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 pharmaceutical composition essentially consisting of a paclitaxel prodrug associated with pharmaceutically acceptable diluents/excipients, for use in the treatment of non-muscle invasive bladder cancer (NMIBC) by intravesical instillation, in particular bladder carcinoma in situ (CIS) and preferably in the treatment of CIS non-responsive or refractory to treatment with the Calmette-Guérin bacillus (BCG), wherein the paclitaxel prodrug consists of the 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, preferably 20% w/w, and
 wherein said pharmaceutical composition is administered as a single weekly dose of 600 mg for 12 consecutive weeks of treatment. 
 
     
     
         2 . The pharmaceutical composition according to  claim 1  for use in the treatment of non-muscle invasive bladder cancer (NMIBC), in particular bladder carcinoma in situ (CIS) and preferably in the treatment of CIS non-responsive or refractory to treatment with BCG, 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 pharmaceutical composition according to  claim 1 , for use in the treatment of bladder carcinoma in situ (CIS) non-responsive or refractory to treatment with BCG. 
     
     
         4 . (canceled) 
     
     
         5 . (canceled) 
     
     
         6 . The pharmaceutical composition according to  claim 1 , for use in the treatment of bladder carcinoma in situ (CIS) non-responsive or refractory to treatment with BCG, wherein said prodrug consists of the chemical conjugate between paclitaxel and HA having a weight average molecular weight ranging from 160,000 to 230,000 Da. 
     
     
         7 . The pharmaceutical composition for use according to  claim 6 , wherein the paclitaxel-HA prodrug consists of the chemical conjugate between paclitaxel and hyaluronic acid with a derivatization degree equal to 20% weight/weight. 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . The pharmaceutical composition according to  claim 1 , wherein the paclitaxel prodrug is formulated in sterile isotonic water containing 5% glucose. 
     
     
         11 .- 13 . (canceled) 
     
     
         14 . The pharmaceutical composition according to  claim 2 , for use in the treatment of bladder carcinoma in situ (CIS) non-responsive or refractory to treatment with BCG. 
     
     
         15 .- 20 . (canceled)