Acidic Insulin Preparations Having Improved Stability

Abstract

The invention relates to a pharmaceutical formulation comprising a polypeptide selected from the group consisting of insulin, an insulin metabolite, an insulin analog, an insulin derivative and combinations thereof; a surfactant or combinations of two or more surfactants; optionally a preservative or combinations of two or more preservatives; and optionally an isotonicizing agent, buffers or further excipients or combinations thereof, the pharmaceutical formulation having a pH in the acidic range.

1 . A pharmaceutical formulation comprising:
 (a) Gly(A21), Arg(B31), Arg(B32)-human insulin;   (b) polysorbate 20;   (c) sodium chloride;   (d) glycerol;   (e) m-cresol; and   (f) water,   wherein the pharmaceutical formulation has a pH in the acidic range from 3.5 to 6.8.   
     
     
         2 . The pharmaceutical formulation as claimed in  claim 1 , wherein the Gly(A21), Arg(B31), Arg(B32)-human insulin is present at a concentration of about 1.4 to about 35 mg per milliliter. 
     
     
         3 . The pharmaceutical formulation as claimed in  claim 1 , wherein the Gly(A21), Arg(B31), Arg(B32)-human insulin is present at a concentration of about 3.6 mg per milliliter. 
     
     
         4 . The pharmaceutical formulation as claimed in  claim 3 , further including zinc. 
     
     
         5 . The pharmaceutical formulation as claimed in  claim 1 , wherein polysorbate 20 is present at a concentration of about 5 to 120 μg per milliliter. 
     
     
         6 . The pharmaceutical formulation as claimed in  claim 1 , wherein polysorbate 20 is present at a concentration of about 20 to 75 μg per milliliter. 
     
     
         7 . The pharmaceutical formulation as claimed in  claim 1 , wherein sodium chloride is present at a concentration of up to 150 mM. 
     
     
         8 . The pharmaceutical formulation as claimed in  claim 1 , wherein glycerol is present at a concentration of about 100 to 250 mM. 
     
     
         9 . The pharmaceutical formulation as claimed in  claim 1 , further comprising a buffer. 
     
     
         10 . The pharmaceutical formulation as claimed in  claim 9 , wherein the buffer is chosen from TRIS, phosphate, citrate, acetate, and glycylglycine. 
     
     
         11 . The pharmaceutical formulation as claimed in  claim 10 , wherein said buffer is present in a concentration of 5-250 mM. 
     
     
         12 . The pharmaceutical formulation as claimed in claimed  1 , wherein the pharmaceutical formulation has a pH in the acidic range from 3.5 to 4.5. 
     
     
         13 . The pharmaceutical formulation as claimed in claimed  1 , wherein the pharmaceutical formulation has a pH of 4 (+/−0.2).