Pharmaceutical compositions of hydrophobic camptothecin derivatives

• US 10,391,056 B2
• Filed: 11/02/2012
• Issued: 08/27/2019
• Est. Priority Date: 11/03/2011
• Status: Active Grant

• Current Assignee: Taiwan Liposome Co., Ltd. (Woods Investment Co. Ltd.), TLC Biopharmaceuticals, Inc. (Woods Investment Co. Ltd.)
• Original Assignee: Taiwan Liposome Co., Ltd. (Woods Investment Co. Ltd.)
• Inventors: Kan, Pei, Hung, ChiaHung, Hong, KeeIung, Tseng, Yun-Long, Chan, Yung-Hsu
• Primary Examiner(s): Roney, Celeste A
• Application Number:
  US14/353,120
• Publication Number:
  US 20140294973A1
• Time in Patent Office: 2,489 Days
• Field of Search: None
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/54 the modifying agent being an organic compound
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61N 5/10 X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy A61N5/01 takes precedence
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention provides a pharmaceutical composition comprising at least one hydrophobic camptothecin derivative or a pharmaceutically acceptable salt of said derivative and a polyethylene glycol (PEG) conjugated phospholipid. Also provided is a method to inhibit cancer cells in a subject in need thereof by administering the pharmaceutical composition of the present invention.

Claims

1. A pharmaceutical composition, comprising:

at least one hydrophobic camptothecin derivative or a pharmaceutically acceptable salt of said derivative; and

at least one polyethylene glycol (PEG) conjugated phospholipid;

wherein the molar ratio of said PEG conjugated phospholipid to said hydrophobic camptothecin derivative or said pharmaceutically acceptable salt of said hydrophobic camptothecin derivative is about 0.45;

1 to about 1.05;

1; and

said hydrophobic camptothecin derivative is a compound selected from the group consisting of;

TLC388HCl;

TLC1988HCl; and

mixtures thereof.

2. The pharmaceutical composition of claim 1, further comprising at least one pH adjusting agent.

3. The pharmaceutical composition of claim 2, wherein the pH adjusting agent is tartaric acid.

4. The pharmaceutical composition of claim 2, wherein the pH adjusting agent is citric acid.

5. The pharmaceutical composition of claim 1, further comprising at least one pharmaceutically acceptable excipient or carrier.

6. The pharmaceutical composition of claim 1, wherein the molar ratio of said PEG conjugated phospholipid to said hydrophobic camptothecin derivative or said pharmaceutically acceptable salt of said hydrophobic camptothecin derivative is about 0.60:

1 to about 1.00;

1.

7. The pharmaceutical composition of claim 1, wherein the molar ratio of said PEG conjugated phospholipid to said hydrophobic camptothecin derivative or said pharmaceutically acceptable salt of said hydrophobic camptothecin derivative is about 0.70:

1 to about 0.90;

1.

8. The pharmaceutical composition of claim 1, wherein said pharmaceutical composition has a pH less than about 4.

9. The pharmaceutical composition of claim 2, wherein the PEG conjugated phospholipid comprises a PEG moiety having a molecular weight from about 1,000 to about 20,000 daltons conjugated to a phospholipid moiety.

10. The pharmaceutical composition of claim 2, wherein the PEG conjugated phospholipid is a PEG-DSPE conjugate.

11. The pharmaceutical composition of claim 10, wherein the PEG-DSPE conjugate is a methoxyl PEG-DSPE conjugate.

12. The pharmaceutical composition of claim 2, wherein the hydrophobic camptothecin derivative or the pharmaceutically acceptable salt of said hydrophobic camptothecin derivative and PEG conjugated phospholipid form micelles with a size less than about 40 nm.

13. A plurality of micelles, wherein each of said micelles comprises a pharmaceutical composition of claim 1.

14. A plurality of micelles of claim 13, further comprising at least one pH adjusting agent.

15. A plurality of micelles of claim 14, wherein the pH adjusting agent is tartaric acid.

16. A plurality of micelles of claim 14, wherein the pH adjusting agent is citric acid.

17. A plurality of micelles of claim 13, further comprising at least one pharmaceutically acceptable excipient or carrier.

18. A plurality of micelles of claim 13, wherein said hydrophobic camptothecin derivative is selected from the group consisting of:

TLC388HCl;

TLC1988HCl; and

mixtures thereof.

19. A plurality of micelles of claim 13, wherein the molar ratio of said PEG conjugated phospholipid to said hydrdophobic camptothecin derivative or said pharmaceutically acceptable salt of said hydrophobic camptothecin derivative is about 0.60:

1 to about 1.00;

1.

20. A plurality of micelles of claim 13, wherein the molar ratio of said PEG conjugated phospholipid to said hydrdophobic camptothecin derivative or said pharmaceutically acceptable salt of said hydrophobic camptothecin derivative is about 0.70:

1 to about 0.90;

1.

21. A plurality of micelles of claim 13, wherein said pharmaceutical composition has a pH less than about 4.

22. A plurality of micelles of claim 13, wherein the PEG conjugated phospholipid comprises a PEG moiety having a molecular weight from about 1,000 to about 20,000 daltons conjugated to a phospholipid moiety.

23. A plurality of micelles of claim 13, wherein the PEG conjugated phospholipid is PEG-DSPE conjugate.

24. A plurality of micelles of claim 23, wherein the PEG-DSPE conjugate is a methoxyl PEG-DSPE conjugate.

25. A plurality of micelles of claim 13, wherein the micelles has a size less than about 40 nm.

26. A pharmaceutical composition, comprising:

at least one compound selected from the group consisting of TLC388HCl or a pharmaceutically acceptable salt of TLC388 HCl;

methoxyl PEG-DSPE conjugate; and

citric acid;

wherein the molar ratio of said methoxyl PEG-DSPE conjugate to said TLC388HCl or a pharmaceutically acceptable salt of TLC388 HCl is greater than about 0.45;

1 to about 0.9;

1; and

wherein said TLC388HCl or a pharmaceutically acceptable salt of TLC388HCl and said methoxyl PEG-DSPE conjugate form micelles.

27. A method of inhibiting the growth of hepatoma, prostate and glioma cancer cells, comprising:

administering to a subject in need thereof an effective amount of a pharmaceutical composition of claim 1.

28. A method of claim 27, further comprising:

exposing said cancer cells to one or more anti-cancer agents.

29. A method of claim 28, wherein said anti-cancer agent is ionizing radiation.

30. A method of claim 27, wherein said anti-cancer agent is conventional chemotherapy.

31. A method of claim 27, wherein said anti-cancer agent is targeted cancer therapy.