Formulation comprising a gemcitabine-prodrug
This invention relates to pharmaceutical formulations of gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate, a monophosphate derivative of the well-known oncology drug gemcitabine. In particular, the invention relates to formulations which comprise a polar aprotic solvent, preferably dimethyl acetamide (DMA). Formulations comprising this solvent provide therapeutically effective treatments of gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate. The invention also relates to methods of using said formulations and kits comprising said formulations.
1. A pharmaceutical formulation, comprising:
gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate;
a polar aprotic solvent; and
optionally one or more pharmaceutically acceptable excipients.
2. The formulation of claim 1 , wherein the polar aprotic solvent is selected from the group consisting of dimethyl acetamide (DMA), dimethylsulfoxide (DMSO), and N-methypyrrolidone (NMP).
3. The formulation of claim 1 , wherein the polar aprotic solvent represents from 30% to 95% by volume of the formulation.
4. The formulation of claim 3 , wherein the polar aprotic solvent represents from 60% to 90% by volume of the formulation.
5. The formulation of claim 1 , further comprising an aqueous vehicle.
6. The formulation of claim 5 , wherein the aqueous vehicle is saline.
7. The formulation of claim 5 , wherein the aqueous vehicle is water for injection (WFI).
8. The formulation of claim 5 , wherein the aqueous vehicle represents 5% to 50% by volume of the formulation.
9. The formulation of claim 8 , wherein the aqueous vehicle represents from 10% to 30% by volume of the formulation.
10. The formulation of claim 1 , wherein the concentration of the gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate in the formulation is from 100 mg per mL to 500 mg per mL.
11. The formulation of claim 10 , wherein the concentration of the gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate in the formulation is from 200 mg per mL to 300 mg per mL.
12. The formulation of claim 1 , further comprising at least one solubilizer.
13. The formulation of claim 12 , wherein the formulation comprises two or more solubilizers.
14. The formulation of claim 12 , wherein at least one solubilizer is a polyethoxylated fatty acid or a mixture thereof.
15. The formulation of claim 1 , wherein the gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate is in the form of a mixture of phosphate diastereoisomers.
16. The formulation of claim 1 , wherein the gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate is in the form of the (S)-phosphate epimer in diastereomeric purity of greater than 90%.
17. The formulation of claim 1 , wherein the formulation is for intravenous administration.
18. The formulation of claim 1 , wherein dilution with an aqueous vehicle forms a formulation for infusion or injection.
19. A method of treating cancer, the method comprising administering to a subject in need thereof a pharmaceutical formulation comprising:
gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate; and
a polar aprotic solvent.
20. The method according to claim 19 , the method further comprising the steps of:
diluting a solution comprising gemcitabine[phenyl-(benzoxy-L-alaninyl)]-phosphate and a polar aprotic solvent with an aqueous vehicle to provide a formulation for infusion or injection; and
administering the formulation for infusion or injection to the subject by infusion or injection.
21. The method according to claim 20 , wherein the administration step is carried out up to 48 hours after the dilution step.
22. The method according to claim 19 , wherein the gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate is in the form of a mixture of phosphate diastereoisomers.
23. The method according to claim 19 , wherein the gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate is in the form of the (S)-phosphate epimer in diastereomeric purity of greater than 90%.
24. A method of preparing a pharmaceutical formulation of gemcitabine[phenyl-(benzoxy-L-alaninyl)]-phosphate for infusion or injection, the method comprising:
diluting a solution comprising gemcitabine[phenyl-(benzoxy-L-alaninyl)]-phosphate and a polar aprotic solvent with an aqueous vehicle to provide the formulation for infusion or injection.