Combination compositions of camptothecins and fluoropyrimidines
Compositions which comprise liposomes having stably associated therewith a camptothecin and a fluoropyrimidine are useful in achieving enhanced therapeutic effects when combinations of these drugs are administered.
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 CuSO 4 .
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 CuSO 4 .
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 (f a >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.