Compositions for delivery of drug combinations

Abstract

Methods to prepare compositions which comprise delivery vehicles having stably associated therewith non-antagonistic combinations of two or more agents. The compositions exhibit non-antagonistic effects when combinations of drugs are administered.

1 . A method to prepare a composition comprising drug delivery vehicles, said vehicles having stably associated therewith at least a first therapeutic agent and a second therapeutic agent in a mole ratio which is non-antagonistic, which method comprises 
 a) determining a mole ratio of said first and second agent which has a non-antagonistic biological effect, and    b) encapsulating with said delivery vehicles a mole ratio of agents determined to be non-antagonistic in step a).    
     
     
         2 . The method of  claim 1 , wherein said agents are antineoplastic agents.  
     
     
         3 . The method of  claim 1 , wherein said non-antagonistic effect is exhibited in a relevant cell culture assay 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.  
     
     
         4 . The method of  claim 3 , wherein said non-antagonistic effect is exhibited over at least 5% of the concentration range such that 1%-99% of the cells are affected (f a =0.01-0.99) in an in vitro assay for cytotoxicity or cytostasis.  
     
     
         5 . The method of  claim 4 , wherein said non-antagonistic effect is exhibited over at least 5% of the concentration range such that 10-90% of the cells are affected (f a =0.1-0.9) in an in vitro assay for cytotoxicity or cytostasis.  
     
     
         6 . The method of  claim 5 , wherein said non-antagonistic effect is exhibited over at least 5% of the concentration range such that 20-80% of the cells are affected (f a =0.2-0.8) in an in vitro assay for cytotoxicity or cytostasis.  
     
     
         7 . The method of  claim 6 , wherein said synergistic effect is exhibited over at least 20% of the concentration range such that 20-80% of the cells are affected in an in vitro assay for cytotoxicity or cytostasis.  
     
     
         8 . The method of  claim 1 , wherein said determining employs testing at least one ratio of said agents at a multiplicity of concentrations and applying an algorithm to calculate a synergistic, additive, or antagonistic effect for said ratio over a range of concentrations.  
     
     
         9 . The method of  claim 8 , which employs testing a multiplicity of ratios.  
     
     
         10 . The method of  claim 8 , wherein said algorithm is the Chou-Talalay median effect method.  
     
     
         11 . The method of  claim 8 , wherein said agents are antineoplastic agents.  
     
     
         12 . The method of  claim 2 , wherein at least one of the 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 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.  
     
     
         13 . The method of  claim 2 , 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    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.    
     
     
         14 . The method of  claim 2 , 
 wherein the first agent is irinotecan and the second agent is 5-FU or FUDR, or    wherein the first agent is cisplatin and the second agent is 5-FU or FUDR, or    wherein the first agent is idarubicin and the second agent is AraC, or    wherein the first agent is oxaliplatin and the second agent is 5-FU or FUDR, or    wherein the first agent is irinotecan and the second agent is cisplatin (or carboplatin), or    wherein the first agent is gemcitabine and the second agent is cisplatin (or carboplatin), or    wherein the first agent is methotrexate and the second agent is 5-FU or FUDR, or    wherein the first agent is paclitaxel and the second agent is cisplatin (or carboplatin), or    wherein the first agent is etoposide and the second agent is cisplatin (or carboplatin), or    wherein the first agent is docetaxel or paclitaxel and the second agent is doxorubicin, or    wherein the first agent is adriamycin and the second agent is vinorelbine, or    wherein the first agent is carboplatin and the second agent is vinorelbine, or    wherein the first agent is 5-FU or FUDR and the second agent is gemcitabine.