Stable formulations for parenteral injection of peptide drugs

Abstract

Stable formulations for parenteral injection of peptide drugs and methods of using such stable formulations are provided. In particular, the present invention provides stable formulations for parenteral injection of glucagon and methods of using such glucagon formulations to treat hypoglycemia, especially severe hypoglycemia in emergency situations.

1 .- 98 . (canceled) 
     
     
         99 . A stable formulation for parenteral injection, comprising:
 (a) a glucagon analog peptide or salt thereof, wherein the glucagon analog peptide has been dried in a non-volatile buffer, and wherein the dried glucagon analog peptide has a pH memory that is about equal to the pH of the glucagon analog peptide in the non-volatile buffer; and   (b) an aprotic polar solvent;   wherein the moisture content of the formulation is less than 5%; and   wherein the dried glucagon analog peptide maintains the pH memory that is about equal to the pH of the glucagon analog peptide in the non-volatile buffer when the dried glucagon analog peptide is reconstituted in the aprotic polar solvent.   
     
     
         100 . The formulation in accordance with  claim 99 , wherein the non-volatile buffer is selected from a glycine buffer, a citrate buffer, a phosphate buffer, and mixtures thereof. 
     
     
         101 . The formulation in accordance with  claim 100 , wherein the non-volatile buffer is a glycine buffer. 
     
     
         102 . The formulation in accordance with  claim 99 , wherein the aprotic polar solvent is selected from dimethylsulfoxide (DMSO), n-methyl pyrrolidone (NMP), ethyl acetate, and mixtures thereof. 
     
     
         103 . The formulation in accordance with  claim 102 , wherein the aprotic polar solvent is DMSO. 
     
     
         104 . The formulation in accordance with  claim 99 , further comprising a co-solvent that depresses the freezing point of the formulation, wherein the co-solvent is selected from ethanol, propylene glycol, glycerol, and mixtures thereof. 
     
     
         105 . The formulation in accordance with  claim 104 , wherein the co-solvent is ethanol or propylene glycol. 
     
     
         106 . The formulation in accordance with  claim 104 , wherein the co-solvent is present in the formulation in an amount ranging from about 10% (w/v) to about 50% (w/v). 
     
     
         107 . The formulation in accordance with  claim 99 , further comprising a stabilizing excipient. 
     
     
         108 . The formulation in accordance with  claim 107 , wherein the stabilizing excipient is selected from a sugar, a starch, and mixtures thereof. 
     
     
         109 . The formulation in accordance with  claim 108 , wherein the stabilizing excipient is a sugar. 
     
     
         110 . The formulation in accordance with  claim 109 , wherein the sugar is trehalose. 
     
     
         111 . The formulation in accordance with  claim 108 , wherein the stabilizing excipient is a starch. 
     
     
         112 . The formulation in accordance with  claim 111 , wherein the starch is hydroxyethyl starch (HES). 
     
     
         113 . The formulation in accordance with  claim 108 , wherein the stabilizing excipient is present in the formulation in an amount ranging from about 1% (w/v) to about 60% (w/v). 
     
     
         114 . The formulation in accordance with  claim 99 , wherein the moisture content of the formulation is from about 0.01% to about 3%. 
     
     
         115 . The formulation in accordance with  claim 99 , wherein the moisture content of the formulation is less than about 2%. 
     
     
         116 . The formulation in accordance with  claim 99 , wherein the pH memory of the glucagon analog peptide when reconstituted in the aprotic polar solvent is within one pH unit of the pH of the glucagon analog peptide in the non-volatile buffer. 
     
     
         117 . The formulation in accordance with  claim 99 , wherein the pH memory of the glucagon analog peptide when reconstituted in the aprotic polar solvent is within a half of a pH unit of the pH of the glucagon analog peptide in the non-volatile buffer. 
     
     
         118 . The formulation in accordance with  claim 99 , wherein the glucagon analog peptide is present in the formulation in an amount ranging from about 0.5 mg/mL to about 100 mg/mL. 
     
     
         119 . The formulation in accordance with  claim 118 , wherein the glucagon analog peptide is present in the formulation in an amount ranging from about 1 mg/mL to about 50 mg/mL. 
     
     
         120 . The formulation in accordance with  claim 99 , wherein the glucagon analog peptide is a hydrochloride salt or an acetate salt. 
     
     
         121 . The formulation in accordance with  claim 99 , wherein the formulation is stable for at least one month at 40° C. 
     
     
         122 . The formulation in accordance with  claim 99 , wherein the formulation is stable for at least one year at room temperature. 
     
     
         123 . The formulation in accordance with  claim 99 , wherein the formulation is administered to a subject via the use of a syringe. 
     
     
         124 . The formulation in accordance with  claim 99 , wherein the formulation is administered to a subject via the use of a pen injection device. 
     
     
         125 . The formulation in accordance with  claim 99 , wherein the formulation is administered to a subject via the use of an auto-injector device. 
     
     
         126 . The formulation in accordance with  claim 99 , wherein the formulation is administered via the use of a pump. 
     
     
         127 . A stable formulation for parenteral administration, comprising:
 (a) a first peptide or salt thereof, wherein the first peptide or salt thereof is a glucagon analog peptide or salt thereof, wherein the glucagon analog peptide has been dried in a first non-volatile buffer, and wherein the dried glucagon analog peptide has a pH memory that is about equal to the pH of the glucagon analog peptide in the non-volatile buffer; and   (b) a second peptide or salt thereof, wherein the second peptide or salt thereof is selected from the group consisting of pramlintide, insulin, leuprolide, an LHRH agonist, parathyroid hormone (PTH), amylin, botulinum toxin, hematide, an amyloid peptide, cholecystokinin, a conotoxin, a gastric inhibitory peptide, an insulin-like growth factor, a growth hormone releasing factor, an anti-microbial factor, glatiramer, glucagon-like peptide-1 (GLP-1), a GLP-1 agonist, exenatide, analogs thereof, and mixtures thereof; wherein the second peptide or salt thereof has been dried in a second non-volatile buffer, and wherein the second dried peptide has a second pH memory that is about equal to the pH of the second peptide in the second non-volatile buffer; and   (c) an aprotic polar solvent, selected from dimethylsulfoxide (DMSO), n-methyl pyrrolidone (NMP), ethyl acetate, and mixtures thereof; wherein the moisture content of the formulation is less than 5%, wherein the first dried peptide maintains the first pH memory that is about equal to the pH of the first peptide in the first non-volatile buffer when the first dried peptide is reconstituted in the aprotic polar solvent, and wherein the second dried peptide maintains the second pH memory that is about equal to the pH of the second peptide in the second non-volatile buffer when the second dried peptide is reconstituted in the aprotic polar solvent.   
     
     
         128 . The formulation in accordance with  claim 127 , wherein the first peptide is a glucagon analog peptide and the second peptide is exenatide. 
     
     
         129 . The formulation in accordance with  claim 127 , further comprising a co-solvent that depresses the freezing point of the formulation, wherein the co-solvent is selected from ethanol, propylene glycol, glycerol, and mixtures thereof. 
     
     
         130 . The formulation in accordance with  claim 127 , further comprising a stabilizing excipient. 
     
     
         131 . The formulation in accordance with  claim 130 , wherein the stabilizing excipient is selected from sugars, starches, and mixtures thereof.