Pharmaceutical Composition Comprising a GLP-1 Agonist, an Insulin and Methionine

Abstract

A liquid composition comprising a GLP-1 agonist or/and a pharmacologically tolerable salt thereof, an insulin 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 where appropriate.

1 . An aqueous liquid composition comprising the following constituents per 1 ml of the composition:
 (a) about 0.025 mg to about 0.1 mg desPro 36 exendin-4(1-39)-Lys 6 -NH2 (“AVE0010”) or a pharmacologically tolerable salt thereof;   (b) about 3.64 mg insulin glargine or a pharmacologically tolerable salt thereof;   (c) about 3.0 mg methionine; and   (d) water present in a quantity sufficient for the volume of the composition to total about 1 mL;   
       wherein the composition has a pH in the range from 3.5 to 4.5, and wherein the composition comprises no buffer substances. 
     
     
         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 1 , wherein the composition exhibits physical integrity after storage for  6  months at a temperature of +25° C. 
     
     
         4 . The aqueous liquid composition of  claim 1 , wherein the composition is suitable for parenteral administration. 
     
     
         5 . The aqueous liquid composition of  claim 1 , wherein at least 80% of the composition's active ingredients are in a substantially chemically unchanged form after storage for 6 months at a temperature of +25° C. 
     
     
         6 . The aqueous liquid composition of  claim 1 , wherein at least 80% of the composition's active ingredients are in a substantially physically unchanged form after storage for 6 months at a temperature of +25° C. 
     
     
         7 . The aqueous liquid composition of  claim 1 , wherein the composition has a pH of about 4.5. 
     
     
         8 . The aqueous liquid composition of  claim 1 , wherein the composition comprises an oxidized methionine content of about 1% or less after 1 month of storage. 
     
     
         9 . The aqueous liquid composition of  claim 1 , wherein the composition is pharmacologically tolerable. 
     
     
         10 . The aqueous liquid composition of  claim 1 , further comprising
 (e) a pharmaceutically acceptable preservative;   (f) a pharmaceutically acceptable isotonicity agent; and   (g) zinc.   
     
     
         11 . The aqueous liquid composition of  claim 1 , further comprising
 (e) m-cresol;   (f) 100-250 mM glycerol; and   (g) about 5 μg to 200 μg zinc.   
     
     
         12 . The aqueous liquid composition of  claim 1 , further comprising
 (e) about 2.7 mg m-cresol;   (f) about 20.0 mg 85% glycerol; and   (g) about 5 μg to 60 μg zinc.   
     
     
         13 . An injection pen comprising the aqueous liquid composition of  claim 1 . 
     
     
         14 . An injection pen comprising the aqueous liquid composition of claim  53 . 
     
     
         15 . An injection pen comprising the aqueous liquid composition of claim  54 . 
     
     
         16 . An injection pen comprising the aqueous liquid composition of claim  55 .