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); and   (c). optionally protamine,   wherein the pharmaceutical formulation is free of glycerol.   
     
     
         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 6.0 to 9.0. 
     
     
         4 . The pharmaceutical formulation according to  claim 3 , wherein
 the pharmaceutical formulation has a pH value in the range from 7.0 to 7.8.   
     
     
         5 . 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. 
     
     
         6 . The pharmaceutical formulation according to  claim 1 , wherein the derivative of insulin is selected from the group comprising insulin detemir and/or insulin degludec. 
     
     
         7 . 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. 
     
     
         8 . 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. 
     
     
         9 . The pharmaceutical formulation according to  claim 1 , wherein said pharmaceutical formulation further comprises sodium chloride. 
     
     
         10 . The pharmaceutical formulation according to  claim 9 , wherein sodium chloride is present in a concentration from 5.0 to 15 mg/mL. 
     
     
         11 . The pharmaceutical formulation according to  claim 9 , wherein sodium chloride is present in a concentration from 5.6 to 6.8 mg/mL. 
     
     
         12 . The pharmaceutical formulation according to  claim 1 , wherein protamine is present in a concentration from 0.1 to 0.5 mg/mL. 
     
     
         13 . The pharmaceutical formulation according to  claim 1 , wherein the pharmaceutical formulation comprises one or more further active pharmaceutical ingredients. 
     
     
         14 . The pharmaceutical formulation according to  claim 13 , wherein the further active pharmaceutical ingredient is an antidiabetic agent. 
     
     
         15 . The pharmaceutical formulation according to  claim 13 , 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.   
     
     
         16 . 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. 
     
     
         17 . The pharmaceutical formulation according to  claim 16 , 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. 
     
     
         18 - 19 . (canceled) 
     
     
         20 . 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. 
     
     
         21 . A kit comprising one or more separate packages of
 (a). the pharmaceutical formulation according to  claim 1 ; and   (b). a medical device.   
     
     
         22 . A kit comprising one or more separate packages of
 (a). the pharmaceutical formulation according to  claim 1 ;   (b). at least one further active pharmaceutical ingredient; and   (c). optionally a medical device.   
     
     
         23 . The kit according to  claim 22 , wherein the further active pharmaceutical ingredient is an antidiabetic agent. 
     
     
         24 . The kit according to  claim 22 , 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). a FGF-21 analogue;   (e). a FGF-21 derivative;   (f). insulin;   (g). human insulin;   (h). an analogue of insulin; and   (i). a derivative of insulin.   
     
     
         25 . The kit according to  claim 21 , 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. 
     
     
         26 . The kit according to  claim 25 , 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. 
     
     
         27 . A method of treating diabetes mellitus in a subject in need thereof comprising using the kit of  claim 21  to administer to the subject the pharmaceutical formulation of the kit employing the medical device of the kit. 
     
     
         28 . A method of treating hyperglycemia in a subject in need thereof comprising using the kit of  claim 21  to administer to the subject the pharmaceutical formulation of the kit employing the medical device of the kit. 
     
     
         29 . A method of lowering blood glucose level in a subject in need thereof comprising using the kit of  claim 21  to administer to the subject the pharmaceutical formulation of the kit employing the medical device of the kit. 
     
     
         30 . A method of treating diabetes mellitus in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the pharmaceutical formulation of  claim 1 . 
     
     
         31 . A method of treating hyperglycemia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the pharmaceutical formulation of  claim 1 . 
     
     
         32 . A method of lowering blood glucose levels in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the pharmaceutical formulation of  claim 1 . 
     
     
         33 . A medical device comprising the pharmaceutical formulation as claimed in  claim 1 , for administering the pharmaceutical formulation to an animal and/or human.