Formulation comprising a gemcitabine-prodrug

Patent metadata

Field	Value
Publication number	US-10117888-B2
Application number	US-201515308475-A
Country	US
Kind code	B2
Filing date	Jun 25, 2015
Priority date	Jun 25, 2014
Publication date	Nov 6, 2018
Grant date	Nov 6, 2018

Abstract

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.

First claim

The invention claimed is:

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.

Assignees

• NuCana plc

Inventors

• Griffith Hugh
• Kennovin Gordon

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K47/22 Primary

  Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones · CPC title

• A61K9/08 Primary

  Solutions {(composition of solutions A61K47/00)} · CPC title

• A61K47/16

  containing nitrogen, {e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates} · CPC title