Liposome-entrapped topoisomerase inhibitors

• US 20030133973A1
• Filed: 08/29/2002
• Published: 07/17/2003
• Est. Priority Date: 09/16/1998
• Status: Active Grant

• Current Assignee: Gail T. Colbern, James L. Slater, Peter K. Working
• Original Assignee: Gail T. Colbern, James L. Slater, Peter K. Working
• Inventors: Slater, James L., Working, Peter K., Colbern, Gail T.
• Granted Patent: US 7,244,449 B2
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/473 ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• 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 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911
• CPC Class Codes: A61K 9/1278 Post-loading, e.g. by ion or pH gradient
• 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
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

A composition for administration of a therapeutically effective dose of a topoisomerase inhibitor I or topoisomerase I/II inhibitor is described. The composition includes liposomes having an outer surface and an inner surface defining an aqueous liposome compartment, and being composed of a vesicle-forming lipid and of a vesicle-forming lipid derivatized with a hydrophilic polymer to form a coating of hydrophilic polymer chains on both the inner and outer surfaces of the liposomes. Entrapped in the liposomes is the topoisomerase inhibitor at a concentration of at least about 0.10 μmole drug per μmole lipid.

Claims

1. A composition for treating a tumor in a subject, comprising

liposomes composed of a vesicle-forming lipid and between about 1-20 mole percent of a vesicle-forming lipid derivatized with a hydrophilic polymer, said liposomes being formed under conditions that distribute the polymer on both sides of the liposomes'"'"' bilayer membranes;

and

entrapped in the liposomes, a topoisomerase inhibitor at a concentration of at least about 0.10 μ

mole drug per μ

mole lipid, said liposomes having an inside/outside ion gradient sufficient to retain the topoisomerase inhibitor within the liposomes at the specified concentration.

2. The composition of claim 1, where the topoisomerase inhibitor is a topoisomerase I inhibitor selected from the group consisting of camptothecin and camptothecin derivatives.

3. The composition of claim 2, wherein the camptothecin derivative is selected from the group consisting of 9-aminocamptothecin, 7-ethylcamptothecin, 10-hydroxycamptothecin, 9-nitrocamptothecin, 10,11-methlyenedioxycamptothecin, 9-amino-10,11-methylenedioxycamptothecin and 9-chloro-10,11-methylenedioxycamptothecin.

4. The composition of claim 2, wherein the camptothecin derivative is selected from the group consisting of irinotecan, topotecan, (7-(4-methylpiperazinomethylene)-10,11-ethylenedioxy-20(S)-camptothecin, 7-(4-methylpiperazinomethylene)-10,11-methylenedioxy-20(S)-camptothecin and 7-(2-N-isopropylamino)ethyl)-(20S)-camptothecin.

5. The composition of claim 1, wherein the topoisomerase inhibitor is a topolsomerase I/II inhibitor selected from the group consisting of 6-[[2-(dimethylamino)-ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one dihydrochloride, azotoxin and 3-methoxy-11H-pyrido[3′

,4′

-4,5]pyrrolo[3,2-c]quinoline-1,4-dione.

6. The composition of claim 1, wherein the hydrophilic polymer is polyethyleneglycol having a molecular weight between 500-5,000 daltons.

7. The composition of claim 1, wherein the liposomes further include a vesicle-forming lipid having a phase transition temperature above 37°

C.

8. The composition of claim 7, wherein the vesicle-forming lipid is selected from the group consisting of hydrogenated soy phosphatidylcholine, distearoylphosphatidylcholine and sphingomyelin.

9. The composition of claim 7, wherein the liposomes are composed of 20-94 mole percent hydrogenated soy phosphatidylcholine and 1-20 mole percent distearoylphosphatidylethanolamine derivatized with polyethyleneglycol and 5-60 mole percent cholesterol.

10. The composition of claim 7, wherein the liposomes are composed of 30-65 mole percent hydrogenated soy phosphatidylcholine, 5-20 mole percent distearoylphosphatidylethanolamine derivatized with polyethyleneglycol and 30-50 mole percent cholesterol.

11. The composition of claim 7, wherein the liposomes are composed of 20-94 mole percent distearoylphosphatidycholine and 1-20 mole percent distearoylphosphatidylethanolamine derivatized with polyethyleneglycol.

12. The composition of claim 1, wherein the liposomes include a polyanionic polymer within the liposomes, said polymer capable of forming a complex with said topoisomerase inhibitor.

13. The composition of claim 12, wherein said polyanionic polymer is selected from dextran sulfate, chondroitin sulfate A, polyvinylsulfuric acid, and polyphosphoric acid.

14. A composition for administration of a topoisomerase inhibitor, comprising

liposomes composed of vesicle-forming lipids and having an inside/outside ion gradient effective to retain the drug within the liposomes;

and

entrapped in the liposomes, the topoisomerase inhibitor at a concentration of at least about 0.20 μ

mole drug per μ

mole lipid.

15. The composition of claim 14, wherein the toposiomerase inhibitor is a topoisomerase I inhibitor selected from MPE-camptothecin, topotecan and (7-(2-N-isopropylamino)ethyl)-(20S)-camptothecin.

16. The composition of claim 14, wherein the toposiomerase inhibitor is a topoisomerase I/II inhibitor selected from the group consisting of 6-[[2-(dimethylamino)-ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one dihydrochloride and 3-methoxy-11H-pyrido[3′

,4′

-4,5]pyrrolo[3,2-c]quinoline-1,4-dione.

17. The composition of claim 14, wherein the liposomes further include a polyanionic polymer within the liposomes, said polymer capable of forming a complex with said topoisomerase inhibitor.

18. A method of treating a tumor in a subject, comprising

preparing liposomes composed of vesicle-forming lipids including between 1-20 mole percent of a vesicle-forming lipid derivatized with a hydrophilic polymer chain, said liposomes being formed under conditions that distribute the polymer on both sides of the liposomes'"'"' bilayer membrane, said liposomes containing a topoisomerase inhibitor entrapped in the liposomes at a concentration of at least about 0.10 mole per μ

mole lipid, the liposomes having an inside/outside ion gradient sufficient to retain the topoisomerase inhibitor within the liposome at the specified concentration; and

administering the liposomes to the subject.

19. The method of claim 18, wherein preparing further comprises entrapping the inhibitor in the liposomes by remote loading.

20. The method of claim 19, wherein entrapping further comprises entrapping the topoisomerase inhibitor in the liposomes using an ammonium sulfate gradient.

21. The method of claim 19, wherein entrapping further comprises entrapping the topoisomerase inhibitor in the liposomes using a polyanionic polymer trapping agent.

22. The method of claim 21, wherein said polyanionic polymer is selected from dextran sulfate, chondroitin sulfate A, polyvinylsulfuric acid, and polyphosphoric acid.

23. The method of claim 18, wherein preparing further includes preparing the liposomes with a vesicle-forming lipid having a phase transition temperature above 37°

C.

24. The method of claim 23, wherein the vesicle-forming lipid is selected from the group consisting of hydrogenated soy phosphatidylcholine, distearoylphosphatidylcholine and sphingomyelin.

25. The method of claim 24, wherein the liposomes are composed of 20-94 mole percent distearoylphosphatidycholine and 1-20 mole percent distearoylphosphatidylethanolamine derivatized with polyethyleneglycol.

26. The method of claim 24, wherein the liposomes are composed of 30-65 mole percent hydrogenated soy phosphatidylcholine, 5-20 mole percent distearoylphosphatidylethanolamine derivatized with polyethyleneglycol and 30-50 mole percent cholesterol.