Methods for producing stable therapeutic 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, wherein the glucagon peptide or salt thereof is not prepared by drying in the presence of a non-volatile buffer having a pH of 2 to 4 to produce a glucagon peptide having a pH memory of 2 to 4;
(b) an ionization stabilizing excipient; and
(c) an aprotic polar solvent;
wherein (i) the glucagon peptide or salt thereof is dissolved in the aprotic solvent in an amount from about 0.1 mg/mL up to the solubility limit of the glucagon peptide or salt thereof, and (ii) the ionization stabilizing excipient is dissolved in the aprotic solvent in an amount to stabilize the ionization of the glucagon peptide or salt thereof.
2. The formulation of claim 1 , wherein the ionization stabilizing excipient is at a concentration of 0.1 mM to less than 100 mM.
3. The formulation of claim 1 , wherein the ionization stabilizing excipient is a mineral acid.
4. The formulation of claim 3 , wherein the mineral acid is hydrochloric acid (HCl).
5. The formulation of claim 1 , wherein the aprotic solvent is dimethylsulfoxide (DMSO).
6. The formulation of claim 1 , wherein the aprotic solvent is a deoxygenated aprotic solvent.
7. The formulation of claim 6 , wherein the deoxygenated aprotic solvent is deoxygenated DMSO.
8. The formulation of claim 1 , wherein the ionization stabilizing excipient is HCl and the aprotic solvent is DMSO.
9. The formulation of claim 1 , wherein the moisture content is less than 10% (w/w).
10. The formulation of claim 1 , further comprising a preservative at less than 10% w/v.
11. The formulation of claim 10 , wherein the preservative is benzyl alcohol.
12. The formulation of claim 1 , further comprising a sugar alcohol at less than 10% w/v.
13. The formulation of claim 12 , wherein the sugar alcohol is trehalose.
14. A method of treating hypoglycemia in a subject in need thereof, the method comprising the step of administering an effective amount of the formulation of claim 1 .
15. The method of claim 14 , wherein the administering is by parenteral injection.
16. The method of claim 15 , wherein the injection is intracutaneous injection.