Pharmaceutical Composition Comprising a GLP-1-Agonist and Methionine

Abstract

A liquid composition comprising a GLP-1 agonist or/and a pharmacologically tolerable salt thereof and, optionally, at least one pharmaceutically acceptable excipient, wherein the composition comprises methionine, as add-on therapy with metformin and/or with long-acting insulin/insulin derivates where appropriate.

1 . An aqueous liquid composition consisting essentially of:
 (a) desPro 36 exendin-4(1-39)-Lys 6 -NH2 (“AVE0010”) or a pharmacologically tolerable salt thereof at a concentration of about 0.025 mg/mL to about 0.1 mg/mL;   (b) insulin glargine or a pharmacologically tolerable salt thereof at a concentration of about 3.64 mg/mL;   (c) L-methionine; and   (d) water.   
     
     
         2 . The aqueous liquid composition of  claim 1 , wherein the composition exhibits chemical integrity after storage for 6 months at a temperature of +25° C. 
     
     
         3 . The aqueous liquid composition of  claim 2 , wherein at least 80% of the liquid composition's active substance is in a substantially chemically unchanged form after storage for 6 months at a temperature of +25° C. 
     
     
         4 . The aqueous liquid composition of  claim 2 , wherein the percentage of oxidized methionine with respect to the entire methionine content of the GLP-1 agonist after storage for 6 months at a temperature of +25° C. is below 0.7%. 
     
     
         5 . The aqueous liquid composition of  claim 2 , wherein the proportion of total impurities with respect to the entire mass of the GLP-1 agonist present in the composition after storage for 6 months at +25° C. is below 10%. 
     
     
         6 . The aqueous liquid composition of  claim 2 , wherein the proportion of proteins of high molecular weight with respect to the entire mass of the GLP-1 agonist in the composition after storage for 6 months at +25° C. is below 0.8%. 
     
     
         7 . An aqueous liquid pharmaceutical composition comprising the following constituents per 1 mL volume of the composition:
 (a) approximately 50 μg desPro 36 exendin-4(1-39)-Lys 6 -NH 2  (“AVE0010”) or a pharmacologically tolerable salt thereof;   (b) approximately 3.5 mg sodium acetate trihydrate;   (c) approximately 2.7 mg m-cresol;   (d) approximately 3.0 mg L-methionine;   (e) approximately 18.0 mg glycerol; and   (f) water,   
       wherein the composition has improved stability and chemical integrity; and 
       wherein the composition has improved compatibility in intramuscular or subcutaneous administration. 
     
     
         8 . An aqueous liquid pharmaceutical composition comprising the following constituents per 1 mL volume of the composition:
 (a) approximately 100 μg desPro 36 exendin-4(1-39)-Lys 6 -NH 2  (“AVE0010”) or a pharmacologically tolerable salt thereof;   (b) approximately 3.5 mg sodium acetate trihydrate;   (c) approximately 2.7 mg m-cresol;   (d) approximately 3.0 mg L-methionine;   (e) approximately 18.0 mg glycerol; and   (f) water,   
       wherein the composition has improved stability and chemical integrity; and 
       wherein the composition has improved compatibility in intramuscular or subcutaneous administration.