Cellulose ether derivatives: a new platform for prodrug formation of fluoroquinolone antibiotics

Novel macromolecular prodrugs of the second-generation fluoroquinolone antibiotic ofloxacin were fabricated based on the hydrophilic biopolymers hydroxypropylcellulose (HPC) and hydroxyethylcellulose (HEC). HPC- and HEC-ofloxacin conjugates were synthesized by activation of ofloxacin with p-toluenesulfonyl chloride under homogeneous reaction conditions at 70 degrees C in a one-pot synthesis. Structures of HPC- and HEC-ofloxacin conjugates were confirmed by spectroscopic and chromatographic techniques. Covalent drug loading was determined by UV/Vis spectrophotometry after hydrolysis of the conjugates. The results indicated significant covalent ofloxacin-loading (degree of substitution, 0.53-0.71 and 0.38-0.47) on HPC and HEC, respectively. All prodrugs were soluble in organic and aqueous solvents. Transmission electron microscopic analysis indicated formation of nanoparticles in the size range 100-250 nm and 150-210 nm for HPC- and HEC-ofloxacin conjugates, respectively. Ofloxacin, HPC-ofloxacin conjugate, and HEC-ofloxacin conjugate were orally administered to healthy male albino rabbits to determine pharmacokinetic parameters. Both HPC- and HEC-ofloxacin conjugates showed sustained release, with an increase in ofloxacin ( control 1-3) half-life from 2.59, 4.56 and 4.63 h to 18.07 and 20.71 h, respectively. The relative AUC values clearly indicate ofloxacin oral bioavailability from conjugates that is enhanced, 1.6-1.8 and 2.1-2.3 times that of control.