Taxol formulation

• US 5,415,869 A
• Filed: 11/12/1993
• Issued: 05/16/1995
• Est. Priority Date: 11/12/1993
• Status: Expired due to Term

• Current Assignee: The Research Foundation for The State University of New York (State University of New York)
• Original Assignee: The Research Foundation for The State University of New York (State University of New York)
• Inventors: Mayhew, Eric, Sharma, Amarnath, Straubinger, Robert M.
• Primary Examiner(s): Rose, Shep K.
• Application Number:
  US08/151,215
• Time in Patent Office: 550 Days
• Field of Search: 424/450
• US Class Current: 424/450
• CPC Class Codes: A61K 31/335 having oxygen as the only ring hetero atom, e.g. fungichromin
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

The present invention relates to a pharmaceutical composition for use in treatment of cancer patients. The composition includes at least one taxane present in a pharmaceutical effective amount and a mixture of one or more negatively charged phospholipids and one or more zwitterion (i.e. uncharged) phospholipids. This mixture entraps the at least one taxane in what is believed to be a liposome. The mixture contains a ratio of negatively charged phospholipids to zwitterion phospholipids of 1:9 to 7:3. The taxol is present in an amount of 1.5-8.0 mole percent taxane. The composition is in the form of particles having a size of 0.025 to 10 microns with substantially no taxane crystals.

Claims

1. A pharmaceutical composition for use in treatment of cancer comprising:

at least one taxane present in said composition in a pharmaceutically effective amount of 1.5-8.0 mol % and

a mixture of one or more negatively charged phospholipids and one or more zwitterion phospholipids in a respective ratio of 1;

9 to 3;

7, wherein said mixture entraps said at least one taxane and said composition is in the form of particles having a size of 0.025 to 10 microns with a substantial absence of taxane crystal formation in said composition.

2. A pharmaceutical composition according claim 1, wherein the negatively charged phospholipid is selected from the group consisting of phosphatidyl inositol, phosphatidyl serine, phosphatidyl glycerol, phosphaphatic acid, diphosphatidyl glycerol, poly(ethylene glycol)-phosphatidyl ethanolamine, dimyristoylphosphatidyl glycerol, dioleoylphosphatidyl glycerol, dilauryloylphosphatidyl glycerol, dipalmitotylphosphatidyl glycerol, distearyloylphosphatidyl glycerol, dimyristoyl phosphatic acid, dipalmitoyl phosphatic acid, dimyristoyl phosphitadyl serine, dipalmitoyl phosphatidyl serine, brain phosphatidyl serine, and mixtures thereof.

3. A pharmaceutical composition according to claim 1, wherein the zwitterion phospholipid is selected from the group consisting of phosphatidyl choline, phosphatidyl ethanolamine, sphingomyelin, lecithin, lysolecithin, lysophatidylethanolamine, cerebrosides, dimyristoylphosphatidyl choline, dipalmitotylphosphatidyl choline, distearyloylphosphatidyl choline, dielaidoylphosphatidyl choline, dioleoylphosphatidyl choline, dilauryloylphosphatidyl choline, 1-myristoyl-2-palmitoyl phosphatidyl choline, 1-palmitoyl-2-myristoyl phosphatidyl choline, 1-palmitoyl-2-stearoyl phosphatidyl choline, 1-stearoyl-2-palmitoyl phosphatidyl choline, dimyristoyl phosphatidyl ethanolamine, dipalmitoyl phosphatidyl ethanolamine, brain sphingomyelin, dipalmitoyl sphingomyelin, distearoyl sphingomyelin, and mixtures thereof.

4. A pharmaceutical composition according to claim 1, wherein the negatively charged phospholipid is phosphatidyl glycerol and the zwitterion phospholipid is phosphatidyl choline.

5. A pharmaceutical composition according to claim 1, wherein said composition contains 1.5-3.3 mol % of said taxane.

6. A pharmaceutical composition according to claim 1, wherein said taxane is selected from the group consisting of taxol, 7-epitaxol, 7-acetyl taxol, 10-desacetyltaxol, 10-desacetyl-7-epitaxol, 7-xylosyltaxol, 10-desacetyl-7-glutaryltaxol, 7-N,N-dimethylglycyltaxol, 7-L-alanyltaxol, taxotere, and mixtures thereof.

7. A pharmaceutical composition according to claim 1 further comprising:

a sterol.

8. A pharmaceutical composition according to claim 7, wherein said sterol is selected from the group consisting of cholesterol, cholesterol derivatives, vitamin D, phytosterols, steroid hormones, cholesteryl esters, and mixtures thereof.

9. A pharmaceutical composition according to claim 7, wherein said composition contains 0.01 to 50 mol % of said sterol.

10. A pharmaceutical composition according to claim 1, wherein said composition is in dry, lyophilized form.

11. A pharmaceutical composition according to claim 1, wherein said composition is a liquid suspension.

12. A method of treating cancer patients comprising:

administering to a cancer patient said pharmaceutical composition according to claim 1 in an effective amount.

13. A pharmaceutical composition for use in treatment of cancer comprising:

at least one taxane present in said composition in a pharmaceutically effective amount of 1.5-8.0 mol % and

a mixture of one or more negatively charged phospholipids and one or more zwitterion phospholipids in a respective ratio of 1;

9 to 3;

7, wherein said mixture forms liposomes which entrap said at least one taxane and said composition is in the form of particles having a size of 0.025 to 10 microns with a substantial absence of taxane crystal formation in said composition.

14. A pharmaceutical composition according claim 13, wherein the negatively charged phospholipid is selected from the group consisting of phosphatidyl inositol, phosphatidyl serine, phosphatidyl glycerol, phosphaphatic acid, diphosphatidyl glycerol, poly(ethylene glycol)-phosphatidyl ethanolamine, dimyristoylphosphatidyl glycerol, dioleoylphosphatidyl glycerol, dilauryloylphosphatidyl glycerol, dipalmitotylphosphatidyl glycerol, distearyloylphosphatidyl glycerol, dimyristoyl phosphatic acid, dipalmitoyl phosphatic acid, dimyristoyl phosphitadyl serine, dipalmitoyl phosphatidyl serine, brain phosphatidyl serine, and mixtures thereof.

15. A pharmaceutical composition according to claim 13, wherein the zwitterion phospholipid is selected from the group consisting of phosphatidyl choline, phosphatidyl ethanolamine, sphingomyelin, lecithin, lysolecithin, lysophatidylethanolamine, cerebrosides, dimyristoylphosphatidyl choline, dipalmitotylphosphatidyl choline, distearyloylphosphatidyl choline, dielaidoylphosphatidyl choline, dioleoylphosphatidyl choline, dilauryloylphosphatidyl choline, 1-myristoyl-2-palmitoyl phosphatidyl choline, 1-palmitoyl-2-myristoyl phosphatidyl choline, 1-palmitoyl-2-stearoyl phosphatidyl choline, 1-stearoyl-2-palmitoyl phosphatidyl choline, dimyristoyl phosphatidyl ethanolamine, dipalmitoyl phosphatidyl ethanolamine, brain sphingomyelin, dipalmitoyl sphingomyelin, distearoyl sphingomyelin, and mixtures thereof.

16. A pharmaceutical composition according to claim 13, wherein said taxane is selected from the group consisting of taxol, 7-epitaxol, 7-acetyl taxol, 10-desacetyltaxol, 10-desacetyl-7-epitaxol, 7-xylosyltaxol, 10-desacetyl-7-sylosyltaxol, 7-glutaryltaxol, 7-N,N-dimethylglycycltaxol, 7-L-alanyltaxol, taxotere, and mixtures thereof.

17. A pharmaceutical composition according to claim 13, wherein said composition is in the form of particles having a size of 1 to 5 microns.

18. A method of treating cancer patients comprising:

administering to a cancer patient said pharmaceutical composition according to claim 13 in an effective amount.

19. A pharmaceutical composition in particulate form for use in treatment of cancer comprising:

at least one taxane present in said composition in a pharmaceutically effective amount of 1.5-8.0 mol % and

a mixture of one or more negatively charged phospholipids and one or more zwitterion phospholipids in a respective molar ratio of 1;

9 to 3;

7, wherein said mixture entraps said at least one taxane within particles having a size of 1 to 5 microns with a substantial absence of taxane crystal formation in said composition.

20. A pharmaceutical composition according claim 19, wherein the negatively charged phospholipid is selected from the group consisting of phosphatidyl inositol, phosphatidyl serine, phosphatidyl glycerol, phosphaphatic acid, diphosphatidyl glycerol, poly(ethylene glycol)-phosphatidyl ethanolamine, dimyristoylphosphatidyl glycerol, dioleoylphosphatidyl glycerol, dilauryloylphosphatidyl glycerol, dipalmitotylphosphatidyl glycerol, distearyloylphosphatidyl glycerol, dimyristoyl phosphatic acid, dipalmitoyl phosphatic acid, dimyristoyl phosphitadyl serine, dipalmitoyl phosphatidyl serine, brain phosphatidyl serine, and mixtures thereof.

21. A pharmaceutical composition according to claim 19, wherein the zwitterion phospholipid is selected from the group consisting of phosphatidyl choline, phosphatidyl ethanolamine, sphingomyelin, lecithin, lysolecithin, lysophatidylethanolamine, cerebrosides, dimyristoylphosphatidyl choline, dipalmitotylphosphatidyl choline, distearyloylphosphatidyl choline, dielaidoylphosphatidyl choline, dioleoylphosphatidyl choline, dilauryloylphosphatidyl choline, 1-myristoyl-2-palmitoyl phosphatidyl choline, 1-palmitoyl-2-myristoyl phosphatidyl choline, 1-palmitoyl-2-stearoyl phosphatidyl choline, 1-stearoyl-2-palmitoyl phosphatidyl choline, dimyristoyl phosphatidyl ethanolamine, dipalmitoyl phosphatidyl ethanolamine, brain sphingomyelin, dipalmitoyl sphingomyelin, distearoyl sphingomyelin, and mixtures thereof.

22. A pharmaceutical composition according to claim 19, wherein said taxane is selected from the group consisting of taxol, 7-epitaxol, 7-acetyl taxol, 10-desacetyltaxol, 10-desacetyl-7-epitaxol, 7-xylosyltaxol, 10-desacetyl-7-sylosyltaxol, 7-glutaryltaxol, 7-N,N-dimethylglycytaxol, 7-L-alanyltaxol, taxotere, and mixtures thereof.

23. A pharmaceutical composition according to claim 19 further comprising:

a sterol.

24. A method of treating cancer patients comprising:

administering to a cancer patient said pharmaceutical composition according to claim 19 in an effective amount.