Stabilized pharmaceutical formulations of insulin analogues and/or insulin derivatives

Abstract

Stabilized pharmaceutical formulations of insulin analogues and/or insulin derivatives are disclosed.

1 . A pharmaceutical formulation comprising
 (a). at least one analogue and/or derivative of insulin;   (b). Zn(II);   (c). sodium chloride; and   (d). optionally protamine;   wherein the pharmaceutical formulation has a pH value in the range from 6.0 to 9.0 and is free of any additional buffering agent.   
     
     
         2 . The pharmaceutical formulation according to  claim 1 , wherein the pharmaceutical formulation is an aqueous pharmaceutical formulation. 
     
     
         3 . The pharmaceutical formulation according to  claim 1 , wherein the pharmaceutical formulation has a pH value in the range from 7.0 to 7.8. 
     
     
         4 . The pharmaceutical formulation according to  claim 1 , wherein the analogue of insulin is selected from the group consisting of insulin aspart, insulin lispro and insulin glulisine. 
     
     
         5 . The pharmaceutical formulation according to  claim 1 , wherein the derivative of insulin is insulin detemir and/or insulin degludec. 
     
     
         6 . The pharmaceutical formulation according to  claim 1 , wherein the analogue and/or derivative of insulin is present in a concentration from 10 U/mL to 1000 U/mL. 
     
     
         7 . The pharmaceutical formulation according to  claim 1 , wherein Zn(II) is present in a concentration from 0.0100 to 0.0600 mg/100 U of the analogue and/or derivative of insulin. 
     
     
         8 . The pharmaceutical formulation according to  claim 1 , wherein sodium chloride is present in a concentration from 0.01 to 15 mg/mL. 
     
     
         9 . The pharmaceutical formulation according to  claim 1 , wherein sodium chloride is present in a concentration from 6.8 to 8.3 mg/mL. 
     
     
         10 . The pharmaceutical formulation according to  claim 1 , wherein protamine is protamine sulfate which is present in a concentration from 0.1 to 0.5 mg/mL. 
     
     
         11 . The pharmaceutical formulation according to  claim 1 , wherein the pharmaceutical formulation is free of any additional buffering agent selected from the group consisting of 2-amino-2-hydroxymethyl-propane-1,3-diol (TRIS), phosphate, citric acid, citrate, acetic acid, acetate, glycylglycine and methionine. 
     
     
         12 . The pharmaceutical formulation according to  claim 1 , wherein the pharmaceutical formulation comprises one or more further active pharmaceutical ingredients. 
     
     
         13 . The pharmaceutical formulation according to  claim 12 , wherein the further active pharmaceutical ingredient is an antidiabetic agent. 
     
     
         14 . The pharmaceutical formulation according to  claim 12 , wherein the further active pharmaceutical ingredient is an antidiabetic agent selected from the group consisting of:
 (a). a GLP-1 receptor agonist;   (b). a dual GLP-1 receptor/glucagon receptor agonist;   (c). human FGF-21;   (d). an FGF-21 analogue;   (e). an FGF-21 derivative;   (f). insulin;   (g). human insulin;   (h). an analogue of insulin; and   (i). a derivative of insulin.   
     
     
         15 . The pharmaceutical formulation according to  claim 1 , wherein the pharmaceutical formulation comprises more than one analogue and/or derivative of insulin, wherein one analogue and/or derivative of insulin is a fast acting insulin and one analogue and/or derivative of insulin is a long acting insulin. 
     
     
         16 . The pharmaceutical formulation according to  claim 15 , wherein the fast acting insulin is one or more insulin selected from the group consisting of insulin aspart, insulin lispro, and insulin glulisine, and wherein the long acting insulin is one or more insulin selected from the group consisting of insulin detemir and insulin degludec. 
     
     
         17 . The pharmaceutical formulation according to  claim 1 , wherein the pharmaceutical formulation consists of:
 (a). 3.5 mg/mL insulin aspart;   (b). 1.72 mg/mL metacresol;   (c). 1.50 mg/mL phenol;   (d). 0.0196 mg/mL Zn(II);   (e). 6.8 mg/mL sodium chloride;   (f). 0.02 mg/mL polysorbate 20;   (g). sodium hydroxide and/or hydrochloric acid to adjust the pH to 7.4, and   (h). water.   
     
     
         18 . The pharmaceutical formulation according to  claim 1 , wherein the pharmaceutical formulation consists of:
 (a). 3.5 mg/mL insulin aspart;   (b). 1.72 mg/mL metacresol;   (c). 1.50 mg/mL phenol;   (d). 0.0196 mg/mL Zn(II);   (e). from 6.8 mg/mL to 8.3 mg/mL sodium chloride;   (f). 0.02 mg/mL polysorbate 20;   (g). from 0.1 mg/mL to 0.5 mg/mL protamine sulfate;   (h). sodium hydroxide and/or hydrochloric acid to adjust the pH to a pH in the range from 7.1 to 7.6; and   (i). water.   
     
     
         19 . A method for preparing the pharmaceutical formulation according to  claim 1 , wherein the components are mixed together in the form of a solution or suspension, the pH is adjusted to reach a desired pH, and water is added to reach a final volume. 
     
     
         20 . A kit comprising one or more separate packages of
 (a). the pharmaceutical formulation as claimed in  claim 1 ;   and   (b). a medical device.   
     
     
         21 . A kit comprising one or more separate packages of
 (a). the pharmaceutical formulation as claimed in  claim 1 ;   and   (b). at least one further active pharmaceutical ingredient;   (c). and optionally a medical device.   
     
     
         22 . The kit according to  claim 20 , wherein the further active pharmaceutical ingredient is an antidiabetic agent. 
     
     
         23 . The kit as claimed in  claim 20 , wherein the further active pharmaceutical ingredient is an antidiabetic agent selected from the group consisting of:
 (a). a GLP-1 receptor agonist;   (b). a dual GLP-1 receptor/glucagon receptor agonist;   (c). human FGF-21;   (d). an FGF-21 analogue;   (e). an FGF-21 derivative;   (f). insulin;   (g). human insulin;   (h). an analogue of insulin; and   (i). a derivative of insulin.   
     
     
         24 . The kit as claimed in  claim 20 , wherein the kit comprises more than one analogue and/or derivative of insulin, wherein one analogue and/or derivative of insulin is a fast acting insulin and one analogue and/or derivative of insulin is a long acting insulin. 
     
     
         25 . The kit according to  claim 24 , wherein the fast acting insulin is selected from the group consisting of insulin aspart, insulin lispro and insulin glulisine, and wherein the long acting insulin is selected from the group consisting of insulin glargin, insulin detemir and insulin degludec. 
     
     
         26 . The pharmaceutical formulation as claimed in  claim 1  for use in the treatment of diabetes mellitus. 
     
     
         27 . The pharmaceutical formulation as claimed in  claim 1  for use in the treatment of hyperglycemia. 
     
     
         28 . The pharmaceutical formulation as claimed in  claim 1  for use in lowering blood glucose level. 
     
     
         29 . A method of treating diabetes mellitus in a subject in need thereof comprising administering the pharmaceutical formulation of  claim 1 . 
     
     
         30 . A method of treating hyperglycemia in a subject in need thereof comprising administering the pharmaceutical formulation of  claim 1 . 
     
     
         31 . A method of lowering blood glucose levels in a subject in need thereof comprising administering the pharmaceutical formulation of  claim 1 . 
     
     
         32 . A medical device for administering the pharmaceutical formulation as claimed in  claim 1  to an animal and/or human.