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.

What is claimed is:  
     
         1 . A pharmaceutical formulation comprising a polypeptide selected from the group consisting of bovine, porcine or human insulin, an insulin analogue, an insulin derivative, an active insulin metabolite and combinations thereof; 
 a surfactant or a combination of two or more surfactants;    optionally a preservative or a combination of two or more preservatives;    and optionally an isotonicizing agent, a buffer or buffers or a further excipient or excipients or a combination thereof;    such pharmaceutical formulation being a clear solution having a pH in the range from 1 to 6.8.    
     
     
         2 . A pharmaceutical formulation according to  claim 1 , having a pH in the range from pH 3.5-6.8.  
     
     
         3 . A pharmaceutical formulation according to  claim 1 , having a pH in the range from pH 3.5-4.5.  
     
     
         4 . A pharmaceutical formulation according to  claim 1  wherein the surfactant is selected from the group consisting of partial and fatty acid esters and ethers of polyhydric alcohols, of glycerol, sorbitol and of sucrose, and polyols.  
     
     
         5 . A pharmaceutical formulation according to  claim 4 , wherein the partial and fatty acid esters and ethers of polyhydric alcohols, of glycerol and sorbitol are selected from the group consisting of Span®, Tween®, polysorbate, Myrj®, Brij®, Triton®, and Cremophor®.  
     
     
         6 . A pharmaceutical formulation according to  claim 5 , wherein the partial and fatty acid esters and ethers of polyhydric alcohols, of glycerol and sorbitol are selected from the group consisting of Tween® 20 and Tween® 80.  
     
     
         7 . A pharmaceutical formulation according to  claim 4 , wherein the polyols are selected from the group consisting of polypropylene glycols, polyethylene glycols, poloxamers, Pluronics®, and Tetronics®.  
     
     
         8 . A pharmaceutical formulation according to  claim 1 , wherein the preservative is selected from the group consisting of phenol, cresol, chlorocresol, benzyl alcohol, and parabens.  
     
     
         9 . A pharmaceutical formulation according to  claim 1 , wherein the isotonicizing agent is selected from the group consisting of mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride, and glycerol.  
     
     
         10 . A pharmaceutical formulation according to  claim 1  wherein the excipients are selected from the group consisting of TRIS, phosphate, citrate, acetate, and glycylglycine  
     
     
         11 . A pharmaceutical formulation according to  claim 1  wherein the excipients are selected from the group consisting of acids, alkalis, and salts.  
     
     
         12 . A pharmaceutical formulation according to  claim 1 , wherein the insulin analog is selected from the group consisting of Gly(A21), Arg(B31), Arg(B32)-human insulin, Lys(B3), Glu(B29)-human insulin, Asp(B28)-human insulin, Lys(B28) Pro(B29)-human insulin, and des(B30)-human insulin.  
     
     
         13 . A pharmaceutical formulation according to  claim 1 , wherein the insulin derivative is selected from the group consisting of B29-N-myristoyl-des(B30) human insulin, B29-N-palmitoyl-des(B30) human insulin, B29-N-myristoyl human insulin, B29-N-palmitoyl human insulin, B28-N-myristoyl Lys B28 Pro B29  human insulin, B28-N-palmitoyl-Lys B28 Pro B29  human insulin, B30-N-myristoyl-Thr B29  Lys B30  human insulin, B30-N-palmitoyl-Thr B29 Lys B30  human insulin, B29-N-(N-palmitoyl-γ-glutamyl)-des(B39) human insulin, B29-N-(N-lithocholyl-γ-glutamyl)-des(B30) human insulin, B29-N-(ω-carboxy-heptadecanoyl)-des(B30) human insulin and B29-N-(ω-carboxy-heptadecanoyl) human insulin.  
     
     
         14 . A pharmaceutical formulation according to  claim 1 , wherein the insulin is present in a concentration of 60 to 6000 nmol/ml.  
     
     
         15 . A pharmaceutical formulation according to  claim 1 , wherein the insulin analog is present in a concentration of 60 to 6000 nmol/ml.  
     
     
         16 . A pharmaceutical formulation according to  claim 1 , wherein the insulin derivative is present in a concentration of 60 to 6000 nmol/ml.  
     
     
         17 . A pharmaceutical formulation according to  claim 14 , wherein the insulin is present in a concentration of 240 to 3000 nmol/ml.  
     
     
         18 . A pharmaceutical formulation according to  claim 15 , wherein the insulin analog is present in a concentration of 240 to 3000 nmol/ml.  
     
     
         19 . A pharmaceutical formulation according to  claim 16 , wherein the insulin derivative is present in a concentration of 240 to 3000 nmol/ml.  
     
     
         20 . A pharmaceutical formulation according to  claim 1  wherein the surfactant is present in a concentration of 5 to 200 μg/ml.  
     
     
         21 . A pharmaceutical formulation according to  claim 20 , wherein the surfactant is present in a concentration of 5 to 120 μg/ml.  
     
     
         22 . A pharmaceutical formulation according to  claim 21 , wherein the surfactant is present in a concentration of 20 to 75 μg/ml.  
     
     
         23 . A pharmaceutical formulation according to  claim 1 , wherein the isotonicizing agent is selected from the group consisting of glycerol and mannitol and wherein the isotonicizing agent is present in a concentration of 100 to 250 mM.  
     
     
         24 . A pharmaceutical formulation according to  claim 23 , wherein NaCl is present in a concentration of 0 to 150 mM.  
     
     
         25 . A pharmaceutical formulation according to  claim 1 , wherein a buffer is present in a concentration of 5 to 250 mM.