Claims
- 1. A composition that comprises liposomes stably associated with at least one water-soluble camptothecin and at least one fluoropyrimidine at a camptothecin-to-fluoropyrimidine mole ratio that has a desired cytotoxic, cytostatic or biologic effect to relevant cells or tumor cell homogenates.
- 2. The composition of claim 1 wherein the desired cytotoxic, cytostatic or biologic effect to relevant cells or tumor cell homogenates is non-antagonistic.
- 3. The composition of claim 1 which further includes leucovorin sufficient to stabilize said fluoropyrimidine.
- 4. The composition of claim 2 which further includes leucovorin sufficient to stabilize said fluoropyrimidine.
- 5. The composition of claim 1 wherein the water-soluble camptothecin is irinotecan (CPT-11), topotecan, 9-aminocamptothecin or lurtotecan.
- 6. The composition of claim 1 wherein the water-soluble camptothecin is a hydrophilic salt of a water-insoluble camptothecin.
- 7. The composition of claim 2 wherein the water-soluble camptothecin is irinotecan (CPT-11) or topotecan.
- 8. The composition of claim 1 wherein the fluoropyrimidine is floxuridine, fluorouracil or UFT (tegafur/uracil).
- 9. The composition of claim 1 wherein said liposomes comprise a phosphatidylcholine-containing lipid.
- 10. The composition of claim 9 wherein said phosphatidylcholine-containing lipid is DSPC or DAPC.
- 11. The composition of claim 1 wherein said liposomes comprise a phosphatidylglycerol or a phosphatidylinositol.
- 12. The composition of claim 11 wherein the phosphatidyl glycerol is DSPG or DMPG.
- 13. The composition of claim 1 wherein said liposomes comprise a sterol.
- 14. The composition of claim 13 wherein said sterol is cholesterol.
- 15. The composition of claim 14 wherein said cholesterol is present at less than 20 mol%.
- 16. The composition of claim 1 wherein said liposomes comprise a metal ion solution.
- 17. The composition of claim 16 wherein said metal ion is copper.
- 18. The composition of claim 17 wherein said metal ion solution is Cu(gluconate)2 or CuSO4.
- 19. The composition of claim 1 wherein said water-soluble camptothecin and fluoropyrimidine are co-encapsulated.
- 20. The composition of claim 1 wherein said water-soluble camptothecin is irinotecan or topotecan and said fluoropyrimidine is floxuridine or 5-FU.
- 21. The composition of claim 20 wherein said liposomes comprise DSPC.
- 22. The composition of claim 20 wherein said liposomes comprise DSPG.
- 23. The composition of claim 20 wherein said liposomes comprise cholesterol.
- 24. The composition of claim 20 wherein said liposomes comprise Cu(gluconate)2 or CuSO4.
- 25. The composition of claim 20 wherein said liposomes comprise triethanolamine (TEA).
- 26. The composition of claim 1 which, when administered to a subject, provides a therapeutic activity greater than that which is obtained when said water-soluble camptothecin and said fluoropyrimidine are administered in the same ratio but not stably associated with liposomes.
- 27. The composition of claim 1 wherein the composition comprises a third agent.
- 28. A method to prepare a composition comprising liposomes, said liposomes having stably associated therewith at least one water-soluble camptothecin and one fluoropyrimidine in a mole ratio which is non-antagonistic, which method comprises
a) determining in a relevant cell culture assay, cell-free assay or tumor cell homogenate for biological activity a mole ratio of said water-soluble camptothecin and fluoropyrimidine agents which is non-antagonistic over at least 5% of the concentration range over which greater than 1% of cells are affected (fa>0.01) by said ratio of agents, and b) encapsulating within said liposomes a mole ratio of water-soluble camptothecin-to-fluoropyrimidine determined to be non-antagonistic in step a).
- 29. A method to treat a disease condition in a subject which method comprises administering to a subject in need of such treatment a therapeutically effective amount of the composition of claim 1.
- 30. The method of claim 29 which further comprises administering leucovorin to said subject.
- 31. The method of claim 29 wherein the subject is a human.
- 32. The method of claim 29 wherein the subject is a non-human mammal or avian.
- 33. A method to deliver a therapeutically effective amount of a fluoropyrimidine/water-soluble camptothecin drug combination by administering a fluoropyrimidine stably associated with a first delivery vehicle and a water-soluble camptothecin stably associated with a second delivery vehicle wherein the ratio of the fluoropyrimidine and the water-soluble camptothecin administered is non-antagonistic.
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims benefit under 35 U.S.C. § 119(e) of U.S. Ser. No. 60/460,169 filed 2 Apr. 2003, the contents of which are incorporated herein by reference.
Provisional Applications (1)
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Number |
Date |
Country |
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60460169 |
Apr 2003 |
US |