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 therapeutic glatiramer or pramlintide peptide, wherein the peptide is not prepared by drying in the presence of a non-volatile buffer;
(b) an ionization stabilizing excipient, wherein the ionization stabilizing excipient is an acid; and
(c) an aprotic polar solvent;
wherein (i) the therapeutic peptide is dissolved in the aprotic solvent in an amount from about 0.1 mg/mL up to the solubility limit of the therapeutic peptide, and (ii) the ionization stabilizing excipient is dissolved in the aprotic polar solvent in an amount to stabilize the ionization of the therapeutic peptide.
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 1 , wherein the aprotic polar solvent is dimethyl sulfoxide (DMSO).
5. The formulation of claim 1 , wherein the aprotic polar solvent is a deoxygenated aprotic polar solvent.
6. The formulation of claim 5 , wherein the deoxygenated aprotic polar solvent is deoxygenated DMSO.
7. The formulation of claim 1 , wherein the ionization stabilizing excipient is a mineral acid and the aprotic polar solvent is DMSO.
8. The formulation of claim 1 , wherein the total moisture content is less than 5% w/w.
9. The formulation of claim 1 , further comprising a preservative at less than 10% w/v.
10. The formulation of claim 9 , wherein the preservative is benzyl alcohol.
11. The formulation of claim 1 , further comprising a sugar alcohol at less than 10% w/v.
12. The formulation of claim 11 , wherein the sugar alcohol is mannitol.