Drug formulations
The invention provides derivatives of decitabine with superior chemical stability and shelf life, with similar physiological activity. The derivatives are provided in a non-aqueous formulation, which further stabilizes the derivatives. Methods of treating one or more myelodysplastic syndromes, leukemia, or solid tumours using the formulations are described.
1. A method of inhibiting DNA methylation in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a formulation comprising:
(a) a compound of the formula:
or a pharmaceutically-acceptable salt thereof; in
(b) a substantially anhydrous solvent comprising about 60% to about 70% propylene glycol; about 20% to about 30% glycerin; and about 5% to about 15% ethanol (w/w/w).
2. The method of claim 1 , wherein the administration is subcutaneous administration.
3. The method of claim 1 , wherein the solvent comprises about 65% propylene glycol; about 25% glycerin; and about 10% ethanol (w/w/w).
4. The method of claim 1 , wherein the salt is a sodium salt.
5. The method of claim 1 , wherein the compound or pharmaceutically-acceptable salt thereof is present in the formulation at a concentration of about 80 mg/mL to about 110 mg/mL.
6. The method of claim 1 , wherein the formulation comprises DMSO.
7. The method of claim 1 , wherein the inhibition of DNA methylation in the subject increases expression of a gene in the subject.
8. The method of claim 1 , wherein the inhibition of DNA methylation in the subject decreases angiogenesis in the subject.
9. A formulation comprising:
(a) a compound of the formula:
or a pharmaceutically-acceptable salt thereof; in
(b) a substantially anhydrous solvent comprising about 60% to about 70% propylene glycol; about 20% to about 30% glycerin; and about 5% to about 15% ethanol (w/w/w),
wherein the compound or the pharmaceutically acceptable salt thereof exhibits a decomposition rate that is lower than a corresponding formulation comprising the compound or the pharmaceutically acceptable salt thereof without the substantially anhydrous solvent.
10. The formulation of claim 9 , wherein the compound or the pharmaceutically salt thereof exhibits a solubility in the substantially anhydrous solvent from about 130 mg/mL to about 150 mg/mL.
11. The formulation of claim 9 , wherein the solvent comprises about 65% propylene glycol; about 25% glycerin; and about 10% ethanol (w/w/w).
12. The formulation of claim 9 , wherein the salt is a sodium salt.
13. The formulation of claim 9 , wherein the compound or pharmaceutically-acceptable salt thereof is present in the formulation at a concentration of about 80 mg/mL to about 110 mg/mL.
14. The formulation of claim 9 , wherein the formulation comprises DMSO.