Stable liquid formulations of cyclophosphamide and its impurities

Patent metadata

Field	Value
Publication number	US-10849916-B2
Application number	US-201916414418-A
Country	US
Kind code	B2
Filing date	May 16, 2019
Priority date	Jul 11, 2014
Publication date	Dec 1, 2020
Grant date	Dec 1, 2020

Abstract

The present invention relates to novel impurities of cyclophosphamide having structure V, VI or VII, stabilized form of these novel impurities, a process of preparing a stabilized form and isolating thereof. The invention also relates cyclophosphamide formulations which include cyclophosphamide, at least one pharmaceutically acceptable excipient, and a certain level of these impurities having structure V, VI or VII. The invention further relate to method of using such stable liquid formulations of cyclophosphamide for parenteral administration in treating various cancer disorders.

First claim

The invention claimed is:

1. A compound of the structure V

2. A compound of the structure VI

3. A compound of the structure VII

4. A stabilized form of the compound of structure V

wherein stabilized form of compound of structure V comprises at least one stabilizer selected from the group comprising of mannitol, sorbitol, xylitol, maltitol, tartaric acid, citric acid, malic acid, oxalic acid; sodium carbonate, sodium bicarbonate, sodium chloride, lactose, sucrose, maltose, starch.

5. A stabilized form of the compound of structure VI

wherein stabilized form of compound of structure VI comprises at least one stabilizer selected from the group comprising of mannitol, sorbitol, xylitol, maltitol, tartaric acid, citric acid, malic acid, oxalic acid; sodium carbonate, sodium bicarbonate, sodium chloride, lactose, sucrose, maltose, starch.

6. A stabilized form of the compound of structure VII

wherein stabilized form of compound of structure VII comprises at least one stabilizer selected from the group comprising of mannitol, sorbitol, xylitol, maltitol, tartaric acid, citric acid, malic acid, oxalic acid; sodium carbonate, sodium bicarbonate, sodium chloride, lactose, sucrose, maltose, starch.

7. A stabilized form of the compound according to claim 4 , wherein stabilizer is mannitol.

8. A stabilized form of the compound according to claim 5 , wherein stabilizer is mannitol.

9. A stabilized form of the compound according to claim 6 , wherein stabilizer is mannitol.

10. A stabilized form of the compound according to the claim 4 , having a ratio of the compound to stabilizer ranging from about 1:0.1 to about 1:25.

11. A stabilized form of the compound according to the claim 5 , having a ratio of the compound to stabilizer ranging from about 1:0.1 to about 1:25.

12. A stabilized form of the compound according to the claim 6 , having a ratio of the compound to stabilizer ranging from about 1:0.1 to about 1:25.

13. A cyclophosphamide formulation comprising cyclophosphamide, a compound of structure V, and at least one pharmaceutically acceptable excipient, wherein the level of the compound of structure V in the formulation is less than about 2.5% by weight.

14. A cyclophosphamide formulation comprising cyclophosphamide, a compound of structure VI, and at least one pharmaceutically acceptable excipient, wherein the level of compound of structure VI in the formulation is less than about 2.5% by weight

15. A cyclophosphamide formulation comprising cyclophosphamide, a compound of structure VII, and at least one pharmaceutically acceptable excipient, wherein the level of the compound of structure VII in the formulation is less than about 2.5% by weight.

16. The stable liquid formulation according to claim 13 wherein the cyclophosphamide in the formulation is cyclophosphamide monohydrate.

17. The stable liquid formulation according to claim 14 wherein the cyclophosphamide in the formulation is cyclophosphamide monohydrate.

18. The stable liquid formulation according to claim 15 wherein the cyclophosphamide in the formulation is cyclophosphamide monohydrate.

19. The stable liquid formulation according to claim 13 wherein the pharmaceutically acceptable excipient is selected from the group comprising of ethanol, polysorbate, cyclodextrin, dimethyl acetamide, polyethoxylated castor oil or combinations thereof.

20. The stable liquid formulation according to claim 14 wherein the pharmaceutically acceptable excipient is selected from the group comprising of ethanol, polysorbate, cyclodextrin, dimethyl acetamide, polyethoxylated castor oil or combinations thereof.

21. The stable liquid formulation according to claim 15 wherein the pharmaceutically acceptable excipient is selected from the group comprising of ethanol, polysorbate, cyclodextrin, dimethyl acetamide, polyethoxylated castor oil or combinations thereof.

22. The stable liquid formulation according to claim 19 wherein pharmaceutically acceptable excipient is ethanol.

23. The stable liquid formulation according to claim 20 wherein pharmaceutically acceptable excipient is ethanol.

24. The stable liquid formulation according to claim 21 wherein pharmaceutically acceptable excipient is ethanol.

Assignees

• Dr Reddys Laboratories Ltd

Inventors

• Shaik Riyaz Ahmed
• Saha Ananya
• Garikipati Svb Janardhan
• Chaurasiya Akash
• Patel Bhavesh Vallabhbhai
• Bhagwatwar Harshal
• Pillai Sumitra Ashok
• Balasubramanian Satheesh
• Mazumder Joydeep

Classifications

• A61K31/675 Primary

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title

• A61K31/664 Primary

  Amides of phosphorus acids · CPC title

• A61K47/26

  Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin · CPC title

• A61K9/08

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

• A61K9/1623

  Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules · CPC title