Claims for Patent: 6,034,175

Summary for Patent: 6,034,175

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, GB)
Assignee:	Zeneca Limited (London, GB)
Application Number:	09/235,270
Patent Claims:	1. A composition containing, as initially made, 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 in a form suitable for injection or sub-dermal implantation selected from the group consisting of: a solution of the salt in a solvent which is a solvent for the free polyester but not a solvent for the free peptide; a dispersion of the salt in a solvent which is a solvent for the free polyester but not a solvent for the free peptide, the particle size of the salt in said dispersion being less than 5 .mu.m; microparticles; and an implant for injection or sub-dermal implantation. 2. The composition of claim 1 wherein the particle size of the salt of said dispersion is less than 0.2 .mu.m. 3. The 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, 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. 4. The 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. 5. The composition as claimed in claim 1 wherein the polyester is selected from the group consisting of polyester 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. 6. A process for th manufacture of a solution or dispersion of a salt as claimed in claim 1, which comprises (a) dissolving the peptide containing at least one basic amino acid, in free base form or in the form of a salt with a weak acid and the carboxy-terminated polyester in a neutral, polar solvent in which both are soluble, removing the solvent or most of the solvent, and adding the remaining concentrated solution to an excess of a non-solvent for the peptide-polyester salt, or (b) dissolving the peptide containing at least one basic amino acid, in free base form or in the form of a salt with a weak acid, and the carboxy-terminated polyester, in a solvent in which both are soluble, and which is capable of being removed by freeze-drying, freezing the resulting solution at high speed, freeze-drying the resulting frozen mixture, dispersing the resulting mixture in a solvent for the polyester component, and allowing the mixture to dissolve as the peptide-polyester salt is formed, or (c) reacting the peptide, containing at least one basic amino acid, in the form of a salt with a strong acid, with a polyester wherein some or all of the polyester is in the form of a carboxylic acid salt with a suitable alkali metal or alkaline earth metal. 7. The composition as claimed in claim 1, comprising a pharmacologically active peptide and a polyester, for extended release of the peptide drug, characterised in that the composition is in the form of microparticles from 0.2 .mu.m to 500 .mu.m in diameter, suspended in a pharmaceutically acceptable injection vehicle. 8. The composition as claimed in claim 7 wherein the injection vehicle is aqueous or is an organic vehicle which is a non-solvent for the materials used, or, for highly lipophilic polyesters, is a hydrophilic organic injection vehicle. 9. An extended release pharmaceutical composition containing, as initially made, a salt formed from a cation derived from a basic peptide drug containing one or more basic groups and having a molecular weight of 300 Da or more, and an anion derived from a carboxy-terminated polyester, said composition being in a form of a pharmaceutically acceptable solution comprising (a) said salt; (b) a solvent which is a solvent for the free polyester but not a solvent for the free peptide, and (c) an excess of polyester such that the polyester carboxy end groups are present in a stoichiometric excess relative to the basic groups of said peptide. 10. The composition as claimed in claim 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. 11. The composition as claimed in claim 9 wherein the 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. 12. The composition as claimed in claim 9 wherein the ratio of basic peptide drug-polyester salt to free polyester is from 1:0 to 0.1:10. 13. The composition as claimed in claim 9 wherein the ratio of total peptide drug/polyester salt and polyester to solvent is from 2% w/v to 40% w/v. 14. A process for the manufacture of a pharmaceutical composition as claimed in claim 9 which comprises (a) dissolving an intimate mixture of the peptide drug and the polyester in the pharmaceutically acceptable solvent; or (b) slowly adding a solution of the peptide drug in a 1-6C alkanol to a solution of the polyester in a solvent suitable for injection, whereafter, if the solvent in the starting peptide solution is not pharmaceutically acceptable for injection, it is removed.

Details for Patent 6,034,175

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Microbix Biosystems Inc.	KINLYTIC	urokinase	For Injection	021846	01/16/1978		2013-05-24
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2013-05-24