Water soluble paclitaxel derivatives

Abstract

Disclosed are water soluble compositions of paclitaxel and docetaxel formed by conjugating the paclitaxel or docetaxel to a water soluble polymer such as poly-glutamic acid, poly-aspartic acid or poly-lysine. Also disclosed are methods of using the compositions for treatment of tumors, auto-immune disorders such as rheumatoid arthritis. Other embodiments include the coating of implantable stents for prevention of restenosis.

What is claimed is:  
     
         1 . A composition comprising a conjugate of a plurality of therapeutic agents and a water-soluble amino acid polymer wherein said plurality of therapeutic agents are covalently bonded to said polymer.  
     
     
         2 . The compostion of  claim 1  wherein at least one of said therapetuic agents is a chemotherapeutic or antiangiogenic drug.  
     
     
         3 . The composition of  claim 1  wherein at least one of said plurality of therapeutic agents is a taxoid, tamoxifen, etoposide, teniposide, fludarabine, doxorubicin, daunomycin, emodin, 5-fluorouracil, FUDR, estradiol, camptothecin, a retinoid, verapamil, an epothilone or a cyclosporin.  
     
     
         4 . The composition of  claim 3 , wherein at least one of said therapetuic agents is a taxoid which is paclitaxel or taxotere.  
     
     
         5 . The composition of  claim 1 , wherein at least one of said therapeutic agents is paclitaxel.  
     
     
         6 . The composition of  claim 5 , wherein at least one of said therapeutic agents is selected from the group consisting of a taxoid, tamoxifen, etoposide, teniposide, fludarabine, doxorubicin, daunomycin, emodin, 5-fluorouracil, FUDR, estradiol, camptothecin, a retinoid, verapamil, an epothilone or a cyclosporin.  
     
     
         7 . The composition of  claim 1 , wherein said polymer has a molecular weight of from about 1 to about 100,000 daltons.  
     
     
         8 . The composition of  claim 7 , wherein said polymer has a molecular weight of from about 20,000 to about 80,000 daltons.  
     
     
         9 . The composition of  claim 8 , wherein said polymer has a molecular weight of from about 25,000 to about 50,000 daltons.  
     
     
         10 . The composition of  claim 7 , wherein said polymer has a molecular weight of about 20,000, about 21,000, about 22,000, about 23,000, about 24,000, about 25,000, about 26,000, about 27,000, about 28,000, about 29,000, about 30,000, about 31,000, about 32,000, about 33,000, about 34,000, about 35,000, about 36,000, about 37,000, about 38,000, about 39,000, about 40,000, about 41,000, about 42,000, about 43,000, about 44,000, about 45,000, about 46,000, about 47,000, about 48,000, about 49,000 or about 50,000 daltons.  
     
     
         11 . The composition of  claim 1  wherein total amount of the plurality of therapeutic agents is at least 10% (w/w) based on the mass of said conjugate.  
     
     
         12 . The composition of  claim 1  wherein the total amount of said therapeutic agents is from about 10% to about 40% (w/w) based on the mass of said conjugate.  
     
     
         13 . The composition of  claim 1  wherein the total amount of said plurality of therapeutic agents is at least 20% (w/w) based on the mass of said conjugate.  
     
     
         14 . The composition of  claim 1  wherein the total amount of said therapeutics agents is from about 20 to about 40% (w/w) based on mass of said conjugate.  
     
     
         15 . A composition comprising a conjugate of a plurality of therapeutic agents and a water-soluble amino acid polymer wherein said plurality of therapeutic agents are covalently bonded to said polymer, and said polymer comprises polyglutamate.  
     
     
         16 . The compostion of  claim 15  wherein at least one of said therapetuic agents is a chemotherapeutic or antiangiogenic drug.  
     
     
         17 . The composition of  claim 15  wherein at least one of said plurality of therapeutic agents is a taxoid, tamoxifen, etoposide, teniposide, fludarabine, doxorubicin, daunomycin, emodin, 5-fluorouracil, FUDR, estradiol, camptothecin, a retinoid, verapamil, an epothilone or a cyclosporin.  
     
     
         18 . The composition of  claim 17 , wherein at least one of said therapetuic agents is a taxoid which is paclitaxel or taxotere.  
     
     
         19 . The composition of  claim 18 , wherein at least one of said therapeutic agents is paclitaxel.  
     
     
         20 . The composition of  claim 19 , wherein at least one of said therapeutic agents is selected from the group consisting of a taxoid, tamoxifen, etoposide, teniposide, fludarabine, doxorubicin, daunomycin, emodin, 5-fluorouracil, FUDR, estradiol, camptothecin, a retinoid, verapamil, an epothilone or a cyclosporin.  
     
     
         21 . The composition of  claim 15 , wherein said polymer has a molecular weight of from about 1 to about 100,000 daltons.  
     
     
         22 . The composition of  claim 21 , wherein said polymer has a molecular weight of from about 20,000 to about 80,000 daltons.  
     
     
         23 . The composition of  claim 22 , wherein said polymer has a molecular weight of from about 25,000 to about 50,000 daltons.  
     
     
         24 . The composition of  claim 21 , wherein said polymer has a molecular weight of about 20,000, about 21,000, about 22,000, about 23,000, about 24,000, about 25,000, about 26,000, about 27,000, about 28,000, about 29,000, about 30,000, about 31,000, about 32,000, about 33,000, about 34,000, about 35,000, about 36,000, about 37,000, about 38,000, about 39,000, about 40,000, about 41,000, about 42,000, about 43,000, about 44,000, about 45,000, about 46,000, about 47,000, about 48,000, about 49,000 or about 50,000 daltons.  
     
     
         25 . The composition of  claim 15  wherein total amount of the plurality of therapeutic agents is at least 10% (w/w) based on the mass of said conjugate.  
     
     
         26 . The composition of  claim 15  wherein the total amount of said therapeutic agents is from about 10% to about 40% (w/w) based on the mass of said conjugate.  
     
     
         27 . The composition of  claim 15  wherein the total amount of said plurality of therapeutic agents is at least 20% (w/w) based on the mass of said conjugate.  
     
     
         28 . The composition of  claim 15  wherein the total amount of said therapeutics agents is from about 20 to about 40% (w/w) based on mass of said conjugate.