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 °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.