Compositions for delivery of drug combinations
Compositions which comprise delivery vehicles having stably associated therewith non-antagonistic combinations of two or more agents, such as antineoplastic agents, are useful in achieving non-antagonistic effects when combinations of drugs are administered.
1. A method to administer a combination of therapeutic agents to a subject for treatment of a disease or condition in said subject which method comprises administering to a subject in need of such treatment a therapeutically effective amount of a composition comprising particulate delivery vehicles having associated therewith at least a first therapeutic agent and a second therapeutic agent, said agents suitable to ameliorate said disease or condition, wherein said first and second agents are in a mole ratio which is non-antagonistic, wherein said ratio exhibits a non-antagonistic cytotoxic or cytostatic effect in an in vitro assay over at least 20% of the concentration range over which the fraction of cells affected is 0.2-0.8, and wherein said first and second agents are associated with the delivery vehicles to maintain said administered ratio in the blood for at least one hour after administration,
wherein said delivery vehicles comprise
liposomes, and/or
lipid micelles, and/or
block copolymer micelles, and/or
polymer microparticles, and/or
polymer nanoparticles, and/or
polymer lipid hybrid systems, and/or
derivatized single chain polymers;
wherein said disease or condition is cardiovascular disease or an autoimmune disease.
2. The method of claim 1 wherein said first and second agents are co-encapsulated.
3. The method of claim 1 wherein the delivery vehicles are liposomes.
4. The method of claim 1 wherein at least one of said first or second agents is selected from the group consisting of a DNA damaging agent, a DNA repair inhibitor, a topoisomerase I inhibitor, a topoisomerase II inhibitor, a cell checkpoint inhibitor, a CDK inhibitor, a receptor tyrosine kinase inhibitor, a cytotoxic agent, an apoptosis inducing agent, an antimetabolite, a cell cycle control inhibitor, a therapeutic lipid, a telomerase inhibitor, an anti-angiogenic agent, a mitochondrial poison, a signal transduction inhibitor and an immunoagent.
5. The method of claim 4 wherein the first agent is a cytotoxic agent and the second agent is a cell-cycle inhibitor, or wherein the first agent is a DNA damaging agent and the second agent is a DNA repair inhibitor, or wherein the first agent is a topoisomerase I inhibitor and the second agent is a S/G 2 or a G 2 /M-checkpoint inhibitor, or wherein the first agent is a G 1 /S checkpoint inhibitor or a cyclin-dependent kinase inhibitor and the second agent is a G 2 /M checkpoint inhibitor, or wherein the first agent is a receptor kinase inhibitor and the second agent is a cytotoxic agent, or wherein the first agent is an apoptosis-inducing agent and the second agent is a cytotoxic agent, or wherein the first agent is an apoptosis-inducing agent and the second agent is a cell-cycle control agent, or wherein the first agent is a telomerase inhibitor and the second agent is a cell-cycle control inhibitor, or wherein the first and second agents are antimetabolites, or wherein the first and second agents are cytotoxic agents, or wherein the first agent is a therapeutic lipid and the second agent is a cytotoxic agent, or wherein the first agent is a topoisomerase I inhibitor and the second agent is a DNA repair inhibitor, or wherein the apoptosis-inducing agent is a serine-containing lipid.
6. The method of claim 5 wherein the first agent is a topoisomerase II inhibitor and the second agent is an antimetabolite or a cell cycle inhibitor.
7. The method of claim 1 wherein the subject is a human.
8. A method to administer a combination of therapeutic agents to a subject for treatment of a disease or condition in said subject which method comprises administering to a subject in need of such treatment a therapeutically effective amount of a composition comprising particulate delivery vehicles having associated therewith at least a first therapeutic agent and a second therapeutic agent, said agents suitable to ameliorate said disease or condition, wherein said first and second agents are in a mole ratio which is non-antagonistic, wherein said ratio exhibits a non-antagonistic effect in an in vitro assay measuring suppression of proinflammatory cytokines, and wherein said first and second agents are associated with the delivery vehicles to maintain said administered ratio in the blood for at least one hour after administration,
wherein said delivery vehicles comprise
liposomes, and/or
lipid micelles, and/or
block copolymer micelles, and/or
polymer microparticles, and/or
polymer nanoparticles, and/or
polymer lipid hybrid systems, and/or
derivatized single chain polymers;
wherein said disease or condition is inflammation.
9. The method of claim 8 wherein said first and second agents are co-encapsulated.
10. The method of claim 8 wherein the delivery vehicles are liposomes.
11. The method of claim 8 wherein the subject is a human.