Claims for Patent: 9,155,722

Summary for Patent: 9,155,722

Title:	Reconstitutable reverse thermal gelling polymers
Abstract:	Biodegradable and bioabsorbable block copolymers, which can be in the form of solid powder or powder wax compositions that can be easily reconstituted into an aqueous polymer solution and exhibit reverse thermal gellation properties upon exposure to elevated temperatures, are provided. Methods of making using these copolymers are also provided.
Inventor(s):	Fowers; Kirk D. (Centerville, UT), Rathi; Ramesh C. (Cottonwood Heights, UT), Piao; Ai-Zhi (Salt Lake City, UT)
Assignee:	PROTHERICS SALT LAKE CITY, INC. (Salt Lake City, UT)
Application Number:	12/886,387
Patent Claims:	1. An AB-, ABA-, or BAB-block copolymer composition, said block copolymer comprising: at least a first AB, ABA, or BAB block copolymer component comprising a first hydrophobic A-block and a first hydrophilic B-block, wherein the first hydrophobic A-block is a biodegradable polyester comprising about 60% to 95% caprolactone by mole percent and at least one second polyester-forming monomer, and the first hydrophilic B-block has a first average molecular weight and comprises polyethylene glycol; at least a second AB, ABA, or BAB block copolymer component comprising a second hydrophobic A-block and a second hydrophilic B-block, wherein the second hydrophobic A-block comprises biodegradable polyester, and the second hydrophilic B-block has a second average molecular weight and comprises polyethylene glycol, wherein the second average molecular weight is different from the first average molecular weight; wherein the block copolymer composition has a total weight average molecular weight from 1500 to 10,000 Daltons, a total A-block content of the composition from about 60 to 85% by weight, and a total B-block content of the composition from about 15% to 40% by weight, wherein the total weight average molecular weight of the B-block in the composition is from 300 to 2000 Daltons, wherein the block copolymer composition is a powder or wax at room temperature, is capable of exhibiting reverse thermal gellation when formed as an aqueous polymer solution, and is capable of being converted into an aqueous polymer solution in less than thirty minutes by agitating without the use of additives or heat exceeding 60.degree. C. 2. An aqueous polymer composition suitable for parenteral administration comprising the block copolymer composition of claim 1. 3. The block copolymer composition of claim 1, wherein the total A-block content of the composition ranges from 65 to 80% by weight and the total B-block content of the composition ranges from 20 to 35% by weight. 4. The block copolymer composition of claim 1, wherein the total A-block content of the composition ranges from 67 to 75% by weight and the total B-block content of the composition ranges from 25 to 33% by weight. 5. The block copolymer composition of claim 1, wherein the second polyester monomer comprises residues of at least one of D,L-lactide, D-lactide, L-lactide, D,L-lactic acid, D-lactic acid, L-lactic acid, glycolide, glycolic acid, .epsilon.-hydroxy hexonoic acid, .gamma.-butyrolactone, .gamma.-hydroxy butyric acid, .delta.-valerolactone, .delta.-hydroxy valeric acid, hydrooxybutyric acids, malic acid, or copolymers thereof. 6. The block copolymer composition of claim 1, wherein the second polyester monomer comprises residues from at least one of D,L-lactide, D-lactide, L-lactide, D,L-lactic acid, D-lactic acid, L-lactic acid, glycolide, glycolic acid, .epsilon.-hydroxy hexonoic acid, or copolymers thereof. 7. The block copolymer composition of claim 1, wherein the second polyester monomer comprises residues from lactide or glycolide or copolymers thereof. 8. The block copolymer composition of claim 1, wherein the biodegradable polyester of the first A-block comprises about 85% caprolactone ki mole percent. 9. The block copolymer composition of claim 1, wherein the biodegradable polyester of the first A-block comprises about 90% caprolactone by mole percent. 10. The block copolymer composition of claim 1, wherein the biodegradable polyester of the first A-block comprises about 90 to 95% caprolactone by mole percent. 11. The block copolymer composition of claim 1, wherein the total weight average molecular weight of the B-block in the composition is from 1000 to 1600 Daltons. 12. The block copolymer composition of claim 1, wherein the total average molecular weight of the B-block in the composition is from 1200 to 1500 Daltons. 13. The block copolymer composition of claim 1, wherein the total weight average molecular weight of the B-block in the composition is from 1200 to 1500 Daltons, and the biodegradable polyester of the first A-block comprises about 90 to 95% caprolactone by mole percent and 5% glycolide. 14. The block copolymer composition of claim 1, wherein the block copolymer composition is capable of exhibiting less than 10% swelling after 5 days of aqueous exposure. 15. The block copolymer composition of claim 1, wherein the block copolymer composition is capable of exhibiting less than 5% swelling after 30 days of aqueous exposure. 16. The block copolymer composition of claim 1, wherein the block copolymer composition is capable of forming said aqueous polymer solution in less than 30 minutes without exposure to additional agents or temperatures exceeding 60.degree. C. 17. The block copolymer composition of claim 1, wherein the solid powder block copolymer composition is capable of forming said aqueous polymer solution in less than 30 minutes without exposure to additional agents or temperatures exceeding 60.degree. C., is capable of exhibiting less than 5% swelling after 30 days of aqueous exposure, and is capable of releasing between about 10 to 15% of paclitaxel in five days and 15% to 20% of paclitaxel in 20 days. 18. The block copolymer composition of claim 1, further comprising a drug. 19. The block copolymer composition of claim 18, wherein said drug is a polypeptide or protein, nucleic acid or gene, hormone, anti-cancer or anti-cell proliferation agent. 20. The block copolymer composition of claim 19, wherein said polypeptide or protein is oxytocin, vasopressin, adrenocorticotropic hormone, epidermal growth factor, platelet-derived growth factor (PDGF), prolactin, luliberin, luteinizing hormone releasing hormone (LHRH), LHRH agonists, LHRH antagonists, growth hormone (human, porcine, bovine, etc.), growth hormone releasing factor, insulin, erythropoietin, somatostatin, glucagon, interleukin-2 (IL-2), interferon-.alpha., .beta., or .gamma., gastrin, tetragastrin, pentagastrin, urogastrone, secretin, calcitonin, enkephalins, endorphins, angiotensins, thyrotropin releasing hormone (TRH), tumor necrosis factor (TNF), nerve growth factor (NGF), granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), macrophage-colony stimulating factor (M-CSF), heparinase, bone morphogenic protein (BMP), hANP, glucagon-like peptide (GLP-1), interleukin-11 (IL-11), renin, bradykinin, bacitracins, polymyxins, colistins, tyrocidine, gramicidins, cyclosporins and synthetic analogues, modifications and pharmacologically active fragments thereof. 21. The block copolymer composition of claim 19, wherein said polypeptide or protein is an enzyme, cytokine, antibody or vaccine. 22. The block copolymer composition of claim 19, wherein said polypeptide or protein is erythropoietin, luteinizing hormone releasing hormone (LHRH), LHRH agonists, LHRH antagonists, growth hormones, tumor necrosis factor (TNF), nerve growth factor (NGF), granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), macrophage-colony stimulating factor (M-CSF), glucagon-like peptide (GLP-1), interleukin-11 (IL-11), cyclosporins and synthetic analogues, modifications or pharmacologically active fragments thereof. 23. The block copolymer composition of claim 18, wherein said drug is paclitaxel. 24. The block copolymer composition of claim 18, wherein said drug is an anti-cancer agent. 25. The block copolymer composition of claim 18, wherein said drug is an anti-cancer agent comprising actinomycin D, anastrozole, azacitidine, bevacizumab, bicalutamide, bleomycin, BCNU, bortezomib, camptothecin, capecitabine, carboplatin, cetuximab, daunorubicin, dasatinib, docetaxel, doxorubicin, liposomal, epirubicin, erlotinib, exemestane, gefitinib, gemcitabine, goserelin, imatinib, STI-571, irinotecan, lapatinib, letrozole, leuprolide, methotrexate, mitomycin, oxaliplatin, paclitaxel, pemetrexed, rituximab, sorafenib, sunitinib, tamoxifen, taxotere, tegafur-uracil, temozolomide, trastuzumab, triptorelin, vinorelbine, porcabazine, dacarbazine, altretamine, displatin, mercaptopurine, thioguanine, fludarabine phosphate, cladribine, pentostatin, fluorouracil, cytarabine, azacitidine, vinblastine, vincristine, etoposide, teniposide, topotecan, dactinomycin, idarubincin, plicamycin, flutamide, leuprolide, gasoerelin, aminoglutethimide, amsacrine, hydroxyurea, asparaginase, mitoxantrone, mitotane, retinoic acid derivative, amifostine, carmustine, lomustine, semustine, anti-VEGF and synthetic analogues, modifications or pharmaceutically equivalents thereof. 26. The block copolymer composition of claim 18, wherein said drug is an anti-cancer agent comprising mitomycin, bleomycin, BCNU, carboplatin, doxorubicin, daunorubicin, methotrexate, paclitaxel, taxotere, actinomycin D, camptothecin, and synthetic analogues, modifications or pharmaceutically equivalents thereof. 27. The block copolymer composition of claim 18, wherein the drug content of said composition is between about 0.01 and 20% by weight. 28. The block copolymer composition of claim 27, wherein the block copolymer composition is capable of forming said aqueous polymer solution in less than 30 minutes without exposure to additional agents or temperatures exceeding 60.degree. C., is capable of exhibiting less than 5% swelling after 30 days of aqueous exposure, and is capable of releasing between about 10 to 15% of a drug comprising paclitaxel in five days and 15% to 20% of the drug in 20 days. 29. The block copolymer composition of claim 1, wherein the first AB, ABA, or BAB block copolymer is an ABA-block copolymer, said ABA-block copolymer comprising: (a) about 60 to 85% by weight of a biodegradable, hydrophobic A-block comprising a biodegradable polyester, wherein said A-block includes about 85% to 95% caprolactone by mole percent and at least one second polyester-forming monomer; and (b) about 15 to 40% by weight of a biodegradable, hydrophilic B-block comprising a polyethylene glycol, wherein the molecular weight of the B-block is between 1000 and 1450 Daltons; wherein the block copolymer composition is a powder or wax at room temperature, is capable of exhibiting reverse thermal gellation when formed as an aqueous polymer solution, and is capable of being converted into an aqueous polymer solution in less than thirty minutes by agitating without the use of additives or heat exceeding 60.degree. C. 30. The block copolymer composition of claim 29, wherein the total weight average molecular weight of the block copolymer in the composition is from 4000 to 8000 Daltons. 31. The block copolymer composition of claim 29, wherein the total weight average molecular weight of the block copolymer in the composition is from 5500 to 7500 Daltons. 32. The block copolymer composition of claim 29, wherein the total A-block content of the composition ranges from 65 to 80% by weight and the total B-block content of the composition ranges from 20 to 35% by weight. 33. The block copolymer composition of claim 29, wherein the total A-block content of the composition ranges from 67 to 75% by weight and the total B-block content of the composition ranges from 25 to 33% by weight. 34. The block copolymer composition of claim 29, wherein the block copolymer composition is capable of forming said aqueous polymer solution in less than 30 minutes without exposure to additional agents or temperatures exceeding 60.degree. C., is capable of exhibiting less than 5% swelling after 30 days of aqueous exposure, and is capable of releasing between about 10 to 15% of paclitaxel in five days and 15% to 20% of paclitaxel in 20 days. 35. The block copolymer composition of claim 1, wherein the first AB, ABA, or BAB block copolymer is an AB-block copolymer, said AB-block copolymer comprising: (a) about 60 to 85% by weight of a biodegradable, hydrophobic A-block comprising a biodegradable polyester, wherein said A-block includes about 85% to 95% caprolactone by mole percent and at least one second polyester-forming monomer; and (b) about 15 to 40% by weight of a biodegradable, hydrophilic B-block comprising a polyethylene glycol, wherein the molecular weight of the B-block is between 300 and 1450 Daltons; wherein the block copolymer composition is a powder or wax at room temperature, is capable of exhibiting reverse thermal gellation when formed as an aqueous polymer solution, and is capable of being converted into an aqueous polymer solution in less than thirty minutes by agitating without the use of additives or heat exceeding 60.degree. C. 36. The block copolymer composition of claim 35, wherein the total weight average molecular weight of block copolymer in the composition is from 1500 to 4500 Daltons. 37. The block copolymer composition of claim 35, wherein the total weight average molecular weight of block copolymer in the composition from 2000 to 4000 Daltons. 38. The block copolymer composition of claim 1, wherein the first AB, ABA, or BAB block copolymer is a BAB-block copolymer, said BAB-block copolymer comprising: (a) about 60 to 85% by weight of a biodegradable, hydrophobic A-block comprising a biodegradable polyester, wherein said A-block includes about 85% to 95% caprolactone by mole percent and at least one second polyester-forming monomer; and (b) about 15 to 40% by weight of a biodegradable, hydrophilic B-block comprising a polyethylene glycol, wherein the molecular weight of the B-block is between 300 and 2000 Daltons; wherein the block copolymer composition is a powder or wax at room temperature, is capable of exhibiting reverse thermal gellation when formed as an aqueous polymer solution, and is capable of being converted into an aqueous polymer solution in less than thirty minutes by agitating without the use of additives or heat exceeding 60.degree. C. 39. The block copolymer composition of claim 38, wherein the total A-block content of the composition ranges from 65 to 80% by weight and the total B-block content of the composition ranges from 20 to 35% by weight. 40. The block copolymer composition of claim 38, wherein the total A-block content of the composition ranges from 67 to 75% by weight and the total B-block content of the composition ranges from 25 to 33% by weight. 41. A method for the administration of at least one drug to a warm blooded animal in a controlled release form which comprises: (1) providing the AB-, ABA-, or BAB-block copolymer composition of claim 1; (2) forming an aqueous solution of said powder or wax composition by combining the copolymer composition with water without exposing to heat exceeding 60.degree. C.; and (3) administering said copolymer composition to said warm blooded animal. 42. The aqueous polymer composition of claim 2, wherein said aqueous polymer composition comprises about 3-50% by weight of said block copolymer. 43. The aqueous polymer composition of claim 42, wherein said aqueous polymer composition comprises about 10-30% by weight of said block copolymer. 44. The aqueous polymer composition of claim 43, wherein said aqueous polymer composition comprises about 23% by weight of said block copolymer.

Details for Patent 9,155,722

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2029-09-18
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2029-09-18
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2029-09-18
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2029-09-18
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2029-09-18
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	02/12/2004		2029-09-18
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	03/28/2007		2029-09-18