Methods for Reducing Cisplatin Nephrotoxicity

Abstract

The present invention provides compositions and methods to reduce renal damage caused by nephrotoxic drugs such as cisplatin. The invention provides compositions comprising a substituted cyclodextrin, cisplatin and a pharmaceutically acceptable carrier, where the cyclodextrin is present in an amount effective for substantially inhibiting the nephrotoxic effect of the cisplatin.

1 . A method of reducing nephrotoxicity associated with administration of cisplatin to a patient in need thereof, the method comprising:
 administering a pharmaceutical composition to the patient, the composition comprising cisplatin, a substituted cyclodextrin, and a pharmaceutically acceptable carrier.   
     
     
         2 . The method of  claim 1  wherein the substituted cyclodextrin is of the formula:
   cyclodextrin-[(O—R—Y) − (Me) + ] n  
 
 where R is selected from the group consisting of straight chained or branched C 1-10  alkyl, alkenyl or alkynyl; 
 Y is an anionic group selected from COO, SO 3 , SO 4 , PO 3 H or PO 4 ; 
 Me is a pharmaceutically acceptable cation; and 
 n is a whole number greater than 1. 
 
     
     
         3 . The method of  claim 2  wherein the cyclodextrin is beta-cyclodextrin. 
     
     
         4 . The method of  claim 3  wherein R is C 1-4  alkyl selected from the group consisting of methyl, ethyl, propyl and butyl. 
     
     
         5 . The method of  claim 4  where R is butyl. 
     
     
         6 . The method of  claim 2  wherein Y is SO 3 . 
     
     
         7 . The method of  claim 3  wherein (O—R—Y) − (Me) +  is —O—(CH 2 ) 4 —SO 3   − Na + . 
     
     
         8 . The method of  claim 7  wherein n is 7. 
     
     
         9 . The method of  claim 1  wherein the substituted cyclodextrin is 2-hydroxypropyl β-cyclodextrin. 
     
     
         10 . The method of  claim 1  wherein the molar ratio of cisplatin to substituted cyclodextrin is selected from a ratio in the range from 50:1 to 1:50. 
     
     
         11 . The method of  claim 10  wherein the molar ratio of cisplatin to substituted cyclodextrin is selected from a ratio in the range from 25:1 to 1:20. 
     
     
         12 . The method of  claim 11  wherein the molar ratio of cisplatin to substituted cyclodextrin is selected from a ratio in the range from 10:1 to 1:10. 
     
     
         13 . The method of  claim 12  wherein the molar ratio of cisplatin to substituted cyclodextrin is selected from a ratio in the range from 2:1 to 1:5. 
     
     
         14 . The method of  claim 13  wherein the molar ratio of cisplatin to substituted cyclodextrin is selected from the group consisting of 2:1; 1:1; 1:2; and 1:5. 
     
     
         15 . A method of reducing nephrotoxicity associated with administration of cisplatin to a patient in need thereof, the method comprising:
 administering to the patient in need thereof a first pharmaceutical composition comprising a substituted cyclodextrin, and   administering to the patient a second pharmaceutical composition comprising cisplatin.   
     
     
         16 . The method of  claim 15  wherein the administering of the first pharmaceutical composition is performed at any period of time selected from within one hour before to within one hour after administering the second pharmaceutical composition. 
     
     
         17 . The method of  claim 16  wherein the administering of the first pharmaceutical composition is performed concurrently with the administering of the second pharmaceutical composition. 
     
     
         18 . The method of  claim 15  wherein said substituted cyclodextrin is a cyclodextrin of the formula:
   cyclodextrin-[(O—R—Y) − (Me) + ] n  
 
 where R is selected from the group consisting of straight chained or branched C 1-10  alkyl, alkenyl or alkynyl; 
 Y is an anionic group selected from COO, SO 3 , SO 4 , PO 3 H or PO 4 ; 
 Me is a pharmaceutically acceptable cation; and 
 n is a whole number greater than 1. 
 
     
     
         19 . The method of  claim 18  wherein said cyclodextrin is β-cyclodextrin; and (O—R—Y) − (Me) +  is —O—(CH 2 ) 4 —SO 3   − Na + . 
     
     
         20 . The method of  claim 15  wherein said cyclodextrin is 2-hydroxypropyl β-cyclodextrin. 
     
     
         21 . The method of  claim 15  wherein the molar ratio of cisplatin in the second composition to substituted cyclodextrin in the first composition is selected from a ratio in the range from 50:1 to 1:50. 
     
     
         22 . The method of  claim 21  wherein the molar ratio of cisplatin in the second composition to substituted cyclodextrin in the first composition is selected from a ratio in the range of 25:1 to 1:20. 
     
     
         23 . The method of  claim 22  wherein the molar ratio of cisplatin in the second composition to substituted cyclodextrin in the first composition is selected from a ratio in the range from 10:1 to 1:10. 
     
     
         24 . The method of  claim 23  wherein the molar ratio of cisplatin in the second composition to substituted cyclodextrin in the first composition is selected from a ratio in the range from 2:1 to 1:5. 
     
     
         25 . The method of  claim 24  wherein the molar ratio of cisplatin in the second composition to substituted cyclodextrin in the first composition is selected from the group consisting of 2:1; 1:1; 1:2; and 1:5. 
     
     
         26 . The method of  claim 1  wherein the pharmaceutical composition is administered intravenously. 
     
     
         27 . The method of  claim 15  wherein the first pharmaceutical composition and the second pharmaceutical composition are both administered intravenously.