Liposome-entrapped topoisomerase inhibitors

• US 7,244,449 B2
• Filed: 08/29/2002
• Issued: 07/17/2007
• Est. Priority Date: 09/16/1998
• Status: Expired due to Term

• Current Assignee: ALZA Corporation (Johnson & Johnson)
• Original Assignee: ALZA Corporation (Johnson & Johnson)
• Inventors: Slater, James L., Working, Peter K., Colbern, Gail T.
• Primary Examiner(s): Kishore; Gollamudi S.
• Application Number:
  US10/230,796
• Publication Number:
  US 20030133973A1
• Time in Patent Office: 1,783 Days
• Field of Search: 424/450, 514/283, 514/279
• 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 polyethyleneglycol having a molecular weight between 500–

5,000 Daltons, said polymer being distributed 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, and wherein the topoisomerase inhibitor is selected from the group consisting of MPE-camptothecin, topotecan, and (7-(2-N-isopropylamino)ethyl)-(20S)-camptothecin.

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

C.

3. The composition of claim 2, wherein the vesicle-forming lipid is selected from the group consisting of hydrogenated soy phosphatidylcholine, distearoylphosphatidylcholine and sphingomyelin.

4. The composition of claim 2, wherein the liposomes are comprised of 20–

94 mole percent hydrogenated soy phosphatidylcholine and [[1–

20 mole percent distearoylphosphatidylethanolamine derivatized with polyethyleneglycol and]]5–

60 mole percent cholesterol; and

wherein said vesicle-forming lipid derivatized with polyethyleneplycol is distearoylphosphatidylethanolamine derivatized with polyethyleneglycol which is present in an amount from 1–

20 mole percent.

5. The composition of claim 2, wherein the liposomes are comprised of 30–

65 mole percent hydrogenated soy phosphatidylcholine[[, 5–

20 mole percent distearoylphosphatidylethanolamine derivatized with polyethyleneglycol]]and 30–

50 mole percent cholesterol; and

wherein said vesicle-forming lipid derivatized with polyethyleneplycol is distearoylphosphatidylethanolamine derivatized with polyethyleneplycol which is present in an amount from 5–

20 mole percent.

6. The composition of claim 2, wherein the liposomes are comprised of 20–

94 mole percent distearoylphosphatidylcholine, and wherein said vesicle-forming lipid derivatized with polyethyleneglycol is distearoylphosphatidylethanolamine derivatized with polyethyleneglycol which is present in an amount from 1–

20 mole percent.

7. The composition of claim 1, wherein the liposomes include a polyanionic polymer.

8. The composition of claim 6, wherein said polyanionic polymer is selected from the group consisting of dextran sulfate, chondroitin sulfate A, polyvinylsulfuric acid, and polyphosphoric acid.

10. The composition of claim 8, wherein the liposomes further include a polyanionic polymer.

12. The method of claim 10, wherein preparing further comprises entrapping the inhibitor in the liposomes by remote loading.

14. The method of claim 12, wherein entrapping further comprises entrapping the topoisomerase inhibitor in the liposomes using a polyanionic polymer trapping agent.

15. The method of claim 14, wherein said polyanionic polymer is selected from the groups consisting of dextran sulfate, chondroitin sulfate A, polyvinylsulfuric acid, and polyphosphoric acid.

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

liposomes composed of vesicle-forming lipids and of a vesicle-forming lipid derivatized with polyethyleneglycol having a molecular weight between 500–

5,000 Daltons, said liposomes having an inside/outside ion gradient effective to retain the topoisomerase inhibitor 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, wherein the topoisomerase inhibitor is selected from the group consisting of MPE-camptothecin, topotecanm and (7-(2-N-isopropylamino)ethyl)-(20S)-camptothecin.

11. 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 polyethyleneglycol having a molecular weight between 500–

5,000 Daltons, said polymer being distributed on both sides of the liposomes'"'"' bilayer membranes, 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, wherein the topoisomerase inhibitor is selected from the group consisting of MPE-camptothecin, topotecan, and (7-(2-N-isopropylamino)ethyl)-(20S)-camptothecin; and

administering the liposomes to the subject.

13. The method of claim 11, wherein entrapping further comprises entrapping the topoisomerase inhibitor in the liposomes using an ammonium sulfate gradient.

16. The method of claim 11, wherein preparing further includes preparing the liposomes with a vesicle-forming lipid having a phase transition temperature above 37°

C.

17. The method of claim 16, wherein the vesicle-forming lipid is selected from the group consisting of hydrogenated soy phosphatidylcholine, distearoylphosphatidylcholine and sphingomyelin.

18. The method of claim 17, wherein the liposomes are comprised of 20–

94 mole percent distearoylphosphatidylcholine and wherein said vesicle-forming lipid derivatized with polyethyleneglycol is distearoylphosphatidylethanolamine derivatized with polyethyleneglycol which is present in an amount from 1–

20 mole percent.

19. The method of claim 17, wherein the liposomes are comprised of 30–

65 mole percent hydrogenated soy phosphatidylcholine[[, 5–

20 mole percent distearoylphosphatidylethanolamine derivatized with polyethyleneglycol]] and 30–

50 mole percent cholesterol; and

wherein said vesicle-forming livid derivatized with polyethyleneplycol is distearoylphosphatidylethanolamine derivatized with polyethyleneplycol which is present in an amount from 5–

20 mole percent.