초록

Low viscosity biodegradable polymer solutions of a liquid biodegradable polymer and biocompatible solvent and methods of using the compositions to form a biodegradable liquid polymer implant are provided.

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1. A liquid polymer composition formulated for administering into a body of an animal or human, comprising: (a) a biodegradable liquid polymer comprising a copolymer of lactide and caprolactone with a molar ratio from 75/25 to 25/75 and a molecular weight of 2000 daltons to 20,000 daltons, the molec

1. A liquid polymer composition formulated for administering into a body of an animal or human, comprising: (a) a biodegradable liquid polymer comprising a copolymer of lactide and caprolactone with a molar ratio from 75/25 to 25/75 and a molecular weight of 2000 daltons to 20,000 daltons, the molecular weight as determined by gel permeation chromatography using a multi-angle light-scattering detector (GPC-MALS);(b) a biocompatible organic solvent; and(c) a therapeutically effective amount of a biologically active agent;wherein the composition, when placed in contact with body fluid of an animal or human, remains in a liquid form and does not form a solid in situ after dissipation of the organic solvent from the composition into said body fluid. 2. The composition of claim 1, wherein the solvent comprises a hydrophilic organic solvent having a water solubility greater than 10% by weight of said solvent in water. 3. The composition of claim 1, wherein the solvent comprises a hydrophilic organic solvent selected from the group consisting of N-methyl-2-pyrrolidone, 2-pyrrolidone, N-ethyl-2-pyrrolidone, N-cyclohexyl-2-pyrrolidone, N-hydroxethyl-2-pyrrolidone, dimethyl acetamide, dimethyl formamide, acetic acid, lactic acid, ethanol, propanol, methyl lactate, ethyl lactate, methyl acetate, diethylene glycol monomethyl ether, glycofurol, glycerol formal, isopropylidene glycerol, dimethyl sulfoxide, ε-caprolactone, butyrolactone, propylene glycol, polyethylene glycol, glycerol, 1,3-butyleneglycol, methoxypolyethylene glycol, methoxypropylene glycol, acetone, methyl ethyl ketone, tetrahydrofuran, and combinations thereof. 4. The composition of claim 1, wherein the solvent comprises a hydrophilic organic solvent selected from the group consisting of N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethyl acetamide, dimethyl sulfoxide, ethyl lactate, glycofurol, glycerol formal, isopropylidene glycerol, propylene glycol, polyethylene glycol, methoxypolyethylene glycol, methoxypropylene glycol, and combinations thereof. 5. The composition of claim 1, wherein the solvent comprises a lipophilic organic solvent having a water solubility less than 10% by weight of the solvent in water. 6. The composition of claim 1, wherein the solvent comprises a lipophilic organic solvent selected from the group consisting of ethyl acetate, ethyl butyrate, ethyl oleate, isopropyl palmitate, ethyl palmitate, methyl palmitate, isopropyl myristate, diethyl malonate, diethyl succinate, dimethyl adipate, dimethyl succinate, dibutyl sebacate, triacetin, triethyl citrate, tributyrin, acetyl triethyl citrate, acetyl tributyl citrate, acetyl trihexyl citrate, butyryl trihexyl citrate, tributyl citrate, caprylic/capric triglycerides, caprylic/capric/linoleic triglyceride, caprylic/capric/succinic triglyceride, propylene glycol dicaprylate/caprate, benzyl alcohol, ethyl benzoate, benzyl benzoate, propylene carbonate, dimethyl carbonate, N,N-diethyl-toluamide, N-dodecyl-2-pyrrolidone, N-octyl-2-pyrrolidone, N-methyl-2-caprolactam, N-dodecyl-caprolactam, heptanoic acid, oleic acid, sesame oil, peanut oil, castor oil, and combinations thereof. 7. The composition of claim 1, wherein the solvent comprises a lipophilic organic solvent selected from the group consisting of ethyl acetate, ethyl oleate, isopropyl myristate, triacetin, triethyl citrate, acetyl tributyl citrate, ethyl benzoate, benzyl benzoate, sesame oil, and combinations thereof. 8. The composition of claim 1, wherein the solvent comprises a combination of a hydrophilic solvent and a lipophilic solvent. 9. The composition of claim 1, wherein the biodegradable liquid polymer is pharmaceutically-acceptable. 10. The composition of claim 1, wherein the organic solvent is dissolvable or dispersible in situ in a body fluid of an animal or human. 11. The composition of claim 1, wherein the composition when placed in a body of an animal or human, forms a biodegradable polymeric implant having a liquid consistency. 12. The composition of claim 1, comprising 30-90% by weight liquid polymer and 10-70% by weight organic solvent, the % by weight based on the total weight of the composition. 13. The composition of claim 1, comprising 0.1-30% by weight active agent. 14. The composition of claim 1, wherein the biologically active agent is selected from the group consisting of cisplatin, carboplatin, anastozole, fulvestrant, exemestane, estradiol, testosterone, misoprostol, follicle-stimulating hormone, dustasteride, doxycycline, ciprofloxacin, quinolone, ivermectin, haloperidol, diazepam, risperidone, olanzapine, naltrexone, fentanyl, buprenorphine, butorphanol, loperamide, nafarelin, buserelin, histrelin, deslorelin, leuprolide, goserelin, triptorelin, ganirelix, abarelix, cetrorelix, teverelix, octreotide, lanreotide, human growth hormone, interferon-alpha, interferon-beta, interferon-gamma, interleukin, calcitonin, growth hormone releasing peptides, glucagon-like peptides, granulocyte-colony stimulating factor, nerve growth factor, platelet-derived growth factor, insulin-like growth factor, vascular endothelial growth factor, fibroblast growth factor, bone morphogenic protein, erythropoietin, and salts, complexes and prodrugs. 15. The composition of claim 1, wherein the organic solvent comprises N-methyl-2-pyrrolidone, and the biologically active agent is selected from the group consisting of cisplatin, carboplatin, buprenorphine, doxycycline, haloperidol, and triptorelin pamoate. 16. The composition of claim 1, wherein the organic solvent comprises triacetin, and the biologically active agent comprises triptorelin pamoate. 17. The composition of claim 1, wherein the copolymer of lactide and caprolactone has a molecular weight of 3,000 daltons to 12,000 daltons. 18. The composition of any of claims 1-17, wherein the biodegradable liquid polymer is a liquid at 25° C. up to 37° C. 19. The composition of any of claims 1-18, packaged for use in forming a biodegradable polymeric material or implant within a body of an animal or human. 20. The composition of any of claims 1-18, for use as a biodegradable polymeric implant to deliver the biologically active agent into a body of an animal or human. 21. Use of the composition of any of claims 1-18, in the preparation of a medicament for forming a biodegradable polymeric material or implant within a body of an animal or human to deliver the biologically active agent into the body. 22. A method of forming a biodegradable polymeric implant within a body of an animal or human, comprising: administering into the body an amount of a liquid polymer composition comprising: (a) a pharmaceutically acceptable, biodegradable liquid polymer comprising a copolymer of lactide and caprolactone with a molar ratio from 75/25 to 25/75 and a molecular weight of 2000 daltons to 20,000 daltons, the molecular weight as determined by gel permeation chromatography using a multi-angle light-scattering detector (GPC-MALS);(b) a biocompatible organic solvent that is dissolvable or dispersible in situ in a body fluid of the animal or human; and(c) a therapeutically effective amount of a biologically active agent; andallowing the solvent to dissipate into body fluids within the body to form the biodegradable polymeric material having a liquid consistency which does not form into a solid in situ;wherein the polymeric material releases the biologically active agent as the polymeric material biodegrades within the body. 23. The method of claim 22, wherein the liquid polymer composition is administered through a syringe or needle of 18-26 gauge. 24. The method of claim 22, wherein the liquid polymer composition is administered into a body tissue within the body of the animal or human to form a liquid implant. 25. The method of claim 22, wherein the implant is in the form of a film. 26. The method of claim 22, wherein the implant is in the form of a plug situated within the body tissue. 27. The method of claim 22, wherein the liquid polymer composition is administered onto a device selected from the group consisting of a catheter, a mesh, a screw, a plate, a tack, a pin, a staple, and a sponge, and the method further comprises placing the device with the composition thereon into the body of the animal or human. 28. The method of any of claims 22-27, further comprising, prior to administering the liquid polymer composition into the body of the animal or human, dissolving the biodegradable liquid polymer in the organic solvent, and adding an effective amount of the biologically active agent to the composition. 29. A kit comprising the composition of claim 1; and directions for preparation and/or administration of the liquid polymer composition to form the polymeric implant. 30. A method of forming a biodegradable polymeric implant within a body of an animal or human, comprising: administering into the body the liquid polymer composition of claim 1; andallowing the solvent to dissipate into body fluids to form the biodegradable polymeric implant having a liquid consistency which does not form into a solid in situ, wherein the biologically active agent is released from the polymeric implant into the body over an extended time period as the polymeric implant biodegrades.