Propylene Glycol-Containing Peptide Formulations which are Optimal for Production and for Use in Injection Devices

Abstract

The present invention relates to pharmaceutical formulations comprising a peptide and propylene glycol, to methods of preparing such formulations, and to uses of such formulations in the treatment of diseases and conditions for which use of the peptide contained in such formulations is indicated. The present invention further relates to methods for reducing the clogging of injection devices by a peptide formulation and for reducing deposits on production equipment during production of a peptide formulation.

1 . A pharmaceutical formulation comprising the peptide Arg 34 , Lys 26 (N-ε-(γ-Glu(N-α-hexadecanoyl)))-GLP-1(7-37) and
 propylene glycol, 
 wherein said propylene glycol is present in said formulation in a final concentration of from 1 mg/ml to 25 mg/ml and 
 wherein said formulation has a pH of from 7.0 to 10.0. 
 
     
     
         2 . The formulation according to  claim 1 , wherein the concentration of propylene glycol is from about 8 mg/ml to about 16 mg/ml. 
     
     
         3 . The formulation according to  claim 1 , wherein the concentration of propylene glycol is from about 13 to about 15 mg/ml. 
     
     
         4 . The formulation according to  claim 1 , wherein the concentration of propylene glycol is from about 13.5 to about 14.5 mg/ml. 
     
     
         5 . The formulation according to  claim 1 , wherein the pH of said formulation is about 7.0 to about 9.5. 
     
     
         6 . The formulation according to  claim 1 , wherein the pH of said formulation is about 7.0 to about 8.3. 
     
     
         7 . The formulation according to  claim 1 , wherein the pH of said formulation is about 7.3 to about 8.3. 
     
     
         8 . The formulation according to  claim 1 , further comprising a preservative. 
     
     
         9 . The formulation according to  claim 8 , wherein said preservative is present in a concentration from 0.1 mg/ml to 20 mg/ml. 
     
     
         10 . The formulation according to  claim 1 , further comprising a buffer. 
     
     
         11 . The formulation according to  claim 10 , wherein said buffer is selected from the group consisting of glycylglycine, L-histidine, Hepes, bicine and disodium phosphate dihydrate. 
     
     
         12 . The formulation according to  claim 10 , wherein said buffer is disodium phosphate dihydrate. 
     
     
         13 . The formulation according to  claim 1 , wherein said peptide consists of Arg 34 , Lys 26 (N-ε-(γ-Glu(N-α-hexadecanoyl)))-GLP-1(7-37). 
     
     
         14 . A method of preparing a peptide formulation suitable for use in an injection device, said method comprising preparing a formulation containing the peptide Arg 34 , Lys 26 (N-ε-(γ-Glu(N-α-hexadecanoyl)))-GLP-1(7-37),
 propylene glycol and 
 optionally a buffer and a preservative, 
 wherein said propylene glycol is present in a concentration from 1 mg/ml to 25 mg/ml, and 
 wherein said formulation has a pH from 7.0 to 10.0. 
 
     
     
         15 . The method according to  claim 14 , wherein said peptide, said propylene glycol and said buffer and preservative are mixed together to produce said formulation as follows:
 a) preparing a first solution by dissolving preservative, propylene glycol and buffer in water;   b) preparing a second solution by dissolving the peptide in water;   c) mixing the first and second solutions; and   d) adjusting the pH of the mixture in c) to a pH of from 7.0 to 10.0.   
     
     
         16 . The method according to  claim 14 , wherein the concentration of propylene glycol is from 8 mg/ml to 16 mg/ml. 
     
     
         17 . The method according to  claim 14 , wherein the pH of said formulation is 7.0 to 9.5. 
     
     
         18 . The method according to  claim 14 , wherein the pH of said formulation is about 7.0 to about 8.0. 
     
     
         19 . The method according to  claim 14 , wherein the pH of said formulation is 7.2 to 8.0. 
     
     
         20 . A method for reducing deposits on production equipment during production of a GLP-1 agonist formulation, said method comprising replacing the isotonicity agent previously utilized in said formulation with propylene glycol at a concentration of between 1-25 mg/ml, wherein said GLP-1 agonist is the peptide Arg 34 , Lys 26 (N-ε-(γ-Glu(N-α-hexadecanoyl)))-GLP-1(7-37). 
     
     
         21 . The method according to  claim 20 , wherein the reduction in deposits on the production equipment during production by the propylene glycol-containing formulation relative to that observed for the formulation containing the previously utilized isotonicity agent is measured by a simulated filling experiment. 
     
     
         22 . The method according to  claim 20 , wherein the isotonicity agent to be replaced by propylene glycol is selected from the group consisting of sorbitol, sucrose, glycine, mannitol, lactose monohydrate, arginin, myo-inositol and dimethylsulfon. 
     
     
         23 . A method for reducing deposits in the final product during production of a GLP-1 agonist formulation, said method comprising replacing the isotonicity agent previously utilized in said formulation with propylene glycol at a concentration of between 1-25 mg/ml wherein said GLP-1 agonist is the peptide Arg 34 , Lys 26 (N-ε-(γ-Glu(N-α-hexadecanoyl)))-GLP-1(7-37). 
     
     
         24 . The method according to  claim 23 , wherein the reduction in deposits in the final product is measured by a reduction in the number of vials and/or cartridges of the propylene glycol-containing formulation that must be discarded due to deposits relative to number of vials and/or cartridges of the formulation containing the previously utilized isotonicity agent that must be discarded due to deposits. 
     
     
         25 . The method according to  claim 23 , wherein the isotonicity agent to be replaced by propylene glycol is selected from the group consisting of sorbitol, glycerol, sucrose, glycine, mannitol, lactose monohydrate, arginin, myo-inositol and dimethylsulfon. 
     
     
         26 . A method for reducing the clogging of injection devices by a GLP-1 agonist formulation, said method comprising replacing the isotonicity agent previously utilized in said formulation with propylene glycol at a concentration of between 1-25 mg/ml.
 wherein said GLP-1 agonist is the peptide Arg 34 , Lys 26 (N-ε-(γ-Glu(N-α-hexadecanoyl)))-GLP-1(7-37).   
     
     
         27 . The method according to  claim 26 , wherein the reduction in clogging of the injection device by the propylene glycol-containing formulation relative to that observed for the formulation containing the previously utilized isotonicity agent is measured in a simulated in use study. 
     
     
         28 . The method according to  claim 26 , wherein the isotonicity agent to be replaced by propylene glycol is selected from the group consisting of inositol, maltose, glycine, lactose and mannitol.