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.

1 . A composition containing or comprising, as initially made, a salt formed from a cation derived from a peptide containing at least one basic group and an anion derived from a carboxy-terminated polyester; the composition being in the form of a solution or 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 μm and preferably less than 0.2 μm; or in the form of microparticles or an implant, for injection or sub-dermal implantation.  
     
     
         2 . A composition as claimed in  claim 1  wherein the peptide is pharmacologically active, and is selected from 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, lysozyme chloride, 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, bone morphogenic protein, and synthetic analogues and modifications and pharmacologically-active fragments thereof.  
     
     
         3 . A composition as claimed in  claim 1  wherein the peptide is pharmacologically inactive and is selected from polyarginine, polylysine and poly(arginine-co-lysine), (co-)polymers of neutral amino acids, in D-, L- or DL-form, with arginine and/or 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 1  wherein the polyester is selected from those derived from hydroxy-acids and those derived from the polycondensation of diols and/or polyols with dicarboxylic acids and/or polycarboxylic acids.  
     
     
         5 . A process for the 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.    
     
     
         6 . A 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 μm to 500 μm in diameter, suspended in a pharmaceutically acceptable injection vehicle.  
     
     
         7 . A composition as claimed in  claim 6  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.  
     
     
         8 . A composition as claimed in  claim 1 , comprising a pharmacologically active peptide and a polyester, for extended release of the peptide drug, characterized in that the composition is in the form of a pharmaceutically acceptable solution, comprising: 
 (a) a peptide drug, containing at least one basic amino acid, as hereinbefore defined, having a molecular weight of at least 300 Da, which is in the form of a salt with the polyester, the salt comprising a cation of the basic peptide and an anion of a carboxy-terminated polyester,    (b) a solvent which is a solvent for the free polyester but not a solvent for the free peptide,    (c) an excess of the polyester, and optionally    (d) some of said peptide in solubilised or colloidally dispersed free form.    
     
     
         9 . A composition as claimed in  claim 8  wherein the basic peptide drug is a synthetic analogue of luteinising hormone releasing hormone, selected from buserelin ([D-Ser(Bu t ) 6 , des-Gly-NH 2   10 ]-LHRH(1-9)NHEt), deslorelin ([D-Trp 6 , des-Gly-NH 2   10 ]-LHRH(1-9)NHEt), fertirelin ([des-Gly-NH 2   10 ]-LHRH(1-9)NHEt), goserelin ([D-Ser(Bu t ) 6 , Azgly 10 ]-LHRH), histrelin ([D-His(Bzl) 6 , des-Gly-NH 2   10 ]-LHRH(1-9)NHEt), leuprorelin ([D-Leu 6 , des-Gly-NH 2   10 ]-LHRH(1-9)NHEt), lutrelin ([D-Trp 6 , MeLeu 7 , des-Gly-NH 2   10 ]-LHRH(1-9)NHEt), nafarelin ([D-Nal 6 ]-LHRH), tryptorelin ([D-Trp]-LHRH), and pharmacologically active salts thereof.  
     
     
         10 . A composition as claimed in  claim 8  wherein the solvent is selected from 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.  
     
     
         11 . A composition as claimed in  claim 8  wherein the ratio of basic peptide drug-polyester salt to free polyester is from 1:0 to 0.1:10.  
     
     
         12 . A composition as claimed in  claim 8  wherein the ratio of total solids to solvent is from 2% w/v to 40% w/v.  
     
     
         13 . A process for the manufacture of a pharmaceutical composition as claimed in  claim 8  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.