Methods for producing stable therapeutic glucagon formulations in aprotic polar solvents
Certain embodiments are directed to a formulation of a therapeutic agent, as well as a method of making such a formulation, comprising at least one therapeutic agent dissolved in an aprotic polar solvent system comprising at least one ionization stabilizing excipient in a concentration sufficient to impart physical and chemical stability to the therapeutic agent.
1. A stable formulation comprising:
(a) a glucagon peptide or salt thereof at a concentration of 5 mg/mL;
(b) sulfuric acid as an ionization stabilizing excipient at a concentration of between greater than 2.0 and up to 12.6 mM;
(c) dimethyl sulfoxide (DMSO) as an aprotic polar solvent; and
(d) trehalose at less than 10, 5, or 3% w/v;
wherein the glucagon peptide or salt thereof and sulfuric acid are dissolved directly in DMSO without drying the glucagon peptide or salt thereof from a buffered aqueous solution prior to reconstitution in DMSO.
2. The formulation of claim 1 , wherein the moisture content is less than 10, 5, or 3% w/w.
3. The formulation of claim 1 , further comprising a preservative at less than 10, 5, or 3% w/v.
4. The formulation of claim 3 , wherein the preservative is benzyl alcohol.
5. A method of treating hypoglycemia in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of the stable formulation of claim 1 .
6. The method of claim 5 , wherein the administering is by parenteral injection.
7. The method of claim 6 , wherein the injection is intracutaneous injection.
8. A method of preparing the stable formulation of claim 1 , wherein the method comprises the steps of: (a) mixing sulfuric acid with DMSO; and (b) dissolving the glucagon peptide or salt thereof directly in DMSO containing sulfuric acid without drying the glucagon peptide or salt thereof from a buffered aqueous solution prior to reconstitution in DMSO, wherein sulfuric acid is present in DMSO at a concentration of between greater than 2.0 and up to 12.6 mM.