Pharmaceutical compositions of hydrophobic camptothecin derivatives

• US 10,980,798 B2
• Filed: 07/03/2019
• Issued: 04/20/2021
• 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, Keelung, Tseng, Yun-Long, Chan, Yung-Hsu
• Primary Examiner(s): Roney, Celeste A
• Application Number:
  US16/502,946
• Publication Number:
  US 20190321356A1
• Time in Patent Office: 657 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 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/54 the modifying agent being an organic compound
• CPC Class Codes: A61K 47/544 Phospholipids
• CPC Class Codes: A61K 47/6907 the form being a microemulsion, nanoemulsion or micelle
• 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

Abstract

Provide is a method of using a topoisomerase I inhibitor in treatment of cancer to reduce bone marrow suppression. The method includes administering to a subject in need thereof an effective amount of a pharmaceutical composition. The composition has at least one hydrophobic topoisomerase I inhibitor or a pharmaceutically acceptable salt thereof, and at least one polyethylene glycol (PEG) conjugated phospholipid, wherein the molar ratio of said PEG conjugated phospholipid to said hydrophobic topoisomerase I inhibitor or said pharmaceutically acceptable salt of said hydrophobic topoisomerase I inhibitor is about 0.45:1 to about 1.05:1.

Claims

1. A method of using a topoisomerase I inhibitor in treatment of cancer to reduce bone marrow suppression, comprising:

administering to a subject in need thereof an effective amount of a pharmaceutical composition that comprises;

at least one hydrophobic topoisomerase I inhibitor or a pharmaceutically acceptable salt thereof; and

at least one polyethylene glycol (PEG) conjugated phospholipid;

wherein the molar ratio of said PEG conjugated phospholipid to said hydrophobic topoisomerase I inhibitor or said pharmaceutically acceptable salt of said hydrophobic topoisomerase I inhibitor is about 0.45;

1 to about 1.05;

1.

2. The method of claim 1, wherein said hydrophobic topoisomerase I inhibitor is selected from the group consisting of:

an acridine compound, an actinomycin, an anthracycline compound, an anthraquinone compound, a berberine alkaloid, a benzofluoranthene compound, a benzophenanthridine alkaloid, a camptothecin derivative, a DNA minor groove binder, an indolocarbazole compound, a naphthoquinone compound, a flavonoid, a quinoline compound, a terbenzimidazole compound, and a tricyclic carboxamide derivative.

3. The method of claim 1, wherein said hydrophobic topoisomerase I inhibitor is selected from the group consisting of:

aclacinomycin A, 5-acridin-9-ylmethylidene-3-amino-2-thioxothiazolidin-4-one, 5-acridin-9-ylmethylidene-2-thioxoimidazolidin-4-one, 3-acridin-9-ylmethylthiazolidine-2,4-dione, silatecan, 9-aminocamptothecin, gimatecan, karenitecin, diflomotecan, rubitecan, 7-ethylcamptothecin, 10-aminocamptothecin, 10,11-methylenedioxycamptothecin, 9-amino-10,11-methylenedioxycamptothecin, 9-chloro-10,11-methylenedioxycamptothecin, TLC388, TLC1988, actinomycin D, NU/ICRF 505, epiberberine, coralyne, beta-lapachone, nitidine, fagaronine, corilagin, rebeccamycin, KT6006, KT6528, ED-110, NB-506, alkannin, shikonin, EMD 21388, EMD 50689, acacetin, kaempferol, saintopin, 5-phenyl-terbenzimidazole (5PTB), topostatin, topostin B567, and intoplicine.

4. The method of claim 1, wherein said hydrophobic topoisomerase I inhibitor is a compound having a water solubility less than camptothecin.

5. The method of claim 4, wherein said hydrophobic topoisomerase I inhibitor is a compound having a water solubility less than 0.511 mg/mL.

6. The method of claim 1, further comprising at least one pH adjusting agent.

7. The method of claim 1, further comprising at least one pharmaceutically acceptable excipient or carrier.

8. The method of claim 1, wherein the molar ratio of said PEG conjugated phospholipid to said hydrophobic topoisomerase I inhibitor or said pharmaceutically acceptable salt of said hydrophobic topoisomerase I inhibitor is about 0.60:

1 to about 1.00;

1.

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

10. The method 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.

11. The method of claim 1, wherein the PEG conjugated phospholipid is a PEG-DSPE conjugate.

12. The method of claim 1, wherein the hydrophobic topoisomerase I inhibitor or the pharmaceutically acceptable salt of said hydrophobic topoisomerase I inhibitor and PEG conjugated phospholipid form micelles with a size less than about 40 nm.

13. The method of claim 1, wherein the hydrophobic topoisomerase I inhibitor comprises one or more electron-affinic moieties being directly or indirectly attached to one of the carbons at the C₅, C₇, C₉, C₁₀, C₁₁, C₁₂ or C₂₀ position of camptothecin.

14. The method of claim 1, wherein the hydrophobic topoisomerase I inhibitor is a camptothecin derivative having a planar pentacyclic ring structure.

15. The method of claim 13, wherein said camptothecin derivative is selected from the group consisting of:

silatecan, 9-aminocamptothecin, gimatecan, karenitecin, diflomotecan, rubitecan, 7-ethylcamptothecin, 10-aminocamptothecin, 10,11-methylenedioxycamptothecin, 9-amino-10,11-methylenedioxycamptothecin, 9-chloro-10,11-methylenedioxycamptothecin, TLC388, and TLC1988.

16. The method of claim 6, wherein the pH adjusting agent is tartaric acid or citric acid.

17. The method of claim 1, wherein the molar ratio of said PEG conjugated phospholipid to said hydrophobic topoisomerase I inhibitor or said pharmaceutically acceptable salt of said hydrophobic topoisomerase I inhibitor is about 0.70:

1 to about 0.90;

1.

18. The method of claim 11, wherein the PEG-DSPE conjugate is a methoxyl PEG-DSPE conjugate.