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;
(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.
5 . The formulation of claim 1 , wherein the aprotic solvent is 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, 5, or 3% w/v.
10 . The formulation of claim 1 , further comprising a preservative at less than 10, 5, or 3% 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, 5, or 3% w/v.
13 . The formulation of claim 12 , wherein the sugar alcohol is mannitol.
14 . A method of treating hypoglycemia by administering an effective amount of a formulation of claim 1 to subject in need thereof.
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.
17 . A method of stably formulating a glucagon peptide comprising the steps of:
(a) determining an appropriate ionization profile for the glucagon peptide or a salt thereof in an aprotic polar solvent system;
(b) mixing at least one ionization stabilizing excipient with the aprotic solvent to impart the appropriate concentration of the at least one ionization stabilizing excipient to establish the ionization profile determined in step (a); and
(c) dissolving the glucagon peptide or salt thereof in the aprotic solvent having an appropriate ionization stabilizing excipient concentration to physically and chemically stabilize the glucagon peptide or salt thereof for at least one year at room temperature.
18 . The method of claim 17 , wherein the ionization stabilizing excipient is hydrochloric acid, Glycine, trimethylglycine, or a combination thereof.
19 . The method of claim 17 , wherein the ionization stabilizing excipient concentration is between 0.1 mM to 100 mM.
20 . The method of claim 17 , wherein the aprotic solvent is DMSO.