Low viscosity liquid polymeric delivery system

Abstract

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.

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 selected from the group consisting of:   (i) a copolymer of caprolactone and 1,4-dioxanone with a molar ratio from 70/30 to 40/60 and an inherent viscosity of 0.08 to 0.24 dl/g;   (ii) a copolymer of caprolactone and trimethylene carbonate with a molar ratio from 90/10 to 50/50 and an inherent viscosity of 0.09 to 0.24 dl/g,   the inherent viscosity as determined in a 0.10 g/dL solution of hexafluoroisopropanol (HFIP) at 25° C.   (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 , comprising 30-90% by weight liquid polymer, 10-70% by weight organic solvent, the % by weight based on the total weight of the composition. 
     
     
         10 . The composition of  claim 1 , comprising 0.1-30% by weight active agent, the % by weight based on the total weight of the composition. 
     
     
         11 . 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. 
     
     
         12 . The composition of  claim 1 , wherein the biodegradable liquid polymer is a liquid at about 25° C. up to about 37° C. 
     
     
         13 . The composition of  claim 1 , packaged for use in forming a biodegradable polymeric material or implant within a body of an animal or human. 
     
     
         14 . The composition of  claim 1  as an implant within a body of an animal or human. 
     
     
         15 . The composition of  claim 1  applied 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. 
     
     
         16 . 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. 
     
     
         17 . A method of forming a biodegradable polymeric implant within a body of an animal or human, comprising:
 administering the composition of  claim 1  into the body; and   allowing the solvent to dissipate into body fluids within the body 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 as the implant biodegrades.