phosphate buffered saline) with 0.05% NaN2 (pH 7.4 ± 0.2) as the release medium. The same in vitro release was carried out for implants O2, O3 and O4. All experiments were carried out in triplicate. The glass vials containing the implants were placed in an incubator and incubated at 37°C and 0 rpm (MINI / 100 / F oven, Genlab Ltd., UK). Sampling followed by complete replacement of the PBS medium was carried out on the 1st, 3rd day and every week thereafter, i.e., on the 7th, 14th, 21st and 28th days etc. The concentration of released drug molecules in the PBS samples was analyzed as described in the following section.

[0174] 3.3 Sample analysis Analysis of Ovalbumin (OVA) in vitro drug release samples was performed using SEC-HPLC (Agilent 1260 Infinity Quaternary System) with UV detection using a Phenomenex® Biosep-SEC-S300 column (length 300 mm, internal diameter 7.8 mm, particle size 5 μm) and Phenomenex® SecurityGuard Cartridges GFC 3000 internal diameter 4×3.0 mm (Phenomenex, Torrance, USA). 20 μL of sample was eluted with 27 mM phosphate buffer and 150 mM NaCl pH 6.35 at a flow rate of 1.0 mL / min for 14 min. Detection was performed by UV detector at 214 nm.

[0175] FIG. 8 shows the in vitro release of O1, O2, and O4 expressed as cumulative release percentage.

[0176] As can be seen from these figures, implants O2 and O4 according to the invention allow sustained release of a therapeutically acceptable dose for at least 196 days without causing an unacceptable burst effect immediately after the start of drug release.

[0177] Example 4: Release of bevacizumab from different implant lengths.

[0178] JPEG2024167337000005.jpg29156

[0179] 4.1 Preparation of BL1 and BS4 implants The preparation method was similar to that of the B1 and B4 implants (example 2.1), except that the implant BL1 was cut to a length of 10 mm and the implant BS4 was cut to a length of 3 mm.

[0180] 4.2 In vitro drug release setting The in vitro release was performed by placing one implant (1) of BL1 in an Eppendorf tube containing 1 mL of PBS (phosphate buffered saline) with 0.05% NaN2 (pH 7.4 ± 0.2) as the release medium. The in vitro release for BS4 was performed by placing two implants (2) in an Eppendorf tube containing 1 mL of PBS (phosphate buffered saline) with 0.05% NaN2 (pH 7.4 ± 0.2) as the release medium. All experiments were performed in triplicate. The Eppendorf tube containing the BL1 implant and the Eppendorf tube containing the two (2) BS4 implants were placed in an incubator and incubated at 37°C and 0 rpm (MINI / 100 / F oven, Genlab Ltd., UK). Sampling followed by complete replacement of the PBS medium was performed on the 1st, 3rd day and every week thereafter, i.e. on the 7th, 14th, 21st and 28th days etc. The concentration of released drug molecules in the PBS samples was analyzed as described in Example 2.3.

[0181] 4.3 Sample analysis The samples were analyzed under Example 2.3.

[0182] Figures 9 and 10 show the in vitro release of B1, BL1 and BS4, expressed as cumulative percentage and daily release in μg, respectively. As can be seen from these figures, the implant BS4 according to the invention allows sustained release of a therapeutically acceptable dose for at least 56 days without causing an unacceptable burst effect immediately after starting the release of the drug. BS4 is even shorter than B1 and BL1, thus contributing substantially to better patient compliance.

[0183] Example 5: Implant width and release of bevacizumab, molecular weight 150 kDa.

[0184] JPEG2024167337000006.jpg29156

[0185] 5.1 Preparation of FN4 implants 50 mg of PLGA 7502 (75 / 25) (Corbion Purac Biomaterials, Gorinchem, The Netherlands) was dissolved in 450 mg of PEGDA 700 (Sigma Aldrich, Basingstoke, UK) to prepare solution A. 6 mg of Irgacure 2959 (Sigma Aldrich, Basingstoke, UK) was dissolved in 1 mL of PBS (0.01 M, pH 7.4) to prepare solution B. 62.5 μL of solution B was placed in a 2 mL Eppendorf tube, followed by the addition of 25 mg of BEZ.

[0186] The mixture was stirred at 250 rpm for 30 seconds using a stir bar. The mixture thus obtained was left to dissolve at 4-7°C for 30 minutes, followed by centrifugation at 2000 rpm for 1 minute to remove air bubbles. 25 mg of solution A was added to the mixture obtained, followed by stirring at 250 rpm for 30 minutes. This was then centrifuged at 2000 rpm for 1 minute to remove air bubbles, followed by stirring at 250 rpm for another 10 minutes. The final mixture obtained was taken out into a silicon tube (inner diameter: 0.305 mm) and crosslinked using a light hammer (LightHammer® 6, Heraeus Noblelight Fusion UV Inc., Gaithersburg, MD, USA). The intensity of the UV light (365 nm) was set to 50%, and the silicone tube was exposed to the UV light for 15 seconds (5 times). The rod-shaped implant was taken out of the silicon tube and dried in vacuum at 25°C for 4 hours. The dried implant was cut into 6.5 mm lengths.

[0187] 5.2 In vitro drug release setting In vitro release was performed by placing four implants (4) of FN4 in an Eppendorf tube containing 1 mL of PBS (phosphate buffered saline) with 0.05% NaN2 (pH 7.4 ± 0.2) as release medium. All experiments were performed in triplicate. The Eppendorf tubes containing the implants were placed in an incubator and incubated at 37°C and 0 rpm (MINI / 100 / F oven, Genlab Ltd., UK). Sampling followed by complete replacement of the PBS medium was performed on days 1, 3 and every week thereafter, i.e., days 7, 14, 21, and 28 etc. The concentration of released drug molecules in the PBS samples was analyzed as described in the following section.

[0188] 5.3 Sample analysis The samples were analyzed under Example 2.3.

[0189] Figures 11 and 12 show the in vitro release of B1, BL1 and FN4, expressed as cumulative percentage and daily release in μg, respectively. As can be seen from these figures, the implant FN4 according to the present invention allows sustained release of a therapeutically acceptable dose for at least 56 days without causing an unacceptable burst effect immediately after starting the drug release. FN4 is even thinner than B1 and BL1, thus contributing substantially to better patient compliance.

[0190] Example 6: Effect of pore-forming / release-modifying agents on the release of bevacizumab, molecular weight 150 kDa

[0191] JPEG2024167337000007.jpg29166

[0192] 6.1 Preparation of FN5 50 mg of PLGA 7502 (75 / 25) (Corbion Purac Biomaterials, Gorinchem, The Netherlands) was dissolved in 600 mg of PEGDA 700 (Sigma Aldrich, Basingstoke, UK) to prepare solution A. 6 mg of Irgacure 2959 (Sigma Aldrich, Basingstoke, UK) was dissolved in 1 mL of PBS (0.01 M, pH 7.4) to prepare solution B. 50 mg of HPMC (10,000 Da) (Sigma Aldrich, Dorset, UK) was dissolved in 1 mL of solution B to prepare solution C. 52.5 μL of solution C was placed in a 2 mL Eppendorf tube. Subsequently, 15 mg of BEZ was added to the Eppendorf tube and stirred with a stir bar at 250 rpm for 30 s. The mixture thus obtained was left to dissolve at 4-7°C for 30 minutes, followed by centrifugation at 2000 rpm for 1 minute to remove air bubbles. To the mixture thus obtained, 30 mg of solution A and 10 μL of solution B were added, followed by stirring at 250 rpm for 30 minutes. This was then centrifuged at 2000 rpm for 1 minute to remove air bubbles, followed by stirring at 250 rpm for another 10 minutes. The final mixture was taken out into a silicon tube (inner diameter: 0.305 mm) and crosslinked using a light hammer (LightHammer® 6, Heraeus Noblelight Fusion UV Inc., Gaithersburg, MD, USA). The intensity of the UV light (365 nm) was set to 50%, and the silicone tube was exposed to the UV light for 15 seconds (5 times). The rod-shaped implant was taken out of the silicon tube and dried in vacuum at 25°C for 4 hours. The dried implant was cut into 6.5 mm lengths.

[0193] 6.2 In vitro drug release setting In vitro release was performed by placing four implants (4) of FN5 in an Eppendorf tube containing 1 mL of PBS (phosphate buffered saline) with 0.05% NaN2 (pH 7.4 ± 0.2) as release medium. All experiments were performed in triplicate. The Eppendorf tubes containing the implants were placed in an incubator and incubated at 37°C and 0 rpm (MINI / 100 / F oven, Genlab Ltd., UK). Sampling followed by complete replacement of the PBS medium was performed on days 1, 3 and every week thereafter, i.e., days 7, 14, 21, and 28 etc. The concentration of released drug molecules in the PBS samples was analyzed as described in the following section.

[0194] 6.3 Sample analysis Bevacizumab assays were performed as described in Example 2.3.

[0195] Figure 13 shows the in vitro release of FN2 and FN5 expressed as a cumulative percentage. As can be seen from this figure, the use of a pore former further improves the release profile of the BEZ active compound over time without causing an unacceptable burst release.

[0196] Example 7: Effect of Pore Forming / Release Modifiers on the Release of Ovalbumin, Molecular Weight 42.7 kDa

[0197] JPEG2024167337000008.jpg29166

[0198] 7.1 Preparation of O7 implants Solution A was prepared by dissolving 16.7 mg of PLGA 7502 (75 / 25) (Corbion Purac Biomaterials, Gorinchem, The Netherlands) in 183.3 mg of PEGDA 700Da (Sigma Aldrich, Basingstoke, UK). Solution B was prepared by dissolving 5 mg of Irgacure 2559 (Sigma Aldrich, Basingstoke, UK) in 1 mL of PBS. Solution C was prepared by placing 30 mg of albumin from chicken egg white freeze-dried powder, i.e. Ovalbumin (Sigma Aldrich, Basingstoke, UK), in 60 μL of solution B in an Eppendorf tube. 60 mg of solution A and 10 mg of PEG400 (Sigma Aldrich, Basingstoke, UK) were added to an Eppendorf tube. 60 μL of solution C was slowly added to the mixture through the Eppendorf tube wall with continuous stirring at 900 rpm for 15 min. The final mixture was drawn into a silicone tube with an inner diameter of 0.635 mm (Polymer System Technology, UK) and crosslinked using UV light (LightHammer® 6, Heraeus Noblelight Fusion UV Inc., Gaithersburg, MD, USA). The intensity of the UV light was set to 50% and the silicone tube was exposed to the UV light for 15 seconds (i.e., a total of 5 runs). The implants were then removed from the silicone tube and dried under vacuum at 25° C. for 4 hours. Rod-shaped implants were cut into lengths of 7.5 mm each.

[0199] 7.2 In vitro drug release setting In vitro release was performed by placing two O7 implants (2) in a glass vial containing 2 mL of PBS (phosphate buffered saline) with 0.05% NaN2 (pH 7.4 ± 0.2) as release medium. All experiments were performed in triplicate. The glass vials containing the implants were placed in a shaking orbital incubator at a speed of 40 rpm and 37°C (GFL Orbital Shaking Incubator, Gesellschaft fur Labortechnik mbH, Germany). Sampling followed by complete replacement of the PBS medium was performed on the 1st, 3rd day and every week thereafter, i.e., on the 7th, 14th, 21st, and 28th days etc. The concentration of released drug molecules in the PBS samples was analyzed as described in the following section.

[0200] 7.3 Sample Analysis Analysis of Ovalbumin (OVA) in vitro drug release samples was performed in Example 3.3.

[0201] Figure 14 shows the in vitro release of O3 and O7 expressed as cumulative release percentage. As can be seen from this figure, the use of a pore former further improves the release profile of Ovalbumin over time without causing unacceptable burst release.

Claims

1. An ophthalmic composition for use in an ocular implant, comprising: (a) at least 20% w / w of a therapeutic agent; and (b) a photopolymerizable composition comprising 55-75 w / w% of polyalkylene glycol diacrylate (PEGDA) fragments or monomers, and mixtures, copolymers, and block copolymers thereof; and (c) 5 w / w % of a biodegradable polymer selected from the group consisting of lactide / glycolide copolymers, including poly(lactide-co-glycolide) (PLGA), and mixtures, copolymers, and block copolymers thereof; and, (d) a photoinitiator comprising 1-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propanone; and, (e) a release modifier selected from polysaccharides including chitosan and cellulosics including hydroxypropyl methylcellulose (HPMC); hyaluronic acid; poloxamers; polyethers including polyethylene glycol (PEG); gelatin; polyvinylpyrrolidone; polyvinyl alcohol, lactose, maltose, glucose, mannitol, sodium chloride, magnesium carbonate, magnesium hydroxide, potassium chloride, sodium bicarbonate, ammonium bicarbonate, potassium bicarbonate, agarose, sucrose, and mixtures thereof; and 1. An ophthalmic composition comprising:

2. 10. The ophthalmic composition of claim 1, wherein the therapeutic agent is present in an amount of 20-40 w / w %.

3. The ophthalmic composition described in claim 1, wherein the ophthalmic implant is rod-shaped.

4. The ophthalmic composition of claim 1, wherein the ophthalmic implant has dimensions of 0.5 mm x 7.5 mm.

5. The ophthalmic composition of claim 1, wherein 75% of the therapeutic agent is released over a period of 196 days.

6. A method for preparing the ophthalmic composition according to any one of claims 1 to 5, comprising the steps of: (a) dissolving the therapeutic agent in a solvent to obtain a solution; (b) mixing the solution obtained in step (a) with the polymerizable composition, the biodegradable polymer, the photoinitiator, and the release modifier; A method comprising:

7. The method of claim 6 , wherein the solvent is an aqueous solvent.

8. 1. A method of making an ocular implant, comprising: (a) providing an ophthalmic composition according to any one of claims 1 to 5; (b) irradiating the ophthalmic composition with light having a wavelength of 200 to 550 nm for a period of time ranging from 1 second to 60 minutes to form the ophthalmic implant; A method comprising:

9. Use of an ophthalmic composition described in any one of claims 1 to 5 for the manufacture of an ophthalmic implant to be administered to an ocular region of a subject.

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