Claims for Patent: 9,132,199

Summary for Patent: 9,132,199

Title:	Reverse thermal gels and uses therefor
Abstract:	Biodegradable triblock copolymer compositions are provided which are useful in tissue engineering and drug delivery. The copolymers are reverse thermal gels in that when heated from a lower temperature to a higher temperature, they gel. These gels are useful in drug delivery when complexed with an active agent. For example the compositions can be used for intraocular injection of active agents, such as anti-angiogenic agents for treatment of a maculopathy or retinitis.
Inventor(s):	Friberg; Thomas R. (Pittsburgh, PA), Park; Daewon (Pittsburgh, PA), Wang; Yadong (Allison Park, PA)
Assignee:	University of Pittsburgh--Of the Commonwealth System of Higher Education (Pittsburgh, PA)
Application Number:	13/581,518
Patent Claims:	1. A reverse thermal gel composition comprising a triblock copolymer, or a pharmaceutically acceptable salt thereof, having the structure B-A-B in which A is one of a polyurethane or poly(ester urethane) group that comprises one or more pendant amine groups, blocked amine groups or active agents and B is a hydrophilic block, wherein the composition is a gel at 35.degree. C.-40.degree. C. and a liquid solution at a lower temperature, and wherein A is a copolymer of a diol and a diisocyanate. 2. The composition of claim 1 in which the diol is an amino-substituted or N-substituted serinol in which the N is substituted with one of a hydrogen, a protective group, or an active agent. 3. The composition of claim 2 in which the N of the N-substituted serinol is --NHR in which R is a protective group. 4. The composition of claim 3 in which R is selected from the group consisting of carbobenzyloxy; p-methoxybenzyl carbonyl; tert-butyloxycarbonyl; 9-fluorenylmethyloxycarbonyl; benzyl; p-methoxybenzyl; 3,4-dimethoxybenzyl; p-methoxyphenyl; tosyl; nosyl (4-nitrobenzenesulfonyl) and 2-nitrobenzenesulfonyl. 5. The composition of claim 3 in which R is tert-butyloxycarbonyl. 6. The composition of claim 1 in which the diol comprises one or more ester groups. 7. The composition of claim 6 in which the diol is a reaction product of a cyclic anhydride and a diol comprising one or more pendant active groups, blocked active groups or active agents. 8. The composition of claim 7 in which the diol is the reaction product of succinic anhydride and the diol is an N-substituted serinol in which the N is substituted with one of a hydrogen, a protective group, or an active agent. 9. The composition of claim 1 in which the diol comprises a pendant amino group or an amine. 10. The composition of claim 1, in which the diisocyanate is hexamethylene diisocyanate (1,6-diisocyanatohexane). 11. The composition of claim 1, comprising a copolymer comprising the structure: ##STR00006## in which R1 is H or a protective group, R2 is isocyanate or --NC(O)-polyethylene glycol (--NC(O)-PEG) and n is greater than 5. 12. The composition of claim 1, comprising a copolymer comprising the structure: ##STR00007## in which R1 is H or a protective group, R3 is PEG and n is greater than 5. 13. The composition of claim 1, comprising a copolymer comprising the structure: ##STR00008## in which R1 is H or a protective group or an active agent, R2 is isocyanate or --NC(O)-PEG and n is greater than 5. 14. The composition of claim 1, comprising a copolymer comprising the structure: ##STR00009## in which R1 is H or a protective group, R3 is PEG and n is greater than 5. 15. The composition of claim 1, the triblock copolymer having an average molecular weight of between about 5,000 and 10,000 Da (Daltons), excluding, when present, the molecular weight of the active agent. 16. The composition of claim 1 in which A is one of a polyurethane or poly(ester urethane) group that comprises one or more pendant charged or active groups. 17. The composition of claim 16 in which the one or more pendant charged or active groups is --NH.sub.2. 18. The composition of claim 17 in which the NH.sub.2 is covalently linked or non-covalently bound to one or more active agents or biologically functional groups. 19. The composition of claim 17 in which the NH.sub.2 is linked to an extracellular matrix (ECM) epitope. 20. The composition of claim 17 in which the NH.sub.2 is linked to a functional entity that aids in evasion of an immune response. 21. The composition of claim 1 in which the active agent is an oligopeptide selected from the group consisting of IKLLI (SEQ ID NO: 1), REDV (SEQ ID NO: 2), LDV, RGDSP (SEQ ID NO: 3), RGDV (SEQ ID NO: 4), LRGDN (SEQ ID NO: 5), RGDT (SEQ ID NO: 6), YIGSR (SEQ ID NO: 7), TTSWSQ (SEQ ID NO: 8), AEIDGIEL (SEQ ID NO: 9), WYRGRL (SEQ ID NO: 10), SIKVAVS (SEQ ID NO: 11), PDSGR (SEQ ID NO: 12), RNIAEIIKDI (SEQ ID NO: 13), DGEA (SEQ ID NO: 14), VTXG (SEQ ID NO: 15), PRRARV (SEQ ID NO: 16), YEKPGSPPREVVPRPRPGV (SEQ ID NO: 17), RPSLAKKQRFRHRNRKGYRSQRGHSRGR (SEQ ID NO: 18), RIQNLLKITNLRIKFVK (SEQ ID NO: 19), RGD, IKVAV (SEQ ID NO: 20) and IKVAVS (SEQ ID NO: 21). 22. The composition of claim 1 further comprising an active agent complexed to the triblock copolymer. 23. The composition of claim 22, in which the active agent is one of bevacizumab, pegaptanib sodium and Ranibizumab. 24. The composition of claim 22 in which the active agent is one or more of an antibiotic, an anti-inflammatory agent, an antiangiogenic agent, a hormone, a cytokine, a chemokine, and a growth factor. 25. The composition of claim 22 in which the active agent is chosen from one or more of: pegaptanib sodium; lucentis; tryptophanyl-tRNA synthetase (TrpRS); AdPEDF; VEGF TRAP-EYE; AG-013958; bevacizumab; JSM6427; TG100801; ATG3; perceiva; E10030; ARC1905; colociximab; endostatin; vatalanib; pazopanib; sirolimus; bevasiranib; AGN211745; nepafenac; ketorolac tromethamine; acetaminophen; bromfenac; ciprofloxacin; norfloxacin; afloxacin; levofloxacin; gentamicin; tobramycin; neomycin; erythromycin; trimethoprim sulphate; polymixin B; ganciclovir and fomivirsen. 26. The composition of claim 1, in which the triblock copolymer is one of: ##STR00010## in which R1 is H and R3 is PEG, complexed with an antiangiogenic agent. 27. The composition of claim 26 in which the antiangiogenic agent is one of bevacizumab and pegaptanib sodium. 28. The composition of claim 1 in which B is selected from the group consisting of PEG; hyaluronan; poly(vinyl alcohol); oligo(vinyl alcohol); a poly(electrolyte); an oligo(electrolyte); and a polycarbohydrate. 29. The composition of claim 1 in which B is a polyethylene glycol. 30. A method of delivering an active agent to a patient, comprising delivering to the patient a reverse thermal gel composition comprising an active agent and a triblock copolymer having the structure B-A-B in which A is one of a polyurethane or poly(ester urethane) group that comprises one or more pendant amine groups, blocked amine groups or active agents and B is a hydrophilic block and the composition is a gel at 37.degree. C. and a liquid at a lower temperature, wherein A is a copolymer of a diol and a diisocyanate. 31. The method of claim 30 in which the active agent is one or more of an antibiotic, an anti-inflammatory agent, an antiangiogenic agent, a hormone, a cytokine, a chemokine and a growth factor. 32. The method of claim 30 in which the active agent is chosen from one or more of: pegaptanib sodium; lucentis; tryptophanyl-tRNA synthetase (TrpRS); AdPEDF; VEGF TRAP-EYE; AG-013958; bevacizumab; JSM6427; TG100801; ATG3; perceiva; E10030; ARC1905; colociximab; endostatin; vatalanib; pazopanib; sirolimus; bevasiranib; AGN211745; nepafenac; ketorolac tromethamine; acetaminophen; bromfenac; ciprofloxacin; norfloxacin; afloxacin; levofloxacin; gentamicin; tobramycin; neomycin; erythromycin; trimethoprim sulphate; polymixin B; ganciclovir and fomivirsen. 33. The method of claim 30, in which the composition is delivered to a patient's eye.

Details for Patent 9,132,199

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	AVASTIN	bevacizumab	Injection	125085	02/26/2004		2030-03-05
Genentech, Inc.	LUCENTIS	ranibizumab	Injection	125156	06/30/2006		2030-03-05
Genentech, Inc.	LUCENTIS	ranibizumab	Injection	125156	08/10/2012		2030-03-05
Genentech, Inc.	LUCENTIS	ranibizumab	Injection	125156	10/13/2016		2030-03-05
Genentech, Inc.	LUCENTIS	ranibizumab	Injection	125156	03/20/2018		2030-03-05