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:
 Arg34, Lys26(N-ε-(γ-Glu(N-α-hexadecanoyl)))-GLP-1(7-37) in a concentration of about 0.1 mg/ml to about 10 mg/ml; and   propylene glycol in a concentration of from about 8 mg/ml to about 16 mg/ml,   wherein said formulation has a pH in the range of from about 7.0 to about 9.5.   
     
     
         2 . The formulation according to  claim 1 , wherein the concentration of propylene glycol is from about 13 mg/ml to about 15 mg/ml. 
     
     
         3 . The formulation according to  claim 1 , wherein the concentration of propylene glycol is from about 13.5 mg/ml to about 14.5 mg/ml. 
     
     
         4 . The formulation according to  claim 1 , wherein said formulation has a pH of from about 7.0 to about 8.3 mg/ml. 
     
     
         5 . The formulation according to  claim 3 , further comprising a buffer. 
     
     
         6 . The formulation according to  claim 5 , wherein the buffer is sodium acetate. 
     
     
         7 . The formulation according to  claim 5 , wherein the buffer is sodium carbonate. 
     
     
         8 . The formulation according to  claim 5 , wherein the buffer is citrate. 
     
     
         9 . The formulation according to  claim 5 , wherein the buffer is glycylglycine. 
     
     
         10 . The formulation according to  claim 5 , wherein the buffer is histidine. 
     
     
         11 . The formulation according to  claim 5 , wherein the buffer is glycine. 
     
     
         12 . The formulation according to  claim 5 , wherein the buffer is lysine. 
     
     
         13 . The formulation according to  claim 5 , wherein the buffer is arginine. 
     
     
         14 . The formulation according to  claim 5 , wherein the buffer is sodium dihydrogen phosphate. 
     
     
         15 . The formulation according to  claim 5 , wherein the buffer is disodium hydrogen phosphate. 
     
     
         16 . The formulation according to  claim 5 , wherein the buffer is sodium phosphate. 
     
     
         17 . The formulation according to  claim 5 , wherein the buffer is tris(hydroxymethyl)aminomethane. 
     
     
         18 . The formulation according to  claim 5 , wherein the buffer is selected from the group consisting of sodium acetate, sodium carbonate, citrate, glycylglycine, histidine, glycine, lysine, arginine, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, tris(hydroxymethyl)-aminomethane, or mixtures thereof. 
     
     
         19 . A pharmaceutical formulation consisting essentially of:
 Arg34, Lys26(N-ε-(γ-Glu(N-α-hexadecanoyl)))-GLP-1(7-37) in a concentration of about 0.1 mg/ml to about 10 mg/ml;   propylene glycol in a concentration of from about 13 mg/ml to about 15 mg/ml;   a buffer,   a preservative;   and water for injection;   wherein said formulation has a pH in the range of from about 7.0 to about 9.5.   
     
     
         20 . The formulation according to  claim 19 , wherein the buffer is selected from the group consisting of sodium acetate, sodium carbonate, citrate, glycylglycine, histidine, glycine, lysine, arginine, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, tris(hydroxymethyl)-aminomethane, or mixtures thereof, and
 wherein the preservative is selected from the group consisting of phenol, m-cresol, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, 2-phenoxyethanol, butyl p-hydroxybenzoate, 2-phenylethanol, benzyl alcohol, chlorobutanol, and thimerosal, or mixtures thereof.   
     
     
         21 . The formulation according to  claim 20 , wherein the buffer is glycylglycine, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate or mixtures thereof, and the preservative is phenol or m-cresol. 
     
     
         22 . The formulation according to  claim 21 , wherein said formulation has a pH of 8.15. 
     
     
         23 . A pharmaceutical formulation for use in an injection device containing a needle, the formulation comprising:
 Arg34, Lys26(N-ε-(γ-Glu(N-α-hexadecanoyl)))-GLP-1(7-37) in a concentration of about 0.1 mg/ml to about 10 mg/ml; and   a propylene glycol isotonic agent in a concentration of from about 13 mg/ml to about 15 mg/ml;   wherein said formulation has a pH of from about 7.0 to about 9.5; and   wherein said formulation exhibits, in a simulated in-use study, reduced clogging of the needle relative to a formulation of the same components but containing mannitol as the isotonic agent.   
     
     
         24 . The formulation of  claim 23 , wherein said formulation exhibits reduced deposits in production filling equipment relative to a formulation of the same components but containing mannitol as the isotonic agent. 
     
     
         25 . The formulation according to  claim 23 , wherein the propylene glycol is present in said formulation in a concentration of from about 13.5 mg/ml to about 14.5 mg/ml. 
     
     
         26 . The formulation according to  claim 23 , further comprising a buffer and a preservative. 
     
     
         27 . The formulation according to  claim 23 , wherein said formulation has a pH of 8.15. 
     
     
         28 . A parenteral administration device for administering Arg34, Lys26(N-ε-(γ-Glu(N-α-hexadecanoyl)))-GLP-1(7-37) to a patient in need thereof, the device comprising:
 an injection device containing a needle with a needle top; 
 a pharmaceutical formulation in the injection device, said formulation comprising: 
 Arg34, Lys26(N-ε-(γ-Glu(N-α-hexadecanoyl)))-GLP-1(7-37) in a concentration of about 0.1 mg/ml to about 10 mg/ml; and 
 a propylene glycol isotonic agent in a concentration of from about 13 mg/ml to about 15 mg/ml; 
 wherein said formulation has a pH of from about 7.0 to about 9.5; and 
 wherein the device, in a simulated in-use study, after multiple uses exhibits no clogging of the needle, no drops at the needle top, no dried drops at the needle top, no gel-like drops on the needle, and no deposits on the needle. 
 
     
     
         29 . The parenteral administration device of  claim 28 , wherein the propylene glycol is present in said formulation in a concentration of from about 13.5 mg/ml to about 14.5 mg/ml. 
     
     
         30 . The parenteral administration device of  claim 28 , wherein said formulation further comprises a buffer and a preservative.