Formulations of bendamustine

Abstract

Methods of treatment using bendamustine formulations designed for small volume intravenous administration are disclosed. The methods conveniently allow shorter administration time without the active ingredient coming out of solution as compared to presently available formulations.

We claim: 
     
         1 . A method of treating chronic lymphocytic leukemia or indolent B cell non-Hodgkin's lymphoma in a subject comprising parenterally administering to the subject a volume of about 100 mL or less of a liquid composition comprising:
 bendamustine;   a charged cyclopolysaccharide; and   a parenterally acceptable diluent;   
       over a period of less than or equal to about 15 minutes. 
     
     
         2 . The method of  claim 1 , wherein the subject is human. 
     
     
         3 . The method of  claim 1 , wherein the concentration of the bendamustine or pharmaceutically acceptable salt thereof is from about 0.05 to about 12.5 mg/mL. 
     
     
         4 . The method of  claim 1 , wherein the concentration of the bendamustine or pharmaceutically acceptable salt thereof is from about 0.1 to about 6.0 mg/mL. 
     
     
         5 . The method of  claim 1 , wherein the concentration of the bendamustine or pharmaceutically acceptable salt thereof is from about 0.05 to about 3.2 mg/mL. 
     
     
         6 . The method of  claim 1 , wherein the concentration of the bendamustine or pharmaceutically acceptable salt thereof is from about 0.5 to about 5.6 mg/mL. 
     
     
         7 . The method of  claim 1 , wherein the volume administered is about 100 ml, about 50 mL, about 30 mL, or about 5 mL. 
     
     
         8 . The method of  claim 1 , wherein the volume administered is about 50 mL. 
     
     
         9 . The method of  claim 1 , wherein the bendamustine is administered to treat chronic lymphocytic leukemia. 
     
     
         10 . The method of  claim 9 , wherein the composition is administered intravenously in a volume of about 50 mL in about 10 minutes or less on days 1 and 2 of a 28 day cycle. 
     
     
         11 . The method of  claim 10 , wherein the composition is administered in about 10 minutes. 
     
     
         12 . The method of  claim 10 , wherein the composition is administered for up to 6 cycles. 
     
     
         13 . The method of  claim 9 , wherein the volume of the composition administered to the subject provides a bendamustine dosage amount ranging from about 25 mg/m 2  to about 100 mg/m 2  to the subject. 
     
     
         14 . The method of  claim 13 , wherein the composition provides a bendamustine dosage of about 100 mg/m 2 . 
     
     
         15 . The method of  claim 9 , wherein the liquid composition comprises from about 1.85 mg/mL to about 4.84 mg/mL of bendamustine or a pharmaceutically acceptable salt thereof. 
     
     
         16 . The method of  claim 1 , wherein the bendamustine is administered to treat indolent B cell non-Hodgkin's lymphoma. 
     
     
         17 . The method of  claim 16 , wherein the composition is administered intravenously in a volume of about 50 mL in about 10 minutes or less on days 1 and 2 of a 21 day cycle. 
     
     
         18 . The method of  claim 17 , wherein the composition is administered in about 10 minutes. 
     
     
         19 . The method of  claim 17 , wherein the composition is administered for up to 8 cycles. 
     
     
         20 . The method of  claim 16 , wherein the volume of the composition administered to the subject provides a bendamustine dosage amount ranging from about 60 mg/m 2  to about 120 mg/m 2  to the subject. 
     
     
         21 . The method of  claim 20 , wherein the composition provides a bendamustine dosage of about 120 mg/m 2 . 
     
     
         22 . The method of  claim 16 , wherein the liquid composition comprises from about 2.19 mg/mL to about 5.59 mg/mL of bendamustine or a pharmaceutically acceptable salt thereof. 
     
     
         23 . The method of  claim 1 , wherein the cyclopolysaccharide is a beta-cyclodextrin. 
     
     
         24 . The method of  claim 1 , wherein the charged cyclopolysaccaride has one or more anionic groups. 
     
     
         25 . The method of  claim 24 , wherein the anionic group is a sulfate, sulfonyl, or carbonyl group. 
     
     
         26 . The method of  claim 24 , wherein the anionic group is a sulfate or sulfonyl group. 
     
     
         27 . The method of  claim 24 , wherein the cyclopolysaccharide is sulfobutyl ether beta-cyclodextrin. 
     
     
         28 . The method of  claim 1 , wherein the proportion of bendamustine to cyclopolysaccaride is between about 1:12,500 and about 1:25, by weight. 
     
     
         29 . The method of  claim 1 , wherein the composition further comprises a stabilizing agent. 
     
     
         30 . The method of  claim 29 , wherein the stabilizing agent is a polypeptide comprising from about 5 to about 50 amino acids, wherein at least about 50% of the amino acids have a positive charge. 
     
     
         31 . The method of  claim 29 , wherein the stabilizing agent is a polypeptide comprising between about 6 and about 20 amino acids, wherein at least about 50% of the amino acids have a positive charge. 
     
     
         32 . The method of  claim 30 , wherein the polypeptide comprises at least one block sequence of 4 arginines. 
     
     
         33 . The method of  claim 32 , wherein the stabilizing agent is polyarginine. 
     
     
         34 . The method of  claim 30 , wherein the stabilizing agent is low molecular weight protamine. 
     
     
         35 . The method of  claim 1 , wherein the charged group on the cyclopolysaccharide is a cationic group. 
     
     
         36 . The composition of  claim 35 , wherein the cationic group is a quaternary ammonium group. 
     
     
         37 . The method of  claim 1 , wherein the bendamustine is present as the hydrochloride salt.