Peptide slow-release formulations

Abstract

A composition for the delayed delivery of a peptide active agent comprising: i) a salt of said peptide active agent comprising at least one positively charged peptide ion and at least one negatively charged counter-ion ii) a sustained-release delivery vehicle. Wherein said at last one negatively charged counter-ion is a halide ion, preferably a chloride or bromide ion.

1 . A composition for the delayed delivery of a peptide active agent comprising:
 i) a salt of said peptide active agent comprising at least one positively charged peptide ion and at least one negatively charged counter-ion, and   ii) a sustained-release delivery vehicle,   
       wherein said at least one negatively charged counter-ion is a halide ion. 
     
     
         2 . A composition as claimed in  claim 1 , wherein said delivery vehicle comprises a bio-tolerable polymer. 
     
     
         3 . A composition as claimed in  claim 2 , wherein said bio-tolerable polymer is selected from poly-lactate, poly-glycolate and poly-lactate-co-glycolate. 
     
     
         4 . A composition as claimed in  claim 1 , wherein said delivery vehicle comprises:
 a) at least one diacyl glycerol;   b) at least one phosphatidyl choline; and   c) at least one oxygen containing organic solvent],   
     
     
         5 . A composition as claimed in  claim 4 , further comprising an aqueous fluid,
 wherein the composition comprises at least one liquid crystalline phase structure.   
     
     
         6 . A pre-formulation comprising a low viscosity mixture of:
 a) at least one diacyl glycerol;   b) at least one phosphatidyl choline;   c) at least one oxygen containing organic solvent; and   d) a salt of at least one somatostatin analogue comprising at least one positively charged peptide ion and at least one negatively charged counter-ion;   
       wherein the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure upon contact with an aqueous fluid and wherein said at least one negatively charged counter-ion is a halide ion. 
     
     
         7 . A preformulation as claimed in  claim 6 , wherein component a) comprises GDO. 
     
     
         8 . A preformulation as claimed in  claim 5 , wherein component b) comprises soy PC. 
     
     
         9 . A preformulation as claimed in  claim 6 , wherein component c) comprises ethanol. 
     
     
         10 . A preformulation as claimed in  claim 6 , wherein said preformulation comprises at least one halide salt of at least one somatostatin analogue selected from octreotide, lanreotide, SOM230 and vapreotide. 
     
     
         11 . A method for the treatment of a human or non-human mammalian subject in need thereof with a somatostatin analogue, said method comprising administering to said subject a pre-formulation comprising a low- viscosity mixture of:
 a) at least one diacyl glycerol;   b) at least one phosphatidyl choline;   c) at least one oxygen containing organic solvent; and   d) a salt of at least one somatostatin analogue comprising at least one positively charged peptide ion and at least one negatively charged counter-ion;   
       wherein said at least one negatively charged counter-ion is a halide ion. 
     
     
         12 . The method as claimed in  claim 11 , wherein the method of treatment is a method for the treatment of at least one condition selected from acromegaly, cancers, carcinomas, melanomas, tumours expressing at least one somatostatin receptor, somatostatin receptor-2-positive tumours, somatostatin receptor-5-positive tumours, prostate cancers, gastro-entero-pancreatic neuroendocrine tumours, carcinoid tumours, insulinomas, gastrinomas, vasoactive intestinal peptide-producing-tumours and glucagonomas, elevated growth hormone, elevated insulin-like growth factor I, varicial bleeding, chemotherapy induced gastro intestinal problems, lymphorrhea, diabetic retinopathy, thyroid eye disease, obesity, pancreatitis, and related conditions. 
     
     
         13 . The method as claimed in  claim 11 , comprising the administration of a composition for the delayed delivery of a peptide active agent, the composition comprising:
 i) a salt of said peptide active agent comprising at least one positively charged peptide ion and at least one negatively charged counter-ion, and   ii) a sustained-release delivery vehicle,   
       wherein said at least one negatively charged counter-ion is a halide ion. 
     
     
         14 . The method as claimed in  claim 11 , comprising the administration of at least one pre-formulation comprising a low viscosity mixture of:
 a) at least one diacyl glycerol;   b) at least one phosphatidyl choline;   c) at least one oxygen containing organic solvent; and   d) a salt of at least one somatostatin analogue comprising at least one positively charged peptide ion and at least one negatively charged counter-ion;   
       wherein the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure upon contact with an aqueous fluid and wherein said at least one negatively charged counter-ion is a halide ion. 
     
     
         15 . The method as claimed in  claim 11 , comprising administration by i.m., s.c. or preferably deep s.c. injection. 
     
     
         16 . The method as claimed in  claim 11 , comprising administration by means of a pre-filled administration device as indicated herein. 
     
     
         17 . The method as claimed in  claim 11 , comprising a single administration every 20 to 180 days. 
     
     
         18 - 22 . (canceled) 
     
     
         23 . A disposable administration device pre-loaded with a measured dose of a preformulation comprising a low viscosity mixture of:
 a) at least one diacyl glycerol;   b) at least one phosphatidyl choline;   c) at least one oxygen containing organic solvent; and   d) a salt of at least one somatostatin analogue comprising at least one positively charged peptide ion and at least one negatively charged counter-ion;   
       wherein said at least one negatively charged counter-ion is a halide ion. 
     
     
         24 . The device of  claim 23 , wherein said device is a syringe or syringe barrel. 
     
     
         25 . A disposable administration device pre-loaded with a measured dose of a composition for the delayed delivery of a peptide active agent, the composition comprising:
 i) a salt of said peptide active agent comprising at least one positively charged peptide ion and at least one negatively charged counter-ion, and   ii) a sustained-release delivery vehicle,   
       wherein said at least one negatively charged counter-ion is a halide ion. 
     
     
         26 . The device according to  claim 23 , wherein the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure upon contact with an aqueous fluid and wherein said at least one negatively charged counter-ion is a halide ion. 
     
     
         27 . The device according to  claim 23 , wherein said device contains a single dose of 1 to 1000 mg of somatostatin analogue halide salt. 
     
     
         28 . The device according to  claim 23 , wherein said device contains octreotide chloride in an amount ranging from about 10 to 360 mg. 
     
     
         29 . The device according to  claim 23 , wherein said device contains octreotide chloride at in an amount ranging from about 0.2 to 3 mg per day between scheduled administrations. 
     
     
         30 . The device according to  claim 23 , wherein said device contains a total volume for administration of no more than 5 ml. 
     
     
         31 . A kit for the administration of at least one somatostatin analogue, said kit containing a measured dose of a formulation comprising a low viscosity mixture of:
 a) at least one diacyl glycerol;   b) at least one phosphatidyl choline;   c) at least one oxygen containing organic solvent; and   d) a salt of at least one somatostatin analogue comprising at least one positively charged peptide ion and at least one negatively charged counter-ion;   
       wherein said at least one negatively charged counter-ion is a halide ion. 
     
     
         32 . The kit according to of  claim 31 , further comprising an administration device. 
     
     
         33 . The kit according to of  claim 31 , wherein said kit contains a composition for the delayed delivery of a peptide active agent, the composition comprising:
 i) a salt of said peptide active agent comprising at least one positively charged peptide ion and at least one negatively charged counter-ion, and   ii) a sustained-release delivery vehicle,   
       wherein said at least one negatively charged counter-ion is a halide ion. 
     
     
         34 . The kit according to of  claim 31 , wherein the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure upon contact with an aqueous fluid. 
     
     
         35 . The kit according to  claim 31 , wherein said kit contains a disposable administration device pre-loaded with the measured dose of the preformulation. 
     
     
         36 . The kit according to  claim 31 , wherein said kit contains instructions for administration by i.m, s./c or preferably deep s.c. injection. 
     
     
         37 . The kit according to  claim 31 , wherein said kit contains instructions for administration for use in a method of treatment of a human or non-human mammalian subject in need thereof, said method comprising administering to said subject the pre-formulation. 
     
     
         38 . A composition according to  claim 1 , wherein said halide ion is a chloride or bromide ion. 
     
     
         39 . A preformulation according to  claim 6 , wherein said halide ion is a chloride or bromide ion. 
     
     
         40 . The method according to  claim 11 , wherein said halide ion is a chloride or bromide ion. 
     
     
         41 . The device according to  claim 23 , wherein said halide ion is a chloride or bromide ion. 
     
     
         42 . The kit according to  claim 31 , wherein said halide ion is a chloride or bromide ion.