PHARMACEUTICAL COMPOSITIONS OF HYDROPHOBIC CAMPTOTHECIN DERIVATIVES

• US 20140294973A1
• Filed: 11/02/2012
• Published: 10/02/2014
• 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.), TLC Biopharmaceuticals, Inc. (Woods Investment Co. Ltd.)
• Inventors: Kan, Pei, Hung, ChiaHung, Hong, Kee-lung, Tseng, Yun-Long, Chan, Yun-Hsu
• Granted Patent: US 10,391,056 B2
• Time in Patent Office: Days
• US Class Current: 424/489
• 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 greater than about 0.45;

1.

2. The pharmaceutical composition of claim 1, wherein said hydrophobic camptothecin derivative comprises at least one compound of formula (I):

3. The pharmaceutical composition of claim 1, wherein said hydrophobic camptothecin derivative comprises at least one compound of formula (II):

4. The pharmaceutical composition of claim 3, wherein:

X is a O, S, —

NR—

, or a bond;

Y is ═

NO—

, —

N(H)O—

, ═

N—

, —

NR—

, O, S;

or a covalent bond;

T is independently CRR′

;

each of R and R′

is independently selected from hydrogen, C_1-4 alkyl, and substituted C_1-4 alkyl;

n is an integer from 0 to 8;

R¹ is optionally substituted heterocyclic, aryl, or heteroaryl;

provided that when X is a bond or CH₂ and n is 1, 2, or 3, then Y, when bound to R¹, is not oxygen; and

provided that when X is a bond or CH₂, n is 1, 2, or 3, and R¹ is heterocyclic containing at least one nitrogen atom, then Y is not bound directly to said nitrogen atom;

R² is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, R^QY-L-C(O)O—

, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, tri lower alkylsilyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue residue, phosphosugar residue, O-quinone, substituted lower alkyl aminomethyl, lower alkylcarbonylamino, lower alkylcarbonyloxy methyl, optionally substituted lower alkylcarbonyloxy methyl, substituted vinyl, 1-hydroxy-2-nitroethyl, alkoxycarbonylethyl, aminocarbonyl, alkylcarbonyl, alkylcarbonyloxymethyl, benzoylmethyl, benzylcarbonyloxymethyl, lower alkyliminomethyl or lower alkoxymethyl;

R³ is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, R^QY-L-C(O)O—

, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, CH₂NR⁷R⁸ (where each of R⁷ and R⁸ is independently H, alkyl of 1-6 carbons, optionally substituted phenyl, hydroxy lower alkyl, amino lower alkyl, or mono- or dialkylamino lower alkyl, or and R⁸ taken together with the nitrogen to which it is attached represent a cyclic amino-), CH₂R⁹ (where R⁹ is lower alkoxy, CN, amino lower alkoxy, mono- or di-lower alkylamino lower alkoxy, lower alkylthio, amino lower alkylthio, or mono- or di-lower alkylamino lower alkylthio), NR¹⁰R¹¹ (where each of R¹⁰ and R¹¹ is independently hydrogen, lower alkyl, phenyl, hydroxy lower alkyl, or amino lower alkyl, or R¹⁰ and R¹¹ taken together with the nitrogen to which they are attached represent a cyclic amino), trialkylsilyl, dialkylamino alkyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue, phosphosugar residue, O-quinone, substituted lower alkyl aminomethyl, or lower alkylcarbonylamino or R³ together with R⁴ is furan, dihydrofuran or 1,4-oxazine-2-one;

R⁴ is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, R^QY-L-C(O)O—

, cyano, nitro, amino, amino lower alkyl, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, carbamoyloxy, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue, phosphosugar residue residue, O-quinone, substituted lower alkyl aminomethyl, or lower alkylcarbonylamino, or R⁴ together with R⁵ is methylenedioxy;

R⁵ is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, R^QY-L-C(O)O—

, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue, phosphosugar residue, O-quinone, substituted lower alkyl aminomethyl, or lower alkylcarbonylamino;

R⁶ is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, R^QY-L-C(O)O—

, cyano, nitro, amino, trialkylsilyl, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue, phosphosugar residue, O-quinone, substituted lower alkyl aminomethyl, or lower alkylcarbonylamino; and

R^Q is an optionally substituted heterocyclic, aryl, or heteroaryl group, or R¹Y together form a NR^aR^b group, where R^a, R^b, and the nitrogen to which they are attached form a cyclic amine or imide ring.

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

6. The pharmaceutical composition of claim 1, wherein the pH adjusting agent is tartaric acid.

7. The pharmaceutical composition of claim 1, wherein the pH adjusting agent is citric acid.

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

9. The pharmaceutical composition of claim 4, wherein said hydrophobic camptothecin derivative is a compound selected from the group consisting of:

TLC388HCl;

TLC1988HCl; and

mixtures thereof.

10. 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.

11. 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.

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

13. The pharmaceutical composition of claim 1, 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.

14. The pharmaceutical composition of claim 1, wherein the PEG conjugated phospholipid is a PEG-DSPE conjugate.

15. The pharmaceutical composition of claim 14, wherein the PEG-DSPE conjugate is a methoxyl PEG-DSPE conjugate.

16. The pharmaceutical composition of claim 1, 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.

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

18. A plurality of micelles of claim 17, further comprising at least one pH adjusting agent.

19. A plurality of micelles of claim 18, wherein the pH adjusting agent is tartaric acid.

20. A plurality of micelles of claim 18, wherein the pH adjusting agent is citric acid.

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

22. A plurality of micelles of claim 17, wherein said hydrophobic camptothecin derivative is selected from the group consisting of:

TLC388HCl;

TLC1988HCl; and

mixtures thereof.

23. A plurality of micelles of claim 17, 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.

24. A plurality of micelles of claim 17, 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.

25. A plurality of micelles of claim 17, wherein said pharmaceutical composition has a pH less than about 4.

26. A plurality of micelles of claim 17, 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

27. A plurality of micelles of claim 17, wherein the PEG conjugated phospholipid is PEG-DSPE conjugate.

28. A plurality of micelles of claim 27, wherein the PEG-DSPE conjugate is a methoxyl PEG-DSPE conjugate.

29. A plurality of micelles of claim 17, wherein the micelles has a size less than about 40 nm.

30. 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 conjugated phospholipid to said TLC388HCl or a pharmaceutically acceptable salt of TLC388 HCl is greater than about 0.45;

1 to about 0.9;

1.

31. A method of inhibiting the growth of cancer cells, comprising:

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

32. A method of claim 31, further comprising:

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

33. A method of claim 32, wherein said anti-cancer agent is ionizing radiation.

34. A method of claim 31, wherein said anti-cancer agent is conventional chemotherapy.

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