Drug formulations
View Patent ↗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 tumors using the formulations are described.
1. 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 formulation of claim 1 , wherein said solvent comprises 60% to 70% propylene glycol; 20% to 30% glycerin; and 5% to 15% ethanol (w/w/w).
3. The formulation of claim 1 , wherein said solvent consists essentially of about 60% to about 70% propylene glycol; about 20% to about 30% glycerin; and about 5% to about 15% ethanol (w/w/w).
4. The formulation of claim 1 , wherein said solvent consists essentially of 60% to 70% propylene glycol; 20% to 30% glycerin; and 5% to 15% ethanol (w/w/w).
5. The formulation of claim 1 , wherein said solvent is about 60% to about 70% propylene glycol; about 20% to about 30% glycerin; and about 5% to about 15% ethanol (w/w/w).
6. The formulation of claim 1 , wherein said solvent is 60% to 70% propylene glycol; 20% to 30% glycerin; and 5% to 15% ethanol (w/w/w).
7. The formulation of claim 1 , wherein said solvent comprises about 65% propylene glycol; about 25% glycerin; and about 10% ethanol (w/w/w).
8. The formulation of claim 1 , wherein said solvent comprises 65% propylene glycol; 25% glycerin; and 10% ethanol (w/w/w).
9. The formulation of claim 1 , wherein said solvent consists essentially of about 65% propylene glycol; about 25% glycerin; and about 10% ethanol (w/w/w).
10. The formulation of claim 1 , wherein said solvent is about 65% propylene glycol; about 25% glycerin; and about 10% ethanol (w/w/w).
11. The formulation of claim 1 , wherein said salt is a sodium salt.
12. The formulation of claim 1 , wherein the compound or pharmaceutically-acceptable salt thereof is present at a concentration of about 80 mg/mL to about 110 mg/mL.
13. The formulation of claim 1 , further comprising DMSO.
14. The formulation of claim 13 , wherein the DMSO is present at a DMSO:compound ratio of about 2: about 1; about 1: about 1; about 0.5: about 1; about 0.3: about 1; or about 0.2-about 0.3: about 1.
15. The formulation of claim 1 , suitable for administration by subcutaneous injection.
16. A kit comprising:
(a) a first vessel containing a compound of the formula:
or a pharmaceutically-acceptable salt thereof; and
(b) a second vessel containing 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).
17. The kit of claim 16 , wherein the compound or pharmaceutically-acceptable salt thereof is lyophilized.
18. The kit of claim 16 , wherein the first vessel contains about 80 mg to about 110 mg of said compound or pharmaceutically-acceptable salt thereof.
19. The kit of claim 16 , wherein the first vessel contains about 100 mg of said compound or pharmaceutically-acceptable salt thereof.
20. The kit of claim 16 , further comprising instructions for administration by subcutaneous injection.
21. The kit of claim 16 , wherein the compound or pharmaceutically-acceptable salt thereof is in the form of a substantially anhydrous powder.
22. The kit of claim 21 , wherein the substantially anhydrous powder consists essentially of said compound or pharmaceutically-acceptable salt thereof and DMSO, the DMSO being present in an amount of up to about 200% w/w.
23. The kit of claim 22 , wherein the DMSO is present in an amount of up to about 100%, up to about 60%, up to about 50%, up to about 40% or up to about 30% w/w.
24. The kit of claim 22 , wherein the DMSO is present in an amount of about 20 to about 30% w/w.
25. A process for preparing a pharmaceutical composition comprising dissolving a compound of the formula:
or a pharmaceutically-acceptable salt thereof, in 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).
26. The process of claim 25 , further comprising:
(a) dissolving said compound or pharmaceutically-acceptable salt thereof in DMSO to produce a solution of said compound in DMSO; and
(b) lyophilizing said solution of step (a) to provide a substantially anhydrous powder.
27. A method for treating a condition, the method comprising administering to a subject in need thereof 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 condition is cancer, myelodysplastic syndrome, leukemia, or solid tumour.
28. The method of claim 27 , wherein the condition is cancer.
29. The method of claim 27 , wherein the condition is myelodysplastic syndrome.
30. The method of claim 27 , wherein the condition is leukemia.
31. The method of claim 27 , wherein the condition is solid tumour.
32. The method of claim 27 , wherein the administration is subcutaneous administration.
33. The method of claim 27 , wherein said solvent comprises about 65% propylene glycol; about 25% glycerin; and about 10% ethanol (w/w/w).
34. The method of claim 27 , wherein said salt is a sodium salt.
35. The method of claim 27 , 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.
36. The method of claim 27 , wherein the formulation further comprises DMSO.
37. The method of claim 30 , wherein the leukemia is acute myeloid leukemia.
38. The method of claim 30 , wherein the leukemia is acute promyelocytic leukemia.
39. The method of claim 30 , wherein the leukemia is acute lymphoblastic leukemia.
40. The method of claim 30 , wherein the leukemia is chronic myelogenous leukemia.