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 these 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 suitable for administration by infusion or injection, the formulation comprising:
gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate;
a polar aprotic solvent;
an aqueous vehicle; and
two or more solubilizers.
2. The formulation of claim 1 , wherein the polar aprotic solvent is selected from dimethyl acetamide (DMA), dimethylsulfoxide (DMSO) and N-methypyrrolidone (NMP).
3. The formulation according to claim 1 , wherein the aqueous vehicle is saline.
4. The formulation according to claim 1 , wherein the aqueous vehicle is WFI.
5. The formulation according to claim 1 , wherein at least one of the two or more solubilizers is a polyethoxylated fatty acid or a mixture thereof.
6. The formulation according to claim 1 , wherein each of the two or more solubilizers is a polyethoxylated fatty acid or a mixture thereof.
7. The formulation of claim 1 , wherein the polar aprotic solvent represents from 30% to 95% by volume of the formulation.
8. The formulation of claim 7 , wherein the polar aprotic solvent represents from 60% to 90% by volume of the formulation.
9. The formulation according to claim 1 , wherein the aqueous vehicle represents 5% to 50% by volume of the formulation.
10. The formulation according to claim 9 , wherein the aqueous vehicle represents from 10% to 30% by volume of the formulation.
11. The formulation according to claim 1 , wherein the concentration of the gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate in the formulation solvent(s) is from 100 mg to 500 mg per mL.
12. The formulation according to claim 11 , wherein the concentration of the gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate in the formulation solvent(s) is from 200 mg to 300 mg per mL.
13. The formulation according to claim 1 , wherein the gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate is in the form of a mixture of phosphate diastereoisomers.
14. The formulation according to 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%.
15. A method of treating cancer, the method comprising administering by infusion or injection to a subject in need thereof a pharmaceutical formulation comprising:
gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate;
a polar aprotic solvent;
an aqueous vehicle; and
two or more solubilizers.
16. The method according to claim 15 , wherein the gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate is in the form of a mixture of phosphate diastereoisomers.
17. The method according to claim 15 , wherein the gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate is in the form of the (S)-phosphate epimer in diastereomeric purity of greater than 90%.
18. The method according to claim 15 , the method further comprising the steps of:
diluting a solution comprising gemcitabine[phenyl-(benzoxy-L-alaninyl)]-phosphate, a polar aprotic solvent and two or more solubilizers 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.
19. The method according to claim 18 , wherein the administration step is carried out up to 48 hours after the dilution step.
20. 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, a polar aprotic solvent and two or more solubilizers with an aqueous vehicle to provide the formulation for infusion or injection.