Pharmaceutical compositions with enhanced stability

Abstract

The present invention provides for a stabilized biodegradable polymeric composition useful as a controlled release delivery system for peptide agents. The compositions of the present invention comprise a) a beneficial salt of a peptide agent formed with a strong acid that minimizes or prevents the interaction/reaction between the peptide agent and the polymer in an organic solution; b) a biodegradable polymer; c) a pharmaceutically acceptable organic solvent; and d) optionally one or more excipients. The present invention also relates to a method of manufacturing and a method of use thereof.

1 . An injectable polymeric composition comprising: 
 a) a salt of a peptide agent formed with a strong acid selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, chromic acid, methanesulfonic acid, trifluromethane sulfonic acid, trichloroacetic acid, dichloroacetic acid, bromoacetic acid, chloroacetic acid, cyanoacetic acid, 2-chloropropanoic acid, 2-oxobutanoic acid, 2-chlorobutanoic acid, 4-cyanobutanoic acid, perchloric acid, and phosphoric acid;    b) a biodegradable polymer;    c) a pharmaceutically acceptable organic solvent, which dissolves biodegradable polymer and is miscible or dispersible in aqueous or biological fluid; and    d) optionally one or more pharmaceutically acceptable excipients.    
     
     
         2 . The injectable polymeric composition of  claim 1  in the form of a solution, a suspension, a gel or a semi-solid.  
     
     
         3 . The injectable polymeric composition of  claim 1  wherein the peptide agent contains at least one basic amine group.  
     
     
         4 . The injectable polymeric composition of  claim 1  wherein the peptide agent is selected from the group consisting of oxytocin, vasopressin, adrenocorticotropic hormone (ACTH), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), prolactin, luteinising hormone, luteinizing hormone releasing hormone (LHRH), LHRH agonists, LHRH antagonists, growth hormones, growth hormone releasing factor, insulin, erythropoietin, somatostatin, glucagon, interleukin, interferon-alpha, interferon-beta, interferon-gamma, gastrin, tetragastrin, pentagastrin, urogastrone, secretin, calcitonin, enkephalins, endorphins, angiotensins, thyrotropin releasing hormone (TRH), tumor necrosis factor (TNF), parathyroid hormone (PTH), nerve growth factor (NGF), granulocyte-colony stimulating factor (G-C SF), granulocyte macrophage-colony stimulating factor (GM-CSF), macrophage-colony stimulating factor (M-CSF), heparinase, vascular endothelial growth factor (VEG-F), bone morphogenic protein (BMP), hANP, glucagon-like peptide (GLP-1), exenatide, peptide YY (PYY), renin, bradykinin, bacitracins, polymyxins, colistins, tyrocidine, gramicidins, cyclosporins enzymes, cytokines, antibodies, vaccines, antibiotics, antibodies, glycoproteins, follicle stimulating hormone, kyotorphin, taftsin, thymopoietin, thymosin, thymostimulin, thymic humoral factor, serum thymic factor, colony stimulating factors, motilin, bombesin, dinorphin, neurotensin, cerulein, urokinase, kallikrein, substance P analogues and antagonists, angiotensin II, blood coagulation factor VII and IX, gramicidines, melanocyte stimulating hormone, thyroid hormone releasing hormone, thyroid stimulating hormone, pancreozymin, cholecystokinin, human placental lactogen, human chorionic gonadotrophin, protein synthesis stimulating peptide, gastric inhibitory peptide, vasoactive intestinal peptide, platelet derived growth factor, and synthetic analogues and modifications and pharmacologically-active fragments thereof.  
     
     
         5 . The injectable polymeric composition of  claim 1  wherein the peptide agent has an N-terminus that is not a primary amine.  
     
     
         6 . The injectable polymeric composition of  claim 5  wherein the peptide agent is selected from the group consisting of luteinizing hormone releasing hormone (LHRH), LHRH analogs, agonists and antagonists.  
     
     
         7 . The injectable polymeric composition of  claim 5  wherein the peptide agent is selected from the group consisting of leuprorelin, buserelin, gonadorelin, deslorelin, fertirelin, histrelin, lutrelin, goserelin, nafarelin, triptorelin, cetrorelix, enfuvirtide, thymosin α1, and abarelix.  
     
     
         8 . The injectable polymeric composition of  claim 1  wherein the peptide agent has an N-terminal primary amine and/or side chain primary amine(s) that are covalently modified with hydrophilic moieties.  
     
     
         9 . The injectable polymeric composition of  claim 8  wherein the hydrophilic moieties include any water-soluble linear or branched oligomers or polymers of a weight average molecular weight ranging from about 500 daltons to about 50,000 daltons.  
     
     
         10 . The injectable polymeric composition of  claim 8  wherein the hydrophilic moieties are polyethylene glycol and/or its derivatives.  
     
     
         11 . The injectable polymeric composition of  claim 1  wherein peptide agent has an N-terminal primary amine and/or side chain primary amine(s) that are covalently modified with lipophilic moieties.  
     
     
         12 . The injectable polymeric composition of  claim 11  wherein the lipophilic moieties are selected from the group consisting of C 2-39 -alkyl, C 2-39 -alkenyl, C 2-39 -alkadienyl and steroidal residues.  
     
     
         13 . The injectable polymeric composition of  claim 1  wherein the peptide agent is present at about 0.01% to about 40% of the composition by weight.  
     
     
         14 . The injectable polymeric composition of  claim 1  wherein the biodegradable polymer is selected from the group consisting of polylactides, polyglycolides, poly(lactide-co-glycolide)s, polycaprolactones, polydioxanones, polycarbonates, polyhydroxybutyrates, polyalkylene oxalates, polyanhydrides, polyesteramides, polyurethanes, polyacetals, polyorthocarbonates, polyphosphazenes, polyhydroxyvalerates, polyalkylene succinates, polyorthoesters, and copolymers, block copolymers, branched copolymers, terpolymers and combinations and mixtures thereof.  
     
     
         15 . The injectable polymeric composition of  claim 1  wherein the biodegradable polymer is poly(lactide-co-glycolide) copolymers having a lactic acid to glycolic acid ratio between about 50:50 to about 100:0, and a weight average molecular weight of between about 2,000 to about 100,000.  
     
     
         16 . The injectable polymeric composition of  claim 15  wherein the poly(lactide-co-glycolide) copolymers contain a hydroxyl, carboxylic, or ester terminal group.  
     
     
         17 . The injectable polymeric composition of  claim 15  wherein the poly(lactide-co-glycolide) copolymers contain a monofunctional alcohol or a polyol residue and does not have a carboxylic acid terminus.  
     
     
         18 . The injectable polymeric composition of  claim 1  wherein the biodegradable polymer is present at about 30% to 70% of the composition by weight.  
     
     
         19 . The injectable polymeric composition of  claim 1  wherein the pharmaceutically acceptable organic solvent is selected from a group of N-methyl-2-pyrrolidone, dimethylsulfoxide, glycerol formal, glycofurol, methoxypolyethylene glycol 350, alkoxypolyethylene glycol, polyethylene glycol esters, benzyl benzoate, ethyl benzoate, esters of citric acid, triacetin, diacetin, triethyl citrate, acetyl triethyl citrate, and mixtures thereof.  
     
     
         20 . The injectable polymeric composition of  claim 1  wherein the pharmaceutically acceptable organic solvent is present at about 30% to about 80% of the composition by weight.  
     
     
         21 . The injectable polymeric composition of  claim 1  further comprising one or more release rate modifying agent.  
     
     
         22 . The injectable polymeric composition of  claim 21  wherein the release rate modifying agents is selected from the group consisting of alkanecarboxylic acid, oleic acid, alkyl alcohol, polar lipids, surfactants, copolymers of polyethyleneglycol and polylactide or poly(lactide-co-glycolide) poloxamers, polyvinyl pyrrolidone, polysorbates, 2-ethoxyethyl acetate, triacetin, triethyl citrate, acetyl tributyl citrate, acetyl triethyl citrate, glycerol triacetate, di(n-butyl)sebecate, polyethylene glycol, sorbitol, triglycerides, medium-chain triglycerides and mixtures thereof.  
     
     
         23 . The injectable polymeric composition of  claim 1  further comprising one or more buffering agents.  
     
     
         24 . The injectable polymeric composition of  claim 23  wherein the buffering agents is selected from the group consisting of calcium carbonate, calcium hydroxide, calcium myristate; calcium oleate, calcium palmitate, calcium stearate, calcium phosphate, magnesium carbonate, magnesium hydroxide, magnesium phosphate, magnesium myristate, magnesium oleate, magnesium palmitate, magnesium stearate, zinc carbonate, zinc hydroxide, zinc myristate, zinc oleate, zinc palmitate, zinc stearate, zinc phosphate, and combinations thereof.  
     
     
         25 . The injectable polymeric composition of  claim 1  further comprising one or more antioxidants.  
     
     
         26 . The injectable polymeric composition of  claim 25  wherein the antioxidants is selected from the group consisting of d-alpha tocopherol acetate, ascorbyl palmitate, butylated hydroxyanidole, butylated hydroxyanisole, butylatedhydroxyquinone, hydroxycomarin, butylated hydroxytoluene, ethyl gallate, propyl gallate, octyl gallate, lauryl gallate, propylhydroxybenzoate, trihydroxybutylrophenone, vitamin E, pegylated vitamin E and vitamin E-TPGS.  
     
     
         27 . An injectable polymeric composition comprising: 
 a) a hydrochloride or mesylate salt of a LHRH agonist or antagonist;    b) a poly(lactide-co-glycolide) copolymer, wherein the ratio of lactide:glycolide of the copolymer is from 50:50 to about 100:0;    c) N-methyl-2-pyrrolidone (NMP); and    d) A triglyceride and/or vitamin E or its derivatives.    
     
     
         28 . The injectable polymeric composition of  claim 27  wherein the LHRH agonist or antagonist is selected from the group consisting of leuprorelin, buserelin, gonadorelin, deslorelin, fertirelin, histrelin, lutrelin, goserelin, nafarelin, triptorelin, cetrorelix, enfuvirtide, thymosin α1, or abarelix.  
     
     
         29 . A method for preparing a salt of a peptide agent comprising the steps of dissolving a free base of a peptide agent in a liquid medium to form a solution, and mixing the solution with an aqueous solution of a strong acid to form the salt of the peptide agent.  
     
     
         30 . A method for preparing a salt of a peptide agent comprising: a) dissolving a first salt of peptide agent formed with a volatile weak acid in a suitable liquid medium to form a solution; b) mixing the solution with an aqueous solution of a strong acid to form a mixture; c) removing the solvent from the mixture and d) removing the weak acid to form a second salt of the peptide agent.  
     
     
         31 . A method for preparing an injectable polymeric composition for forming a sustained controlled release system to deliver a therapeutic amount of peptide agent to a subject comprising the steps of: 
 a. dissolving a biodegradable polymer in a pharmaceutically acceptable organic solvent;    b. combining a salt of a peptide agent formed with a strong acid with the polymer solution of step a) and mixing to form an injectable composition;    wherein the strong acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, chromic acid, methanesulfonic acid, trifluromethane sulfonic acid, trichloroacetic acid, dichloroacetic acid, bromoacetic acid, chloroacetic acid, cyanoacetic acid, 2-chloropropanoic acid, 2-oxobutanoic acid, 2-chlorobutanoic acid, 4-cyanobutanoic acid, perchloric acid, and phosphoric acid.    
     
     
         32 . The method of  claim 31  wherein the biodegradable polymer is dissolved with one or more pharmaceutically acceptable excipients in a pharmaceutically acceptable organic solvent.  
     
     
         33 . A method for in situ formation of an implant within a living body comprising: 
 a. administering an injectable polymeric composition into the body of a subject, the composition comprising a salt of a peptide agent formed with a strong acid, a biodegradable polymer, a pharmaceutically acceptable organic solvent and optionally, one or more pharmaceutically acceptable excipients;    b. allowing the pharmaceutically acceptable organic solvent to dissipate from the composition to form a biodegradable implant;    wherein the strong acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, chromic acid, methanesulfonic acid, trifluromethane sulfonic acid, trichloroacetic acid, dichloroacetic acid, bromoacetic acid, chloroacetic acid, cyanoacetic acid, 2-chloropropanoic acid, 2-oxobutanoic acid, 2-chlorobutanoic acid, 4-cyanobutanoic acid, perchloric acid, and phosphoric acid.    
     
     
         34 . The method of  claim 33  wherein the injectable polymeric composition is administered subcutaneously.  
     
     
         35 . The method of  claim 33  wherein the injectable polymeric composition is administered intramuscularly.  
     
     
         36 . A method for producing a polymeric composition as a controlled release system to deliver a therapeutic amount of a peptide agent to a subject, the method comprising: 
 a. dissolving a biodegradable polymer in an organic solvent;    b. dissolving or suspending a salt of the peptide agent formed with a strong acid in the polymer solution of step a) to form an uniform formulation; and    c. forming microparticles or nanoparticles comprising the biodegradable polymer encapsulating the peptide agent,    wherein the strong acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, chromic acid, methanesulfonic acid, trifluromethane sulfonic acid, trichloroacetic acid, dichloroacetic acid, bromoacetic acid, chloroacetic acid, cyanoacetic acid, 2-chloropropanoic acid, 2-oxobutanoic acid, 2-chlorobutanoic acid, 4-cyanobutanoic acid, perchloric acid, and phosphoric acid.    
     
     
         37 . A method for producing a polymeric composition as a controlled release system to deliver a therapeutic amount of a peptide agent to a subject, the method comprising: 
 a. dissolving a biodegradable polymer in an organic solvent; and    b. dissolving or suspending a salt of the peptide agent formed with a strong acid in the polymer solution of step a) to form an uniform formulation; and    c. forming a solid polymer matrix comprising the biodegradable polymer encapsulating the peptide agent,    wherein the strong acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, chromic acid, methanesulfonic acid, trifluromethane sulfonic acid, trichloroacetic acid, dichloroacetic acid, bromoacetic acid, chloroacetic acid, cyanoacetic acid, 2-chloropropanoic acid, 2-oxobutanoic acid, 2-chlorobutanoic acid, 4-cyanobutanoic acid, perchloric acid, and phosphoric acid.    
     
     
         38 . The method of  claim 37  wherein the solid polymer matrix is in the form of microparticles, nanoparticles, rod, film, grain, cylinder or wafer.  
     
     
         39 . The method of  claim 38  wherein the solid polymer matrix is suitable for parenteral administration; mucosal administration; ophthalmic administration; subcutaneous or intramuscular injection or insertion; or inhalation.