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 comprising:
gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate;
dimethyl acetamide (DMA); and
optionally one or more pharmaceutically acceptable excipients.
2. The formulation according to claim 1 , further comprising an aqueous vehicle.
3. The formulation according to claim 2 , wherein the aqueous vehicle is saline.
4. The formulation according to claim 2 , wherein the aqueous vehicle is water for injection (WFI).
5. The formulation according to claim 1 , further comprising at least one solubilizer.
6. The formulation according to claim 5 , wherein the formulation comprises two or more solubilizers.
7. The formulation according to claim 5 , wherein each solubilizer is a polyethoxylated fatty acid or a mixture thereof.
8. The formulation according to claim 1 , wherein the formulation comprises:
from 30% to 95% by volume DMA;
from 5% to 50% by volume aqueous vehicle; and
from 100 mg to 300 mg per ml gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate.
9. The formulation according to claim 1 , wherein the formulation comprises:
from 20% to 80% by volume DMA;
from 30% to 80% by volume solubilizer or solubilizers; and
from 50 mg to 150 mg per ml gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate.
10. The formulation according to claim 9 , wherein the formulation comprises:
from 20% to 80% by volume DMA;
from 20% to 60% by volume a first solubilizer;
from 10% to 40% by volume a second solubilizer; and
from 50 mg to 150 mg per ml gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate.
11. The formulation of claim 10 , further comprising from 3% to 15% by volume aqueous vehicle.
12. The formulation according to claim 1 , wherein the formulation comprises:
from 0.5% to 7.5% by volume DMA;
from 0.5% to 7.5% by volume solubilizer or solubilizers;
from 85% to 99% by volume aqueous vehicle and
from 2.0 mg to 12.0 mg per ml gemcitabine-[phenyl-(benzoxy-L-alaninyl)]phosphate.
13. The formulation according to claim 1 wherein the formulation is for intravenous administration.
14. The formulation according to claim 1 wherein dilution with an aqueous vehicle forms a formulation for intravenous administration.
15. The formulation according to claim 1 , wherein the gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate is in the form of a mixture of phosphate diastereoisomers.
16. The formulation according to claim 1 , wherein the gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate is in the form of the (S)-phosphate epimer in substantially diastereomerically pure form.
17. A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical formulation comprising:
gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate; and
dimethyl acetamide (DMA).
18. The method according to claim 17 , further comprising the steps of:
diluting a solution comprising gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate and DMA 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. The method according to claim 17 , wherein the gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate is in the form of a mixture of phosphate diastereoisomers.
21. The method according to claim 17 , wherein the gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate is in the form of the (S)-phosphate epimer in substantially diastereomerically pure form.
22. The method according to claim 17 , further comprising the steps of:
diluting a solution comprising gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate and DMA with a diluent solution to provide an intermediate formulation, said first diluent solution comprising at least one solubilizer;
diluting the intermediate formulation 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.
23. The method according to claim 22 , wherein at least one solubilizer is a polyethoxylated fatty acid or a mixture thereof.
24. A method of preparing a pharmaceutical formulation of gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate for infusion or injection, comprising:
diluting a solution comprising gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate and dimethyl acetamide (DMA) with an aqueous vehicle to provide the formulation for infusion or injection.
25. The method according to claim 24 , the method further comprising the steps of:
diluting a solution comprising gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate and DMA with a diluent solution to provide an intermediate formulation, said first diluent solution comprising at least one solubilizer;
diluting the intermediate formulation with an aqueous vehicle to provide the formulation for infusion or injection.
26. The method according to claim 25 , wherein at least one solubilizer is a polyethoxylated fatty acid or a mixture thereof.
27. A kit comprising:
a first formulation comprising:
from 30% to 95% by volume dimethyl acetamide (DMA);
from 5% to 50% by volume aqueous vehicle; and
from 100 mg to 400 mg per ml gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate; and
a second formulation comprising:
from 10% to 40% by volume DMA;
from 20% to 60% by volume a first solubilizer; and
from 30% to 80% by volume a second solubilizer.
28. The kit according to claim 27 , wherein the gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate is in the form of a mixture of phosphate diastereoisomers.
29. The kit according to claim 27 , wherein the gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate is in the form of the (S)-phosphate epimer in substantially diastereomerically pure form.