Claims for Patent: 5,889,110

Summary for Patent: 5,889,110

Title:	Salts of peptides with carboxy-terminated polyesters
Abstract:	This invention relates to novel salts composed of a cation derived from a peptide containing at least one basic group and an anion derived from a carboxy-terminated polyester, processes for the manufacture of such salts, and the use of such salts in the manufacture of extended release pharmaceutical compositions. The salts of the invention possess a variety of properties which are useful in the formulation of extended release pharmaceutical compositions, whether the salts are in pure form or are in admixture with either an excess of the peptide in its free, unbound form or an excess of the free polyester.
Inventor(s):	Hutchinson; Francis Gowland (Lymm, GB2)
Assignee:	Zeneca Limited (London, GB)
Application Number:	08/473,303
Patent Claims:	1. A composition suitable for injection, comprising a salt formed from a cation derived from a peptide containing one or more basic groups and an anion derived from a carboxy-terminated polyester, wherein said salt is dissolved in a pharmaceutically acceptable organic solvent which is a solvent for the free polyester but not a solvent for the free peptide, and wherein the peptide present in said composition is essentially completely in the form of said peptide/polyester salt. 2. A composition as claimed in claim 1 wherein the peptide is pharmacologically active, and is selected from the group consisting of oxytocin, vasopressin, adrenocorticotrophic hormone (ACTH), epidermal growth factor (EGF), prolactin, luteinising hormone, follicle stimulating hormone, luliberin or luteinizing hormone releasing hormone (LHRH), insulin, somatostatin, glucagon, interferon, gastrin, tetragastrin, pentagastrin, urogastrone, secretin, calcitonin, enkephalins, endorphins, kyotorphin, taftsin, thymopoietin, thymosin, thymostimulin, thymic humoral factor, serum thymic factor, tumour necrosis factor, colony stimulating factors, motilin, bombesin, dinorphin, neurotensin, cerulein, bradykinin, urokinase, kallikrein, substance P analogues and antagonists, angiotensin II, nerve growth factor, blood coagulation factor VII and IX, renin, bradykinin, tyrocidin, gramicidines, growth hormones, melanocyte stimulating hormone, thyroid hormone releasing hormone, thyroid stimulating hormone, parathyroid hormone, pancreozymin, cholecystokinin, human placental lactogen, human chorionic gonadotrophin, protein synthesis stimulating peptide, gastric inhibitory peptide, vasoactive intestinal peptide, platelet derived growth factor, growth hormone releasing factor, and bone morphogenic protein, and synthetic analogues and pharmacologically-active fragments thereof. 3. A composition as claimed in claim 1 wherein the peptide is pharmacologically inactive and is selected from the group consisting of polyarginine, polylysine and poly(arginine-co-lysine), (co-)polymers of neutral amino acids, in D-, L- or DL-form, with arginine, lysine or arginine and lysine in D-, L- or racemic form, or peptides or (co-)polypeptides in which the peptide chains are terminated in whole or in part by a basic group at the N-terminus and the backbone is comprised of neutral amino acid residues. 4. A composition as claimed in claim 2 wherein the basic peptide drug is a synthetic analogue of luteinising hormone releasing hormone, selected from the group consisting of buserelin ([D-Ser(Bu.sup.t).sup.6, des-Gly-NH.sub.2.sup.10 ]-LHRH(1-9)NHEt), deslorelin ([D-Trp.sup.6, des-Gly-NH.sub.2.sup.10 ]-LHRH(1-9)NHEt), fertirelin ([des-Gly-NH.sub.2.sup.10 ]-LHRH(1-9)NHEt), goserelin ([D-Ser(Bu.sup.t).sup.6, Azgly.sup.10 ]-LHRH), histrelin ([D-His(Bzl).sup.6, des-Gly-NH.sub.2.sup.10 ]-LHRH(1-9)NHEt), leuprorelin ([D-Leu.sup.6, des-Gly-NH.sub.2.sup.10 ]-LHRH(1-9)NHEt), lutrelin ([D-Trp.sup.6, MeLeu.sup.7, des-Gly-NH.sub.2.sup.10 ]-LHRH(1-9)NHEt), nafarelin ([D-Nal.sup.6 ]-LHRH), and tryptorelin ([D-Trp.sup.6 ]-LHRH), and pharmacologically active salts thereof. 5. A composition as claimed in claim 1 wherein the pharmaceutically acceptable solvent is selected from the group consisting of benzyl benzoate, benzyl alcohol, ethyl lactate, glyceryl triacetate, esters of citric acid, and low molecular weight (<1000) polyethylene glycols, alkoxypolyethylene glycols and polyethylene glycol acetates. 6. The composition as claimed in claim 1 wherein the polyester is selected from the group consisting of polyesters derived from hydroxy-acids, polyesters derived from the polycondensation of diols with dicarboxylic acids, polyesters derived from the polycondensation of polyols with polycarboxylic acids, and polyesters derived from ring opening polycondensation of acid dimers. 7. The composition as claimed in claim 1, wherein the carboxylic acid end groups of said polyester are present in a stoichiometric excess relative to the basic groups of said peptide. 8. Microparticles suitable for injection comprising a composition consisting essentially of a salt formed from a cation derived from a peptide containing one or more basic groups and an anion derived from a carboxy-terminated polyester, wherein the peptide present in said composition is essentially completely in the form of peptide/polyester salt. 9. Microparticles suitable for injection comprising a composition consisting essentially of a salt formed from a cation derived from a peptide containing one or more basic groups and an anion derived from a carboxy-terminated polyester, said composition being characterized by being soluble in a non-solvent for said peptide, as determined by forming a clear solution in dichloromethane. 10. The microparticles as claimed in claim 8 or 9, wherein the carboxylic acid end groups of said polyester are present in a stoichiometric excess relative to the basic groups of said peptide. 11. An injectable composition comprising microparticles as claimed in claim 8 or 9 having a diameter of 0.2 .mu.m to 500 .mu.m suspended in a pharmaceutically acceptable injection vehicle, wherein said microparticles comprise a composition consisting essentially of a salt of a pharmaceutically active peptide with said polyester. 12. The injectable composition of claim 11 wherein said microparticles are suspended in an aqueous injection vehicle. 13. The injectable composition of claim 11 wherein said microparticles are suspended in an organic injection vehicle. 14. The injectable composition of claim 11 wherein the polyester comprises a homo- or co-polymer of lactic acid and glycolic acid. 15. The injectable composition of claim 13 wherein the injection vehicle is selected from the group consisting of ethyl oleate, isopropyl myristate, vegetable oil, fatty glycerides and mixtures thereof. 16. Microparticles comprising a composition consisting essentially of a salt formed from a cation derived from a peptide containing one or more basic groups and an anion derived from a carboxy-terminated polyester, which composition has been prepared from at least an approximately stoichiometric equivalent of said polyester carboxylic acid end groups relative to said basic peptide groups, obtainable by a process comprising i) dissolving the basic peptide and carboxy-terminated polyester in a first solvent in which both the peptide and the polyester are soluble to form a first solution; ii) freezing said first solution at high speed to form a frozen mixture; iii) freeze-drying the frozen mixture to remove said first solvent, forming a freeze-dried product; iv) dispersing the freeze-dried product into a second solvent which is a solvent for the polyester and a non-solvent for the peptide to form a second solution containing said peptide/polyester salt; and v) removing said second solvent from said second solution by a procedure selected from the group consisting of spray-drying, spray-congealing, evaporation and phase separation coacervation to form a solid product which is in the form of microparticles, or from which said microparticles are thereafter formed. 17. Microparticles comprising a composition consisting essentially of a salt formed from a cation derived from a peptide containing one or more basic groups and an anion derived from a carboxy-terminated polyester, which composition has been prepared from at least an approximately stoichiometric equivalent of said polyester carboxylic acid end groups relative to said basic peptide groups, obtainable by a process comprising i) dissolving the basic peptide and carboxy-terminated polyester in a first solvent in which both the peptide and the polyester are soluble to form a first solution; ii) freezing said first solution at high speed to form a frozen mixture; iii) freeze-drying the frozen mixture to remove said first solvent, forming a freeze-dried product; iv) dispersing the freeze-dried product into a second solvent which is a solvent for the polyester and a non-solvent for the peptide to form a second solution containing said peptide/polyester salt; v) dispersing said second solution in an aqueous phase to form an aqueous dispersion; and vi) drying said aqueous dispersion to form a solid product which is in the form of microparticles, or from which said microparticles are thereafter formed. 18. The microparticles according to claim 17 wherein the aqueous dispersion is dried by a method selected from the group consisting of removal of said second solvent in vacuo followed by freeze drying; and removal of said second solvent and water in a single freeze drying step. 19. Microparticles comprising a composition consisting essentially of a salt formed from a cation derived from a peptide containing one or more basic groups and an anion derived from a carboxy-terminated polyester, which composition has been prepared from at least an approximately stoichiometric equivalent of said polyester carboxylic acid end groups relative to said basic peptide groups, obtainable by a process comprising i) dissolving the basic peptide and carboxy-terminated polyester in a first solvent in which both the peptide and the polyester are soluble to form a first solution; ii) freezing the first solution at high speed to form a frozen mixture; iii) freeze-drying the frozen mixture to remove said first solvent, forming a freeze-dried product; iv) dispersing the freeze-dried product into a second solvent which is a solvent for the polyester and a non-solvent for the peptide to form a second solution containing said peptide/polyester salt; v) dispersing the second solution in an aqueous phase to form an aqueous dispersion containing microparticles; vi) separating said microparticles from said aqueous dispersion; and vii) drying said microparticles. 20. The microparticles according to claim 17 or 19, wherein the aqueous phase comprises a viscosity-enhancing polymer. 21. The microparticles according to claim 17 or 19, wherein step v) is carried out in the absence of carbon dioxide in an inert atmosphere. 22. Microparticles comprising a composition consisting essentially of a salt formed from a cation derived from a peptide containing one or more basic groups and an anion derived from a carboxy-terminated polyester, which composition has been prepared from at least an approximately stoichiometric equivalent of said polyester carboxylic acid end groups relative to said basic peptide groups, obtainable by a process comprising i) dissolving the basic peptide and carboxy-terminated polyester in a first solvent in which both the peptide and the polyester are soluble to form a first solution; ii) freezing said first solution at high speed to form a frozen mixture; iii) freeze-drying the frozen mixture to remove said first solvent, forming a freeze-dried product; iv) dispersing the freeze-dried product into a second solvent which is a solvent for the polyester and a non-solvent for the peptide to form a second solution containing said peptide/polyester salt; v) removing said second solvent from the second solution to form a first solid product; vi) subjecting the first solid product to polymer melt processing techniques to form a second solid product; and vii) reducing the size of the second solid product to form said microparticles. 23. The microparticles according to claim 22 wherein step vii) is carried out by a procedure selected from the group consisting of comminution and milling. 24. Microparticles comprising a composition consisting essentially of a salt formed from a cation derived from a peptide containing one or more basic groups and an anion derived from a carboxy-terminated polyester, which composition has been prepared from at least an approximately stoichiometric equivalent of polyester carboxylic acid end groups relative to basic peptide group, obtainable by a process comprising i) dissolving the carboxy-terminated polyester in a first solvent to form a first solution; ii) dissolving the basic peptide in a hydroxylic solvent to form a second solution; iii) adding said second solution to said first solution to form a third solution; and iv) removing the first solvent and hydroxylic solvent from the third solution to form a solid product which is in the form of microparticles, or from which said microparticles are thereafter formed. 25. The microparticles according to claim 24 wherein step iv) is carried out by a procedure selected from the group consisting of spray-drying, evaporation, freeze drying, phase separation coacervation, and spray-congealing. 26. Microparticles comprising a composition consisting essentially of a salt formed from a cation derived from a peptide containing one or more basic groups and an anion derived from a carboxy-terminated polyester, which composition has been prepared from at least an approximately stoichiometric equivalent of polyester carboxylic acid end groups relative to basic peptide groups, obtainable by a process comprising i) dissolving the carboxy-terminated polyester in a first solvent to form a first solution; ii) adding the basic peptide to said first solution to form a mixture; iii) adding a hydroxylic solvent to the mixture to form a suspension; iv) forming the suspension into a clear solution; v) removing the solvent from the clear solution to form a clear viscous liquid; and vi) subjecting said clear viscous liquid to a procedure comprising dissolving said viscous liquid in the first solvent and drying the resultant solution at least once to form a first solid product from which said microparticles are thereafter formed. 27. The microparticles according to claim 26 wherein the solvent is removed in step v) by evaporation. 28. Microparticles comprising a composition consisting essentially of a salt formed from a cation derived from a peptide containing one or more basic groups and an anion derived from a carboxy-terminated polyester, which composition has been prepared from at least an approximately stoichiometric equivalent of said polyester carboxylic acid end groups relative to said basic peptide groups, obtainable by a process comprising i) dissolving the carboxy-terminated polyester in a first solvent to form a first solution; ii) adding the basic peptide to said first solution to form a suspension; iii) adding a hydroxylic solvent to the suspension and forming the suspension into a clear solution; and iv) removing the solvent from the clear solution to form a first solid product which is in the form of microparticles, or from which said microparticles are thereafter formed. 29. The microparticles according to claim 28 wherein the first solid product is subjected to a procedure comprising dissolving said first solid product in the first solvent and drying the resultant solution at least once prior to the formation of said microparticles. 30. The microparticles according to claim 28 wherein in step iv) said first solid product is formed by a procedure selected from the group consisting of spray-drying, evaporation, freeze drying, phase separation coacervation, and spray-congealing. 31. Microparticles comprising a composition consisting essentially of a salt formed from a cation derived from a peptide containing one or more basic groups and an anion derived from a carboxy-terminated polyester, which composition has been prepared from at least an approximately stoichiometric equivalent of polyester carboxylic acid end groups relative to basic peptide groups, obtainable by a process comprising i) dissolving the carboxy-terminated polyester in a first solvent to form a first solution; ii) dissolving the basic peptide in a hydroxylic solvent to form a second solution; iii) adding said second solution to said first solution to form a third solution; iv) removing the hydroxylic solvent and first solvent from said third solution to form a solid product; v) dissolving the solid product in a third solvent which is a solvent for the polyester and a non-solvent for the peptide to form a fourth solution; vi) dispersing said fourth solution in an aqueous phase to form an aqueous dispersion; and vii) drying said aqueous dispersion to form microparticles. 32. The microparticles according to claim 31 wherein the hydroxylic solvent and first solvent is removed in step iv) by evaporation. 33. The microparticles according to any of claims 24, 26, 28 and 31 wherein the first solvent is selected from the group consisting of dichloromethane and acetone. 34. The microparticles according to any one of claims 24, 26, 28 and 31 wherein the hydroxylic solvent is selected from the group consisting of methanol, ethanol and propylene-1,2-diol. 35. The microparticles according to any of claims 16, 17, 19, 22, 24, 26, 28 and 31 which composition has been prepared from a stoichiometric excess of polyester carboxylic acid end groups relative to basic peptide groups. 36. The microparticles according to any one of claims 16, 17, 19 or 22 obtainable by a process in which step ii) is carried out by a process selected from the group consisting of adding the first solution dropwise to liquid nitrogen; and adding the first solution into a mixture of solid carbon dioxide and hexane. 37. The microparticles according to claim 16 wherein the second solution is sterile-filtered prior to the second solvent being removed. 38. The microparticles according to any one of claims 16, 17, 19, or 22, wherein the first solvent is acetic acid. 39. The microparticles according to any one of claims 16, 17, 19, or 22, wherein the first solvent is dimethyl sulfoxide. 40. The microparticles according to any one of claims 16, 17, 19, or 22, wherein the second solvent is selected from dichloromethane and acetone. 41. The microparticles according to any one of claims 16, 17, 19, or 22, wherein the second solvent is selected from the group consisting of benzyl benzoate, benzyl alcohol, ethyl lactate, glyceryl triacetate, esters of citric acid, low molecular weight polyethylene glycols, alkoxypolyethylene glycols and polyethylene glycol acetates. 42. The microparticles according to any one of claims 24, 26, 28 or 31 wherein the first solvent is selected from the group consisting of benzyl benzoate, benzyl alcohol, ethyl lactate, glyceryl triacetate, esters of citric acid, low molecular weight polyethylene glycols, alkoxypolyethylene glycols and polyethylene glycol acetates. 43. The microparticles as claimed in claim 8 or 9 wherein the polyester is selected from the group consisting of polyesters derived from hydroxy-acids, polyesters derived from the polycondensation of diols with dicarboxylic acids, the polyesters derived from the polycondensation of polyols with polycarboxylic acids, and polyesters derived from ring opening polycondensation of acid dimers. 44. A microparticles as claimed in claim 8 or 9 wherein the peptide is pharmacologically active, and is selected from the group consisting of oxytocin, vasopressin, adrenocorticotrophic hormone (ACTH), epidermal growth factor (EGF), prolactin, luteinising hormone, follicle stimulating hormone, luliberin or luteinizing hormone releasing hormone (LHRH), insulin, somatostatin, glucagon, interferon, gastrin, tetragastrin, pentagastrin, urogastrone, secretin, calcitonin, enkephalins, endorphins, kyotorphin, taftsin, thymopoietin, thymosin, thymostimulin, thymic humoral factor, serum thymic factor, tumour necrosis factor, colony stimulating factors, motilin, bombesin, dinorphin, neurotension, cerulein, bradykinin, urokinase, kallikrein, substance P analogues and antagonists, angiotensin II, nerve growth factor, blood coagulation factor VII and IX, renin, bradykinin, tyrocidin, gramicidines, growth hormones, melanocyte stimulating hormone, thyroid hormone releasing hormone, thyroid stimulating hormone, parathyroid hormone, pancreozymin, cholecystokinin, human placental lactogen, human chorionic gonadotrophin, protein synthesis stimulating peptide, gastric inhibitory peptide, vasoactive intestinal peptide, platelet derived growth factor, growth hormone releasing factor, and bone morphogenic protein, and synthetic analogues and modifications and pharmacologically-active fragments thereof. 45. The microparticles as claimed in claim 8 or 9 wherein the basic peptide drug is a synthetic analogue of luteinising hormone releasing hormone, selected from the group consisting of buserelin ([D-Ser(Bu.sup.t).sup.6, des-Gly-NH.sub.2.sup.10 ]-LHRH(1-9)NHEt), deslorelin ([D-Trp.sup.6, des-Gly-NH.sub.2.sup.10 ]-LHRH(1-9)NHEt), fertirelin ([des-Gly-NH.sub.2.sup.10 ]-LHRH(1-9)NHEt), goserelin ([D-Ser(Bu.sup.t).sup.6, Azgly.sup.10 ]-LHRH), histrelin ([D-His(Bzl).sup.6, des-Gly-NH.sub.2.sup.10 ]-LHRH(1-9)NHEt), leuprorelin ([D-Leu.sup.6, des-Gly-NH.sub.2.sup.10 ]-LHRH(1-9)NHEt), lutrelin ([D-Trp.sup.6, MeLeu.sup.7, des-Gly-NH.sub.2.sup.10 ]-LHRH(1-9)NHEt), nafarelin ([D-Nal).sup.6 ]-LHRH, and tryptorelin ([D-Trp.sup.6 ]-LHRH), and pharmacologically active salts thereof. 46. The microparticles according to claim 31, wherein the aqueous phase comprises a viscosity-enhancing polymer. 47. The microparticles according to claim 31, wherein step vi) is carried out in the absence of carbon dioxide in an inert atmosphere.

Details for Patent 5,889,110

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Microbix Biosystems Inc.	KINLYTIC	urokinase	For Injection	021846	01/16/1978		2016-03-30
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2016-03-30