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 at least one peptide and propylene glycol, wherein said propylene glycol is present in said formulation in a final concentration of from about 1 mg/ml to about 100 mg/ml and wherein said formulation has a pH of from about 7.0 to about 10.0. 
     
     
         2 . The formulation according to  claim 1 , wherein the concentration of propylene glycol is from about 1 mg/ml to about 50 mg/ml. 
     
     
         3 . The formulation according to  claim 1 , wherein the concentration of propylene glycol is from about 5 mg/ml to about 25 mg/ml. 
     
     
         4 . The formulation according to  claim 1 , wherein the concentration of propylene glycol is from about 8 mg/ml to about 16 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 1 , wherein said peptide is a GLP-1 agonist. 
     
     
         13 . The formulation according to  claim 12 , wherein said GLP-1 agonist is selected from the group consisting of GLP-1(7-36)-amide, GLP-1(7-37), a GLP-1(7-36)-amide analogue, a GLP-1(7-37) analogue, or a derivative of any of these. 
     
     
         14 . The formulation according to  claim 13 , wherein said GLP-1 agonist is a derivative of GLP-1(7-36) or GLP-1(7-37) or a GLP-1(7-36)-amide analogue or a GLP-1(7-37) analogue, where said derivative has a lysine residue and a lipophilic substituent attached with or without a spacer to the epsilon amino group of said lysine. 
     
     
         15 . The formulation according to  claim 14 , wherein said lipophilic substituent has from 8 to 40 carbon atoms. 
     
     
         16 . The formulation according to  claim 15 , wherein said spacer is an amino acid. 
     
     
         17 . The formulation according to  claim 16 , wherein said GLP-1 agonist is Arg 34 ,Lys 26 (N-ε-(γ-Glu(N-α-hexadecanoyl)))-GLP-1(7-37). 
     
     
         18 . The formulation according to  claim 12 , wherein said GLP-1 agonist is selected from the group consisting of Gly 8 -GLP-1(7-36)-amide, Gly 8 -GLP-1(7-37), Val 8 -GLP-1(7-36)-amide, Val 8 -GLP-1(7-37), Val 8 Asp 22 -GLP-1(7-36)-amide, Val 8 Asp 22 -GLP-1(7-37), Val 8 Glu 22 -GLP-1(7-36)-amide, Val 8 Glu 22 -GLP-1(7-37), Val 8 Lys 22 -GLP-1(7-36)-amide, Val 8 Lys 22 -GLP-1(7-37), Val 8 Arg 22 -GLP-1(7-36)-amide, Val 8 Arg 22 -GLP-1(7-37), Val 8 His 22 -GLP-1(7-36)-amide, Val 8 His 22 -GLP-1(7-37), Arg34GLP-1(7-37); Arg26,34,Lys36GLP-1(7-36); Arg26GLP-1(7-37); and Gly8,Arg26,34,Glu37,Lys38GLP-1(7-38) analogues thereof and derivatives of any of these. 
     
     
         19 . The formulation according to  claim 1 , wherein said peptide is selected from insulin, an insulin analogue, a derivative of insulin or an insulin analogue or a mixture of any of the foregoing. 
     
     
         20 . The formulation according to  claim 19 , wherein said peptide is an insulin derivative in which said derivative contains a lysine residue to which a lipophilic substituent of at least six carbon atoms is attached. 
     
     
         21 . The formulation according to  claim 20 , wherein the insulin derivative is Lys β29 (Nε-tetradecanoyl) des(B30) human insulin. 
     
     
         22 . The formulation according to  claim 20 , wherein said insulin derivative is N □B29 -octanoyl insulin. 
     
     
         23 . The formulation according to  claim 19 , wherein said peptide is a 30/70 mixture of insulin aspart and insulin aspart protamine. 
     
     
         24 . The formulation according to  claim 1 , wherein said peptide is human growth hormone (hGH) or Met-hGH. 
     
     
         25 . The formulation according to  claim 24 , wherein said peptide is exendin 4, an exendin 4 analogue or a derivative of exendin 4 or an exendin 4 analogue. 
     
     
         26 . The formulation according to  claim 25 , wherein said peptide is exendin 4. 
     
     
         27 . The formulation according to  claim 25 , wherein said peptide is HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK-amide.