Formulations of phosphoramidate derivatives of nucleoside drugs

Patent metadata

Field	Value
Publication number	US-12357652-B2
Application number	US-202318371865-A
Country	US
Kind code	B2
Filing date	Sep 22, 2023
Priority date	Dec 23, 2015
Publication date	Jul 15, 2025
Grant date	Jul 15, 2025

Abstract

This invention relates to pharmaceutical formulations and formulation strategies of protides (phosphoramidate derivatives of nucleosides) and, in particular, protides useful in the treatment of cancer such as NUC-3373 (5-fluoro-2′-deoxyuridine-5′-O-[1-naphthyl (benzoxy-L-alaninyl)] phosphate) and NUC-7738 (3′-deoxyadenosine-5′-O-[phenyl(benzyloxy-L-alaninyl)] phosphate). In particular, the invention relates to formulations which comprise a polar aprotic solvent, for example dimethyl acetamide (DMA).

First claim

What is claimed is:

1. A pharmaceutical stock solution to prepare a formulation for intravenous administration to a human patient in need thereof comprising:
50 to 150 mg/mL 5-fluoro-2′-deoxyuridine-5′-O-[1-naphthyl (benzoxy-L alaninyl)] phosphate (NUC-3373) or a pharmaceutically acceptable salt thereof; 20-55% by volume dimethyl acetamide (DMA); 20%-70% by volume one or more pharmaceutically acceptable non-ionic solubilizers; and optionally one or more pharmaceutically acceptable excipients.

2. The pharmaceutical stock solution of claim 1 , wherein the solubilizer is a polyethoxylated fatty acid or a mixture thereof.

3. The pharmaceutical stock solution of claim 2 , wherein the solubilizer is polyethoxylated sorbitan monooleate.

4. The pharmaceutical stock solution of claim 1 , wherein the stock solution comprises 35%-70% by volume one or more pharmaceutically acceptable non-ionic solubilizers.

5. The pharmaceutical stock solution of claim 1 , wherein the administration is through a central venous access device (CVAD).

6. The pharmaceutical stock solution of claim 1 , wherein the administration is through a peripheral vein.

7. A pharmaceutical formulation for intravenous administration to a human patient in need thereof comprising:
1 to 15 mg/mL 5-fluoro-2′-deoxyuridine-5′-O-[1-naphthyl (benzoxy-L alaninyl)] phosphate (NUC-3373) or a pharmaceutically acceptable salt thereof; 0.1-12% by volume dimethyl acetamide (DMA); 0.1%-12% by volume one or more pharmaceutically acceptable non-ionic solubilizers; an aqueous vehicle; and optionally one or more pharmaceutically acceptable excipients.

8. The pharmaceutical formulation of claim 7 , wherein the solubilizer is a polyethoxylated fatty acid or a mixture thereof.

9. The pharmaceutical formulation of claim 8 , wherein the solubilizer is polyethoxylated sorbitan monooleate.

10. The pharmaceutical formulation of claim 7 , wherein the aqueous vehicle is water for infusion (WFI).

11. The pharmaceutical formulation of claim 7 , wherein the aqueous vehicle is saline.

12. The pharmaceutical formulation of claim 7 , wherein the administration is through a central venous access device (CVAD).

13. The pharmaceutical formulation of claim 7 , wherein the administration is through a peripheral vein.

14. A method of preparing a pharmaceutical formulation for intravenous administration to a human patient in need thereof, comprising the step of diluting a stock solution with an aqueous vehicle to provide the pharmaceutical formulation;
wherein the stock solution comprises 50 to 150 mg/mL 5-fluoro-2′-deoxyuridine-5′-O-[1-naphthyl (benzoxy-L alaninyl)] phosphate (NUC-3373) or a pharmaceutically acceptable salt thereof; 20-55% by volume dimethyl acetamide (DMA); 20%-70% by volume one or more pharmaceutically acceptable non-ionic solubilizers; and optionally one or more pharmaceutically acceptable excipients; and
wherein the pharmaceutical formulation comprises 1 to 15 mg/mL 5-fluoro-2′-deoxyuridine-5′-O-[1-naphthyl (benzoxy-L alaninyl)] phosphate (NUC-3373) or a pharmaceutically acceptable salt thereof; 0.1-12% by volume dimethyl acetamide (DMA); 0.1%-12% by volume the one or more pharmaceutically acceptable non-ionic solubilizers; the aqueous vehicle; and optionally the one or more pharmaceutically acceptable excipients.

15. The method of claim 14 , wherein the solubilizer is a polyethoxylated fatty acid or a mixture thereof.

16. The method of claim 15 , wherein the solubilizer is polyethoxylated sorbitan monooleate.

17. The method of claim 14 , wherein the aqueous vehicle is water for infusion (WFI).

18. The method of claim 14 , wherein the aqueous vehicle is saline.

19. The method of claim 14 , wherein the administration is through a central venous access device (CVAD).

20. The method of claim 14 , wherein the administration is through a through a peripheral vein.

Assignees

• NuCana plc

Inventors

• Kennovin Gordon
• Griffith Hugh

Classifications

• A61K47/22

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

• A61P35/02

  specific for leukemia · CPC title

• A61K31/7072

  having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine · CPC title

• A61K9/08

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

• A61K47/20

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