Liposome-entrapped topoisomerase inhibitors

• US 7,279,179 B2
• Filed: 10/08/2004
• Issued: 10/09/2007
• Est. Priority Date: 09/16/1998
• Status: Expired due to Fees

• 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:
  US10/962,246
• Publication Number:
  US 20050106231A1
• Time in Patent Office: 1,096 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 administration of 7-(2-(N-isopropylamino)ethyl)-(20S)-camptothecin, comprising

liposomes composed of at least about 20 mole percent of a vesicle-forming lipid derivatized with a hydrophilic polymer chain, said liposomes having an inside/outside ion gradient effective to retain the 7-(2-(N-isopropylamino)ethyl)-(20S)-camptothecin within the liposomes;

and

entrapped in the liposomes, the 7-(2-(N-isopropylamino)ethyl)-(20S)-camptothecin at a concentration of at least about 0.20 μ

mole drug per mole lipid, wherein said liposome composition provides at least a four-fold increase in anti-tumor activity over the anti-tumor activity of the drug in free-form.

2. The composition of claim 1, wherein the hydrophilic polymer is polyethyleneglycol having a molecular weight between about 500 Daltons and about 5,000 Daltons.

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

C.

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

5. The composition of claim 1, wherein the liposomes are comprised of between about 20–

95 mole percent hydrogenated soy phosphatidylcholine and between about 1–

20 mole percent distearoylphosphatidylethanolamine derivatized with polyethyleneglycol.

6. The composition of claim 1, wherein the liposomes are comprised of 95 mole percent hydrogenated soy phosphatidylcholine and 5 mole percent distearoylphosphatidylethanolamine derivatized with polyethyleneglycol.

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

8. The composition of claim 7, wherein said polyanionic polymer is selected from the group consisting of dextran sulfate, chondroitin sulfate A, polyvinylsulfuric acid, and polyphosphoric acid.

9. The composition of claim 1, wherein the anti-tumor activity is measured using an HT-29 tumor model.

10. A composition for administration of 7-(2-(N-isopropylamino)ethyl)-(20S)-camptothecin, comprising

liposomes composed of vesicle-forming lipids derivatized with a hydrophilic polymer chain and having an inside/outside ion gradient effective to retain the 7-(2-(N-isopropylamino)ethyl)-(20S)-camptothecin within the liposomes;

and

entrapped in the liposomes, the 7-(2-(N-isopropylamino)ethyl)-(20S)-camptothecin at a concentration of at least about 0.20 μ

mole drug per μ

mole lipid,

wherein said liposome composition provides at least a four-fold increase in anti-tumor activity over the anti-tumor activity of the drug in free-form.

11. The composition of claim 10, wherein the hydrophilic polymer is polyethyleneglycol having a molecular weight between about 500 Daltons and about 5,000 Daltons.

12. The composition of claim 10, wherein the liposomes further comprise a vesicle-forming lipid having a phase transition temperature above 37°

C.

13. The composition of claim 12, wherein the vesicle-forming lipid is selected from the group consisting of hydrogenated soy phosphatidylcholine, distearoylphosphatidylcholine and sphingomyelin.

14. The composition of claim 10, wherein the liposomes are comprised of 20–

95 mole percent hydrogenated soy phosphatidylcholine and 1–

20 mole percent distearoylphosphatidylethanolamine derivatized with polyethyleneglycol and 5–

60 mole percent cholesterol.

15. The composition of claim 10, 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.

16. The composition of claim 10, wherein the liposomes are comprised of 20–

95 mole percent distearoylphosphatidycholine and 1–

20 mole percent distearoylphosphatidylethanolamine derivatized with polyethyleneglycol.

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

18. The composition of claim 17, wherein said polyanionic polymer is selected from the group consisting of dextran sulfate, chondroitin sulfate A, polyvinylsulfuric acid, and polyphosphoric acid.

19. The composition of claim 10, wherein the anti-tumor activity is measured using an HT-29 tumor model.

20. 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 topoisomerase inhibitor per μ

mole lipid, wherein said liposomes have an inside/outside ion gradient sufficient to retain the topoisomerase inhibitor within the liposomes at the specified concentration prior to in vivo administration, and wherein said liposome-entrapped topoisomerase inhibitor has a longer blood circulation lifetime than the topoisomerase inhibitor in free form, and wherein the topoisomerase inhibitor is an ionizable camptothecin derivative, wherein said liposome composition provides at least a four-fold increase in anti-tumor activity over the anti-tumor activity of the drug in free-form.

21. A composition according to claim 20, wherein the hydrophilic polymer is polyethyleneglycol having a molecular weight between 500 and 5,000 daltons.

22. A composition according to claim 20, wherein the liposomes include a vesicle-forming lipid having a phase transition temperature above 37°

C.

23. A composition according to claim 20, which comprises a vesicle-forming lipid selected from the group consisting of hydrogenated soy phosphatidylcholine, distearoyl phosphatidylcholine, and sphingomyelin.

24. A composition according to claim 20, wherein the liposomes are composed of 20–

95 mole percent distearoyl phosphatidyl choline and 1–

20 mole percent distearoyl phosphatidylethanolamine derivatized with polyethyleneglycol.

25. A composition according to claim 20, wherein the camptothecin derivative is selected from the group consisting of 9-aminocamptothecin, 7-ethylcamptothecin, 10-hydroxycamptothecin, 9-nitrocamptothecin, 10,11-methylenedioxycamptothecin, 9-chloro-10,11 -methylenedioxycamptothecin, irinotecan, 7-(4-methylpiperazinomethylene)-10,11 -ethylenedioxy-20(S)-camptothecin (MPE-camptothecin), 7-(4-methylpiperazinomethylene)-10,11 -methylenedioxy-20(S)-camptothecin, 9-dimethyl-aminomethyl-10-hydroxycamptothecin (topotecan) and 7-(2-(N-isopropylamino)ethyl)-(20S)-camptothecin (CKD-602).

26. A composition according to claim 20, wherein the liposomes include a polyanionic polymer within the liposomes, said polymer capable of forming a complex with said topoisomerase inhibitor.

27. A composition according to claim 26, wherein said polyanionic polymer is selected from dextran sulfate, chondroitin sulfate A, polyvinylsulfuric acid, and polyphosphoric acid.

28. 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, a topoisomerase inhibitor which is an ionizable camptothecin derivative at a concentration of at least about 0.20 μ

mole topoisomerase inhibitor per μ

mole lipid, wherein said liposome composition provides at least a four-fold increase in anti-tumor activity over the anti-tumor activity of the drug in free-form.

29. A composition according to claim 28, wherein the camptothecin derivative is selected from the group consisting of 9-aminocamptothecin, 7-ethylcamptothecin, 10-hydroxycamptothecin, 9-nitrocamptothecin, 10,11-methylenedioxycamptothecin, 9-chloro-10,11 -methylenedioxycamptothecin, irinotecan, 7-(4-methylpiperazinomethylene)-10,11 -ethylenedioxy-20(S)-camptothecin (MPE-camptothecin), 7-(4-methylpiperazinomethylene)-10,11 -methylenedioxy-20(S)-camptothecin, 9-dimethyl-aminomethyl-10-hydroxycamptothecin (topotecan) and 7-(2-(N-isopropylamino)ethyl)-(20S)-camptothecin (CKD-602).

30. A composition according to claim 28, wherein the liposomes include a polyanionic polymer within the liposomes, said polymer capable of forming a complex with said topoisomerase inhibitor.

31. A composition according to claim 28, wherein said polyanionic polymer is selected from dextran sulfate, chondroitin sulfate A, polyvinylsulfuric acid, and polyphosphoric acid.