DOSE REGIME FOR CAMPTOTHECIN DERIVATIVES

• US 20140135357A1
• Filed: 11/12/2013
• Published: 05/15/2014
• Est. Priority Date: 11/12/2012
• Status: Abandoned Application

• 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.), TLC Biopharmaceuticals, Inc. (Woods Investment Co. Ltd.)
• Inventors: HONG, Keelung, TSENG, Yun-Long, KUO, Min-Wen
• Application Number:
  US14/077,353
• Publication Number:
  US 20140135357A1
• Time in Patent Office: Days
• US Class Current: 514/283
• 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 47/24 containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/107 Emulsions ; Emulsion preconcentrates; Micelles composition of emulsions A61K47/00
• CPC Class Codes: C07D 491/22 in which the condensed system contains four or more hetero rings

Abstract

The present invention is directed to a method of inhibiting cancer cell growth, comprising administering a pharmaceutical composition to a subject in need thereof. The pharmaceutical composition comprises at least one camptothecin derivative or a pharmaceutically acceptable salt thereof; and at least one PEG phospholipid, and provides a sustained release of topotecan as an active ingredient.

Claims

1. A method for inhibiting cancer cell growth in a subject, said method comprising the step of:

administering to said subject a composition comprising;

at least one compound of formula (I);

2. The method of claim 1,

wherein said pharmaceutically acceptable salt of said compound is TLC388HCl.

3. The method of claim 1,

wherein said compound is S,S-TLC388, S,R-TLC388, or a mixture thereof.

4. The method of claim 3,

wherein said compound is a diastereomeric mixture of S,S-TLC388 and S,R-TLC388 in a molar ratio of about 2:

1 (S,S-TLC388;

S,R-TLC388).

5. The method of claim 1,

wherein said composition is administered at a level of 1.5 mg/m² to about 60 mg/m².

6. The method of claim 1,

wherein said composition is administered at a level of greater than about 40 mg/m².

7. The method of claim 1,

wherein said administering step is repeated weekly.

8. The method of claim 1,

wherein the C_max of said topotecan is about 1 ng/mL to about 3720 ng/mL.

9. The method of claim 1,

wherein the C_max of said topotecan is about 25 ng/mL to about 3720 ng/mL.

10. The method of claim 1,

wherein the t_max of said topotecan is about 0.4 hours to about 1.9 hours.

11. The method of claim 1,

wherein the t_max of said topotecan is about 0.8 hours to about 1.0 hours.

12. The method of claim 1,

wherein the AUC_0-8hr of said topotecan is about 5 hr-ng/mL to about 500 hr-ng/mL.

13. The method of claim 1,

wherein the AUC_0-8hr of said topotecan is about 140 hr-ng/mL to about 500 hr-ng/mL.

14. The method of claim 1,

wherein the t_1/2 of said topotecan is about 4 hours to about 12.5 hours.

15. The method of claim 1,

wherein the t_1/2 of said topotecan is about 4.5 hours to about 7.5 hours.

16. The method of claim 1,

wherein said composition further provides a sustained release of TLC-U2 to said subject over a period of at least about 8 hours.

17. The method of claim 16,

wherein the C_max of said TLC-U2 is about 2 ng/mL to about 105 ng/mL.

18. The method of claim 16,

wherein the C_max of said TLC-U2 is about 50 ng/mL to about 110 ng/mL.

19. The method of claim 16,

wherein the t_max of said TLC-U2 is about 0.2 hours to about 0.7 hours.

20. The method of claim 16,

wherein the t_max of said TLC-U2 is about 0.3 hours to about 0.5 hours.

21. The method of claim 16,

wherein the AUC_0-8hr of said TLC-U2 is about 2.5 hr-ng/mL to about 115 hr-ng/mL.

22. The method of claim 16,

wherein the AUC_0-8hr of said TLC-U2 is about 70 hr-ng/mL to about 115 hr-ng/mL.

23. The method of claim 16,

wherein the t_1/2 of said TLC-U2 is about 1.5 hours to about 3.5 hours.

24. The method of claim 16,

wherein the t_1/2 of said TLC-U2 is about 1.5 hours to about 3.0 hours.

25. The method of claim 1,

wherein said composition further provides a sustained release of TLC-U1 to said subject over a period of at least about 8 hours.

26. The method of claim 25,

wherein the C_max of said TLC-U1 is about 5 ng/mL to about 450 ng/mL.

27. The method of claim 25,

wherein the C_max of said TLC-U1 is about 200 ng/mL to about 450 ng/mL.

28. The method of claim 25,

wherein the t_max of said TLC-U1 is about 0.2 hours to about 0.7 hours.

29. The method of claim 25,

wherein the t_max of said TLC-U1 is about 0.3 hours to about 0.6 hours.

30. The method of claim 25,

wherein the AUC_0-8hr of said TLC-U1 is about 5 hr-ng/mL to about 430 hr-ng/mL.

31. The method of claim 25,

wherein the AUC_0-8hr of said TLC-U1 is about 270 hr-ng/mL to about 430 hr-ng/mL.

32. The method of claim 25,

wherein the t_1/2 of said TLC-U1 is about 1.5 hours to about 5.6 hours.

33. The method of claim 25,

wherein the t_1/2 of said TLC-U1 is about 1.8 hours to about 3.5 hours.

34. The method of claim 1,

wherein said composition further comprises at least one pH adjusting agent.

35. The method of claim 1,

wherein the molar ratio of said PEG conjugated phospholipid to said compound or pharmaceutically acceptable salt of said compound is about 0.60:

1 to about 1.00;

1.

36. The method of claim 1,

wherein the molar ratio of said PEG conjugated phospholipid to said compound or pharmaceutically acceptable salt of said compound is about 0.70:

1 to about 0.90;

1.

37. The method of claim 1,

wherein said composition has a pH less than about 4.

38. The method of claim 1,

wherein said PEG conjugated phospholipid comprises a PEG moiety having a molecular weight from about 1,000 to about 20,000 daltons.

39. The method of claim 1,

wherein said PEG conjugated phospholipid is a PEG-DSPE (distearoyl-phosphatidylethanolamine) conjugate.

40. The method of claim 39,

wherein the PEG-DSPE conjugate is a methoxyl PEG-DSPE conjugate.

41. The method of claim 1, wherein the composition is administered as a single dose.