JP-7855531-B2 - Biodegradable compositions and implants

Inventors

• タクール， ラグー ラジ シン
• ジョーンズ， デイヴィッド
• ソナウェイン， ラウル
• ワン， ユージン

Assignees

• レ‐ヴァーナ セラピューティクス エルティーディー

Dates

Publication Date

20260508

Application Date

20210618

Priority Date

20200619

Claims (13)

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, 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 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 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, 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) 10-50% w/w of the therapeutic agent b) 1-20% w/w of 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, 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 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 .

Description

This invention relates to biodegradable compositions and implants for the controlled release of therapeutic agents. More specifically, this invention relates to biodegradable ophthalmic compositions and implants for the controlled release of therapeutic agents in the eye. 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 profound economic consequences for individuals, families, public health, and society. The World Health Organization estimates that approximately 285,000,000 people worldwide suffer from visual impairment, of which 39,000,000 are blind and 246,000,000 have reduced vision. Diseases originating from the posterior segment (PS), or back of 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. If left untreated, these can lead to permanent vision loss and are the cause of most cases of blindness. The PS of the eye, including the retina, choroid, and vitreous humor, is difficult to access due to its recessed location within the orbit. Therefore, delivering therapeutic agents to ocular PS remains one of the most challenging issues for pharmaceutical scientists and retinal specialists. Multiple approaches are used to deliver therapeutic agents to the ocular suppositories (PS) of the eye, including systemic, topical, periorbital (or transscleral), and intravitreous routes. Topical (e.g., eye drops) and systemic (e.g., oral tablets) routes, due to multiple ocular barriers, can lead to therapeutic agent-related toxicity and low or subthermal drug levels, requiring unnecessarily high concentrations of the agent for low therapeutic efficacy. 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. An alternative system is needed for the ocular delivery of therapeutic agents. International Publication No. 2017081154 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 3 to 70% w/w of one or more compounds of formula I, In the formula, 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) a 0.1 to 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, and d) a photoinitiator. In a further embodiment, the present invention relates to the above-mentioned ophthalmic composition for use in the preparation of ophthalmic implants. 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. 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. This invention provides ophthalmic compositions and implants that can be administered to the eye in various forms to achieve controlled release of therapeutic agents. The 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. The presence of one or more compounds of formula I in the photopolymerizable composition allows for optimized implant delivery and complete degradation after the release of the therapeutic compound has been stopped. The disintegration of the implant according to this invention occurs along with drug release. Complete disintegration of the discharged implant also allows for the injection of additi