Stable glucagon formulations for the treatment of hypoglycemia

Abstract

The delivery of biopharmaceutical and other therapeutic agents parenterally to an animal via a minimally invasive, low pain administration is provided. The agents are delivered to the patient via, e.g., the epidermal, dermal, or subcutaneous layer of the skin in a concentrated form of injectable glucagon that is dissolved in a pharmaceutically acceptable carrier.

What is claimed is: 
     
         1 . A stable glucagon composition, said composition comprising: glucagon or a glucagon analog that has been dried with a carbohydrate and a buffer having a pH of about 2.0 to about 3.5. 
     
     
         2 . The stable glucagon composition of  claim 1 , wherein said glucagon composition is reconstituted with a pharmaceutically acceptable carrier. 
     
     
         3 . The stable glucagon composition of  claim 2 , wherein said pharmaceutically acceptable carrier is an aqueous carrier. 
     
     
         4 . The stable glucagon composition of  claim 2 , wherein said pharmaceutically acceptable carrier is a non-aqueous carrier selected from the group consisting of lipids, aryl benzonates, alkyl benzonates and triacetin. 
     
     
         5 . The stable glucagon composition of  claim 3 , wherein said aqueous carrier is water. 
     
     
         6 . The stable glucagon composition of  claim 2 , wherein said glucagon composition is mixed with said pharmaceutically acceptable carrier to form a suspension. 
     
     
         7 . The stable glucagon composition of  claim 2 , wherein said glucagon composition is mixed with said pharmaceutically acceptable carrier to form a paste. 
     
     
         8 . The stable glucagon composition of  claim 4 , wherein said non-aqueous carrier is selected from the group consisting of triacetin, benzyl benzoate, miglyol, palm oil and mineral oil. 
     
     
         9 . The stable glucagon composition of  claim 1 , wherein said buffer has a pH of about 3.0. 
     
     
         10 . The stable glucagon composition of  claim 1 , wherein said buffer is selected from a glycine buffer, a citrate buffer, a phosphate buffer and mixture thereof. 
     
     
         11 . The stable glucagon composition of  claim 10 , wherein said buffer is a glycine buffer. 
     
     
         12 . The stable glucagon composition of  claim 10 , wherein said buffer is a citrate buffer. 
     
     
         13 . The stable glucagon composition of  claim 1 , wherein said carbohydrate is selected from the group consisting of sugars and starches. 
     
     
         14 . The stable glucagon composition of  claim 13 , wherein said carbohydrate is selected from the group consisting of trehalose, hydroxyethyl starch (HES), dextran and mixtures thereof. 
     
     
         15 . The stable glucagon composition of  claim 14 , wherein said carbohydrate is trehalose. 
     
     
         16 . The stable glucagon composition of  claim 14 , wherein said carbohydrate is hydroxyethyl starch (HES). 
     
     
         17 . The stable glucagon composition of  claim 14 , wherein said carbohydrate is a mixture of trehalose and hydroxyethyl starch (HES). 
     
     
         18 . The stable glucagon composition of  claim 1 , further comprising a surfactant. 
     
     
         19 . The stable glucagon composition of  claim 18 , wherein said surfactant is polysorbate 20 (Tween® 20). 
     
     
         20 . The stable glucagon composition of  claim 1 , further comprising an antioxidant. 
     
     
         21 . The stable glucagon composition of  claim 20 , wherein the antioxidant is selected from the group consisting of ascorbic acid, cysteine, methionine, monothioglycerol, sodium thiosulphate, sulfites, BHT, BHA, ascorbyl palmitate, propyl gallate, and Vitamin E. 
     
     
         22 . The stable glucagon composition of  claim 1 , further comprising a chelator. 
     
     
         23 . The stable glucagon composition of  claim 22 , wherein the chelator is selected from the group consisting of EDTA, tartaric acid and salts thereof, glycerin, and citric acid and salts thereof. 
     
     
         24 . The stable glucagon composition of  claim 1 , further comprising a preservative. 
     
     
         25 . The stable glucagon composition of  24 , wherein in the preservative is selected from the group consisting of benzyl alcohols, methyl parabens and propyl parabens. 
     
     
         26 . A stable pharmaceutical formulation for parenteral injection, said pharmaceutical formulation comprising: glucagon or a glucagon analog that has been dried with a carbohydrate and a buffer having a pH of about 2.0 to about 3.5, and a pharmaceutically acceptable carrier or diluent. 
     
     
         27 . A method for treating a disease, condition or disorder that may be treated, alleviated or prevented by administering to a subject the pharmaceutical formulation of  claim 26  in an amount effective to treat, alleviate or prevent the disease, condition or disorder. 
     
     
         28 . The method of  claim 27 , wherein the disease, condition or disorder comprises hypoglycemia. 
     
     
         29 . The method of  claim 27 , wherein said administration is accomplished via use of a pen injection device. 
     
     
         30 . The method of  claim 27 , wherein said administration is accomplished via use of an auto-injector device. 
     
     
         31 . The use of the pharmaceutical formulation of  claim 26  for the treatment of a disease, condition or disorder that may be treated, alleviated or prevented by administering a glucagon or glucagon analog. 
     
     
         32 . The use of  claim 31 , wherein the disease, condition or disorder is hypoglycemia. 
     
     
         33 . The use of any one of  claims 31 , wherein the administration is parenteral administration. 
     
     
         34 . The use of  claim 31 , wherein said administration is accomplished via use of a pen injection device. 
     
     
         35 . The use of  claim 31 , wherein said administration is accomplished via use of a auto-injector device. 
     
     
         36 . A stable pharmaceutical formulation for parenteral injection, said pharmaceutical formulation consisting essentially of glucagon or a glucagon analog that has been dried with a carbohydrate and a buffer having a pH of about 2.0 to about 3.5, and a pharmaceutically acceptable carrier or diluent. 
     
     
         37 . A method for treating hypoglycemia in a subject in need thereof, said method comprising administering to said subject the pharmaceutical formulation of  claim 26  in an amount effective to treat hypoglycemia.