Formulation comprising a gemcitabine-prodrug

Patent metadata

Field	Value
Publication number	US-11040051-B2
Application number	US-202017010338-A
Country	US
Kind code	B2
Filing date	Sep 2, 2020
Priority date	Jun 25, 2014
Publication date	Jun 22, 2021
Grant date	Jun 22, 2021

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 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.

Assignees

• NuCana plc

Inventors

• Griffith Hugh
• Kennovin Gordon

Classifications

• A61K47/22 Primary

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

• A61K47/20

  containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids · CPC title

• A61K47/18

  Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids · CPC title

• A61K31/7068 Primary

  having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid · CPC title

• A61K9/08 Primary

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