Paclitaxel-hyaluronic acid conjugate in the treatment of non-muscle invasive bladder cancer

Abstract

A pharmaceutical composition is described, essentially consisting of the paclitaxel prodrug associated with pharmacologically acceptable diluents/excipients, for use in the treatment of non-muscle invasive bladder cancer (NMIBC) by means of intravesical instillations according to a single weekly dose of 600 mg of said prodrug, or two weekly doses equal to a total of 1,200 mg, for 12 or 6 consecutive weeks of treatment.The paclitaxel prodrug used was prepared according to an indirect synthesis process between molecules of hyaluronic acid (HA) and paclitaxel by introducing a spacer (4-bromobutyric acid) between the hyaluronic acid and chemotherapeutic agent.

1 . A method of treating non-muscle invasive bladder cancer (NMIBC) by intravesical instillation, which comprises administering to a patient in need thereof a pharmaceutical composition comprising a paclitaxel prodrug associated with pharmaceutically acceptable diluents/excipients,
 wherein the pharmaceutical composition is administered as,
 a) a single weekly dose of 600 mg for 12 consecutive weeks of treatment; or 
 b) a double weekly dose for a total of 1,200 mg of said composition per week for 6 consecutive weeks of treatment, and 
 wherein the paclitaxel prodrug consists of a conjugate between paclitaxel and hyaluronic acid by means of 4-bromobutyric acid, said HA being bound indirectly to the paclitaxel through the ester bond between the carboxyl of HA and the 4-bromobutyric acid spacer in turn bound with an ester bond through its carboxyl to the hydroxyl group of the carbon in C2′ of paclitaxel, with a derivatization degree within the range of 18-21% weight/weight. 
   
     
     
         2 . The method according to  claim 1 , wherein the paclitaxel-HA prodrug consists of the chemical conjugate between paclitaxel and hyaluronic acid with a derivatization degree equal to 20% weight/weight. 
     
     
         3 . The method according to  claim 1 , wherein the non-muscle invasive bladder cancer (NMIBC) is bladder carcinoma in situ (CIS) non-responsive or refractory to treatment with Calmette-Guérin bacillus (BCG). 
     
     
         4 . The method according to  claim 1 , wherein the hyaluronic acid in said paclitaxel prodrug has a weight average molecular weight ranging from 160,000 to 230,000 Da. 
     
     
         5 . The method according to  claim 4 , wherein the paclitaxel-HA prodrug consists of the chemical conjugate between paclitaxel and hyaluronic acid with a derivatization degree equal to 20% weight/weight. 
     
     
         6 . The method according to  claim 1 , wherein the paclitaxel prodrug is formulated in sterile isotonic water containing 5% glucose. 
     
     
         7 . The method according to  claim 2 , wherein the non-muscle invasive bladder cancer (NMIBC) is bladder carcinoma in situ (CIS) non-responsive or refractory to treatment with BCG. 
     
     
         8 . The method according to  claim 4 , wherein the non-muscle invasive bladder cancer (NMIBC) is bladder carcinoma in situ (CIS) non-responsive or refractory to treatment with BCG. 
     
     
         9 . The method according to  claim 1 , wherein the wherein the pharmaceutical composition is administered as a single weekly dose of 600 mg for 12 consecutive weeks of treatment. 
     
     
         10 . The method according to  claim 1 , wherein the wherein the pharmaceutical composition is administered as a double weekly dose for a total of 1,200 mg of said composition per week for 6 consecutive weeks of treatment. 
     
     
         11 . The method according to  claim 9 , wherein the paclitaxel prodrug is formulated in sterile isotonic water containing 5% glucose.