Novel formulations

Abstract

According to the invention there is provided inter alia an aqueous liquid pharmaceutical formulation comprising insulin or an insulin analogue, ionic zinc, a chelating agent and polysorbate 80.

1 . An aqueous liquid pharmaceutical formulation comprising insulin or an insulin analogue, ionic zinc, a chelating agent and polysorbate 80. 
     
     
         2 . The formulation according to  claim 1  comprising insulin lispro as an insulin analogue. 
     
     
         3 . The formulation according to  claim 1  comprising insulin aspart as an insulin analogue. 
     
     
         4 . The formulation according to  claim 1  comprising insulin glulisine as an insulin analogue. 
     
     
         5 . The formulation according to  claim 1  comprising recombinant human insulin as an insulin. 
     
     
         6 . The formulation according to  claim 1 , wherein the insulin or insulin analogue is present at a concentration of 10-1000 U/ml. 
     
     
         7 . The formulation according to  claim 1 , wherein the ionic zinc is present at a concentration of more than 0.25% by weight of zinc based on the weight of insulin or insulin analogue in the formulation. 
     
     
         8 . The formulation according to  claim 7 , wherein the ionic zinc is present at a concentration of 0.25-1% by weight of zinc based on the weight of insulin or insulin analogue in the formulation. 
     
     
         9 . The formulation according to  claim 1 , wherein the chelating agent has a metal binding stability constant logK with respect to zinc binding of at least 4.5 at 25° C. 
     
     
         10 . The formulation according to  claim 1 , wherein the chelating agent is EDTA. 
     
     
         11 . The formulation according to  claim 1 , wherein the chelating agent is selected from citrate, EGTA, pyrophosphate, alginate, ethylenediamine and histidine. 
     
     
         12 . The formulation according to  claim 11 , wherein the chelating agent is citrate. 
     
     
         13 . The formulation according to  claim 12  wherein the source of the citrate is citric acid. 
     
     
         14 . The formulation according to  claim 1 , wherein the chelating agent is present at a concentration of 0.1-50 mM. 
     
     
         15 . The formulation according to  claim 10  wherein EDTA as chelating agent is present at a concentration of 0.1-2 mM. 
     
     
         16 . The formulation according to  claim 12  wherein citrate as chelating agent are present at a concentration of 2.5-50 mM. 
     
     
         17 . The formulation according to  claim 10 , wherein the molar ratio of ionic zinc to EDTA as chelating agent is in the range 1:0.8 to 1.0:2.0. 
     
     
         18 . The formulation according to  claim 11 , wherein the molar ratio of ionic zinc to citrate as chelating agent is in the range 1:20-1:100. 
     
     
         19 . The formulation according to  claim 1 , wherein the polysorbate 80 is present at a concentration of 1-500 μg/ml. 
     
     
         20 . The formulation according to  claim 1 , further comprising an uncharged tonicity modifier. 
     
     
         21 . The formulation according to  claim 20 , wherein the uncharged tonicity modifier is selected from the group consisting of trehalose, mannitol, glycerol or 1,2-propanediol. 
     
     
         22 . The formulation according to  claim 21 , wherein the uncharged tonicity modifier is glycerol. 
     
     
         23 . The formulation according to  claim 1 , wherein the composition is isotonic. 
     
     
         24 . The formulation according to  claim 1 , wherein the pH is in the range 5.5 to 9.0. 
     
     
         25 . The formulation according to  claim 24 , wherein the pH is in the range 7.0 to 7.5. 
     
     
         26 . The formulation according to  claim 24 , wherein the pH is in the range 7.6 to 8.0. 
     
     
         27 . The formulation according to  claim 1 , further comprising a preservative. 
     
     
         28 . The formulation according to  claim 27 , wherein the preservative is selected from the group consisting of phenol, m-cresol, chlorocresol, benzyl alcohol, propylparaben, methylparaben, benzalkonium chloride and benzethonium chloride. 
     
     
         29 . The formulation according to  claim 1 , wherein the ionic strength of the formulation is less than 40 mM. 
     
     
         30 . A method of treatment of diabetes mellitus which comprises administering to a subject in need thereof an effective amount of a formulation according to  claim 1 . 
     
     
         31 . An injection device for single or multiple use comprising a container containing one dose or a plurality of doses of the formulation according to  claim 1  together with an injection needle.