Pharmaceutical Formulations of Biodegradable Biocompatible Camptothecin-Polymer Conjugates

Abstract

A camptothecin/polymer dual phase drug release system is described that is stable in both liquid and lyophilized states. The polymer contains acetals and/or ketals.

What is claimed is: 
     
         1 . A pharmaceutical composition suitable for intravenous administration comprising a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein one of R 1  is H or 
       
       
         
           
           
               
               
           
         
       
       and the other is 
       
         
           
           
               
               
           
         
       
       one of R 2  is H or 
       
         
           
           
               
               
           
         
       
       and the other is 
       
         
           
           
               
               
           
         
       
       CPT is camptothecin;
 n is 32-3320; 
 m is 0-833; 
 k is 1-216; 
 wherein k, m, and n are selected so that about 5% to about 6% of the compound by weight is camptothecin; 
 mannitol; 
 one or more buffers; and 
 a surfactant; 
 wherein the molecular weight of the compound is from about 10 kD to about 500 kD, and the pharmaceutical composition has a pH of about 4.0 to 5.2. 
 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the one or more buffers are sodium citrate and citric acid buffer, and the surfactant is Polysorbate 80. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein about 5.5% of the compound by weight is camptothecin. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the mannitol is present at a concentration of between about 1 mg/mL to about 25 mg/mL. 
     
     
         5 . The pharmaceutical composition of  claim 4 , wherein the mannitol is present at a concentration of about 20 mg/mL. 
     
     
         6 . The pharmaceutical composition of  claim 2 , wherein the sodium citrate is present at a concentration of between about 0.5 mg/mL to about 5 mg/mL. 
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein the sodium citrate is present at a concentration of about 4.5 mg/mL. 
     
     
         8 . The pharmaceutical composition of  claim 2 , wherein citric acid is present at a concentration of between about 0.1 mg/mL to about 4.5 mg/mL. 
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein citric acid is present at a concentration of about 2.8 mg/mL. 
     
     
         10 . The pharmaceutical composition of  claim 2 , wherein the Polysorbate 80 is present at a concentration of between about 0.1 mg/mL to about 4.5 mg/mL. 
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein the Polysorbate 80 is present at a concentration of about 0.2 mg/mL. 
     
     
         12 . The pharmaceutical composition of  claims 1 , wherein the pharmaceutical composition is a storage stable aqueous solution. 
     
     
         13 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is a highly storage stable aqueous solution. 
     
     
         14 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is a lyophilized cake suitable for intravenous administration after reconstitution. 
     
     
         15 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is suitable for lyophilization and reconstitution. 
     
     
         16 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is storage stable and the pH of the pharmaceutical composition is about 4.2 to about 4.8. 
     
     
         17 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is an injectable solution prepared using a liquid to reconstitute a lyophilized cake comprising the compound of formula (I). 
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein the liquid is sterile water, 0.9% Normal Saline or 0.45% Normal Saline. 
     
     
         19 . The pharmaceutical composition of  claim 17 , wherein the liquid is 0.45% Normal Saline. 
     
     
         20 . The pharmaceutical composition of  claim 1 , wherein about 5.5% of the compound by weight is camptothecin, the concentration of mannitol is about 20 mg/mL, the concentration of Polysorbate 80 is about 0.2 mg/mL, the concentration of sodium citrate is about 4.5 mg/mL, the concentration of citric acid is about 2.8 mg/mL, and the pharmaceutical composition has a pH of about 4.2 to about 4.8.