Peptide slow-release formulations

Abstract

Disclosed herein are compositions for the delayed delivery of peptide active agents, including compositions comprising; i) a salt of a peptide active agent comprising at least one positively charged peptide ion and at least one negatively charged counter-ion selected from a halide ion, a chloride and a bromide ion; and ii) a sustained-release delivery vehicle.

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 chloride or bromide ion.   
     
     
         2 . A composition according to claim wherein said delivery vehicle comprises a bio-tolerable polymer. 
     
     
         3 . A composition according to  claim 2  wherein said bio-tolerable polymer is selected from poly-lactate, poly-glycolate and poly-lactate-co-glycolate (PLGA). 
     
     
         4 . A composition according to  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 according to  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 peptide active agent 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 chloride or bromide ion.   
     
     
         7 . A preformulation according to  claim 6  wherein component a) comprises GDO. 
     
     
         8 . A preformulation according to  claim 6  wherein component b) comprises soy PC. 
     
     
         9 . A preformulation according to  claim 6  wherein component c) comprises ethanol. 
     
     
         10 . A preformulation according to  claim 6  wherein said preformulation comprises at least one chloride or bromide salt of a least one somatostatin analogue selected from:
 octreotide; 
 lanreotide, of sequence NH 2 -(D)Naph-Cys-Tyr-(D)Trp-Lys-Val-Cys-Thr-CONH 2  or its cyclic derivative of sequence NH 2 -(D)Naph-Cys-Tyr-(D)Phe-Lys-Val-Cys-Thr-CONH 2  both having a Cys-Cys intramolecular disulphide crosslink; 
 pasireotide (SOM230); 
 vapreotide; 
 SST-14; and 
 SST-28. 
 
     
     
         11 . A method for the treatment of a human or non-human mammalian subject in need thereof with a peptide active agent, 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 peptide active agent 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 chloride or bromide ion.   
     
     
         12 . The method according to  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 according to  claim 11  comprising the administration of at least one 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 chloride or bromide ion. 
 
     
     
         14 . The method according to  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 chloride or bromide ion. 
 
     
     
         15 . The method according to  claim 11  comprising administration by i.m., s.c. or deep s.c. injection. 
     
     
         16 . The method according to  claim 11  comprising administration by means of a pre-filled administration device. 
     
     
         17 . The method according to  claim 11  comprising a single administration every 20 to 180 days. 
     
     
         18 . 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 peptide active agent 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 chloride or bromide ion.   
     
     
         19 . The device according to  claim 18 , wherein said device is a syringe or syringe barrel. 
     
     
         20 . The device according to  claim 18  containing 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 chloride or bromide ion. 
 
     
     
         21 . The device according to  claim 18 , wherein said device contains 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 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 chloride or bromide ion.   
     
     
         22 . The device according to  claim 18 , wherein said device contains a single dose of 1 to 1000 mg of somatostatin analogue chloride or bromide salt. 
     
     
         23 . The device according to  claim 18 , wherein said device contains octreotide chloride in an amount ranging from 10 to 360 mg. 
     
     
         24 . The device according to  claim 18 , wherein said device contains octreotide chloride in an amount ranging from 0.2 to 3 mg per day between scheduled administrations. 
     
     
         25 . The device according to  claim 18 , wherein said device contains a total volume for administration of no more than 5 ml. 
     
     
         26 . A kit for the administration of at least one peptide active agent, 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 peptide active agent 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 chloride or bromide ion.   
     
     
         27 . The kit according to  claim 26 , further comprising an administration device. 
     
     
         28 . The kit according to  claim 26 , wherein said kit contains 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 chloride or bromide ion.   
     
     
         29 . The kit according to  claim 26 , wherein said kit contains 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 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 chloride or bromide ion.   
     
     
         30 . The kit according to  claim 26 , wherein said kit contains 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 chloride or bromide ion.   
     
     
         31 . The kit according to  claim 26 , wherein said kit contains instructions for administration by i.m., s.c. or deep s.c. injection. 
     
     
         32 . The kit according to  claim 26 , 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 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 chloride or bromide ion.   
     
     
         33 - 37 . (canceled) 
     
     
         38 . A composition according to  claim 1  wherein said peptide active agent is water soluble. 
     
     
         39 . A composition according to  claim 1  comprising at least one solvent selected from the group consisting of: an alcohol, a sulfoxide, and/or an amide. 
     
     
         40 . A composition according to  claim 1  comprising at least one solvent selected from the group consisting of: ethyanol, dimethylsulfoxide (DMSO), N-methyl pyrrolidone (NMP) and dimethylacetamide (DMA). 
     
     
         41 . A composition according to  claim 1  wherein said peptide active agent is not octreotide. 
     
     
         42 . A composition according to  claim 1  wherein said peptide active agent is not a somatostatin analogue. 
     
     
         43 . A pre-formulation according to  claim 6  wherein said peptide active agent is water soluble. 
     
     
         44 . A pre-formulation according to  claim 6  wherein said organic solvent comprises at least one solvent selected from the group consisting of: an alcohol, a sulfoxide, and/or an amide. 
     
     
         45 . A pre-formulation according to  claim 6  wherein said organic solvent comprises at least one solvent selected from the group consisting of: ethanol, dimethylsulfoxide (DMSO), N-methyl pyrrolidone (NMP) and dimethylacetamide (DMA). 
     
     
         46 . A pre-formulation according to  claim 6  wherein said peptide salt is present in an amount of 0.1-10 wt % of the pre-formulation. 
     
     
         47 . A pre-formulation according to  claim 6  wherein said peptide active agent is not octreotide. 
     
     
         48 . A pre-formulation according to  claim 6  wherein said peptide active agent is not a somatostatin analogue. 
     
     
         49 . A method as claimed in  claim 11  comprising a single administration every 7 days.