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 comprising:
a) dissolving a compound in a substantially anhydrous solution to form a formulation, wherein the substantially anhydrous solution comprises:
i) about 65% propylene glycol (w/w);
ii) about 25% glycerin (w/w); and
iii) about 10% ethanol (w/w) of the formulation; and
b) storing the formulation for a day.
2. The method of claim 1 , further comprising storing the formulation for a week.
3. The method of claim 1 , further comprising storing the formulation for 1-12 months.
4. The method of claim 1 , wherein the formulation is stored at a temperature of 2° C. to 30° C.
5. The method of claim 1 , wherein the formulation is stored at a temperature of 2° C. to 6° C.
6. The method of claim 1 , wherein the formulation is stored at a temperature of 25° C.
7. The method of claim 1 , wherein the compound is a compound of Formula I:
(5-azacytosine group)-L-(guanine group) (I),
wherein L is a phosphorus-containing linker wherein the number of phosphorus atoms in L is 1, or a pharmaceutically-acceptable salt thereof.
8. The method of claim 1 , wherein the compound is present in the formulation at a concentration of 1 mg/mL to 130 mg/mL.
9. The method of claim 1 , wherein the compound is present in the formulation at a concentration of 80 mg/mL to 110 mg/mL.
10. The method of claim 7 , wherein the compound is a compound of the formula:
or a pharmaceutically acceptable salt thereof.
11. The method of claim 10 , wherein the pharmaceutically acceptable salt is a sodium salt.
12. The method of claim 1 , wherein the formulation retains about 65% efficacy after storage for 3 months at 25° C. and 60% relative humidity.
13. The method of claim 1 , further comprising, after (b), administering a therapeutically effective amount of the formulation to a subject in need thereof, wherein the administering treats a condition in the subject.
14. The method of claim 13 , wherein the administering inhibits DNA methylation in the subject.
15. The method of claim 13 , wherein the condition is a myelodysplastic syndrome.
16. The method of claim 13 , wherein the condition is leukemia.
17. The method of claim 13 , wherein the administration is subcutaneous administration.
18. The method of claim 1 , wherein the formulation further comprises dimethyl sulfoxide (DMSO).
19. The method of claim 18 , wherein DMSO is present in the formulation in an amount of up to about 200% w/w when compared to an amount of the compound present in the formulation.