Some aspects of this disclosure relate to a method of treating an opthalmic disease affecting an eye of a patient comprising forming a covalently-crosslinked hydrogel in situ at a peri-ocular, intra-ocular, or intra-vitreal site for controlled release of a therapeutic agent.
대표청구항▼
1. A synthetic, biocompatible polymeric hydrogel for delivering a therapeutic agent to an eye comprising: a first water soluble synthetic precursor covalently crosslinked to form the biocompatible hydrogel, a hydrophobic drug in a particulate form free of encapsulating materials and being in direct
1. A synthetic, biocompatible polymeric hydrogel for delivering a therapeutic agent to an eye comprising: a first water soluble synthetic precursor covalently crosslinked to form the biocompatible hydrogel, a hydrophobic drug in a particulate form free of encapsulating materials and being in direct contact with the hydrogel that is released from the hydrogel during a period of time within a range from two months to two years,wherein, before crosslinking, the first precursor comprises a water-degradable group and the first precursor and any other precursors that contribute to form the hydrogel are free of hydrophobic polymeric blocks,wherein the hydrogel is internally covalently crosslinked and is low-swelling, as measurable by the hydrogel having a weight increasing no more than about 50% upon exposure to a physiological solution for twenty-four hours relative to a weight of the hydrogel at the time of formation, and wherein the hydrogel is water-degradable, as measurable by the hydrogel being dissolvable in vitro in an excess of water by degradation of the water-degradable group. 2. The hydrogel of claim 1 wherein the first precursor comprises poly(ethylene) glycol repeats. 3. The hydrogel of claim 1 wherein the first precursor comprises nucleophilic functional groups before the crosslinking and further comprising a second precursor that comprises electrophilic functional groups before the crosslinking and the nucleophilic functional groups react with the electrophilic functional groups to covalently crosslink the precursors. 4. The hydrogel of claim 1 wherein the drug comprises a small molecule drug. 5. The hydrogel of claim 1 wherein the water-degradable group is an ester. 6. The hydrogel of claim 1 wherein the drug comprises an anti-VEGF drug. 7. The hydrogel of claim 1 wherein the drug is an ophthalmic drug for treating an ophthalmic disease. 8. The hydrogel of claim 7 wherein the ophthalmic drug is chosen from the group consisting of brinzolamide, betaxolol, ciprofloxacin, travoprost, fluorometholone, bimatoprost, prednisolone, cyclosporine, loteprednol, etabonate, pegaptanib, azelastine, latanoprost, and timolol. 9. The hydrogel of claim 7 wherein the drug is for a disease chosen from the group consisting of elevated intraocular pressure, ocular hypertension, and open-angle glaucoma. 10. The hydrogel of claim 7 wherein the drug is for an ophthalmic disease chosen from the group consisting of age-related macular degeneration (AMD), cystoid macular edema (CME), diabetic macular edema (DME), and retinal vein occlusion. 11. The hydrogel of claim 7 wherein the drug comprises an anti-VEGF drug. 12. The hydrogel of claim 11 wherein the first precursor comprises poly(ethylene) glycol repeats. 13. The hydrogel of claim 12 wherein the first precursor comprises nucleophilic functional groups before the crosslinking and the second precursor comprises electrophilic functional groups before the crosslinking and the nucleophilic functional groups react with the electrophilic functional groups to covalently crosslink the precursors. 14. The hydrogel of claim 12 wherein the first precursor comprises electrophilic functional groups before the crosslinking and the second precursor comprises nucleophilic functional groups before the crosslinking, and the nucleophilic functional groups react with the electrophilic functional groups to covalently crosslink the precursors. 15. The hydrogel of claim 1 wherein the first precursor comprises an acrylate-capped polyethylene glycol. 16. The hydrogel of claim 7 wherein the ophthalmic drug is chosen from the group consisting of steroids, NSAIDS, antiangiogenic agents, anti-inflammatories, anti-mitotics, intraocular pressure lowering drugs, and chemotherapeutics. 17. The hydrogel of claim 1 wherein the drug comprises meclofenamate, mefanamic acid, sulindac, diflunisal, piroxicam, etodolac, flurbiprofen, fenoprofen calcium, indomethacin, celecoxib, or nepafenac. 18. A synthetic, biocompatible polymeric device for delivering a drug to an eye, the device consisting essentially of a hydrogel and a drug dispersed in the hydrogel, wherein the hydrogel is formed from one or more water soluble synthetic precursors covalently crosslinked to form the hydrogel, the drug is hydrophobic and in a particulate form free of encapsulating materials and in direct contact with the hydrogel, with the drug being released from the hydrogel during a period of time within a range from two months to two years, wherein the hydrogel is free of hydrophobic polymeric blocks,wherein the hydrogel is internally covalently crosslinked and is low-swelling, as measurable by the hydrogel having a weight increasing no more than about 50% upon exposure to a physiological solution for twenty-four hours relative to a weight of the hydrogel at the time of formation, and wherein the hydrogel is water-degradable, as measurable by the hydrogel being dissolvable in vitro in an excess of water by degradation of the water-degradable group. 19. The hydrogel of claim 18 wherein the first precursor comprises poly(ethylene) glycol repeats. 20. The hydrogel of claim 18 wherein the first precursor comprises nucleophilic functional groups before the crosslinking and further comprising a second precursor that comprises electrophilic functional groups before the crosslinking and the nucleophilic functional groups react with the electrophilic functional groups to covalently crosslink the precursors. 21. The hydrogel of claim 18 wherein the drug comprises a small molecule drug. 22. The hydrogel of claim 18 wherein the water-degradable group is an ester. 23. The hydrogel of claim 18 wherein the drug comprises an anti-VEGF drug. 24. The hydrogel of claim 18 wherein the drug is an ophthalmic drug for treating an ophthalmic disease. 25. The hydrogel of claim 24 wherein the ophthalmic drug is chosen from the group consisting of brinzolamide, betaxolol, ciprofloxacin, travoprost, fluorometholone, bimatoprost, prednisolone, cyclosporine, loteprednol, etabonate, pegaptanib, azelastine, latanoprost, and timolol. 26. The hydrogel of claim 24 wherein the drug is for a disease chosen from the group consisting of elevated intraocular pressure, ocular hypertension, and open-angle glaucoma. 27. The hydrogel of claim 24 wherein the drug is for an ophthalmic disease chosen from the group consisting of age-related macular degeneration (AMD), cystoid macular edema (CME), diabetic macular edema (DME), and retinal vein occlusion. 28. The hydrogel of claim 24 wherein the drug comprises an anti-VEGF drug. 29. The hydrogel of claim 28 wherein the first precursor comprises poly(ethylene) glycol repeats. 30. The hydrogel of claim 29 wherein the first precursor comprises nucleophilic functional groups before the crosslinking and the second precursor comprises electrophilic functional groups before the crosslinking and the nucleophilic functional groups react with the electrophilic functional groups to covalently crosslink the precursors. 31. The hydrogel of claim 29 wherein the first precursor comprises electrophilic functional groups before the crosslinking and the second precursor comprises nucleophilic functional groups before the crosslinking, and the nucleophilic functional groups react with the electrophilic functional groups to covalently crosslink the precursors. 32. The hydrogel of claim 18 wherein the first precursor comprises an acrylate-capped polyethylene glycol. 33. The hydrogel of claim 32 wherein the ophthalmic drug is chosen from the group consisting of steroids, NSAIDS, antiangiogenic agents, anti-inflammatories, anti-mitotics, intraocular pressure lowering drugs, and chemotherapeutics. 34. The hydrogel of claim 32 wherein the drug comprises meclofenamate, mefanamic acid, sulindac, diflunisal, piroxicam, etodolac, flurbiprofen, fenoprofen calcium, indomethacin, celecoxib, or nepafenac.
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