Therapeutically Effective Controlled Release Formulationof Pirfenidone from Nontoxic Biocompatible Carboxymethyl Pullulan-Poly(vinylalcohol) Interpenetrating Polymer Networks

摘要

The present study was conducted to develop therapeutically effective controlled release formulation of pirfenidone (PFD) and explore the possibility to reduce the total administered dose and dosing regimen. For this purpose, pH-sensitive biomaterial was prepared by inducing carboxymethyl group on pullulan by Williamson ether synthesis reaction, and further, interpenetrating polymeric network microspheres were prepared by glutaraldehyde-assisted water-in-oil (w/o) emulsion cross-linking method, which showed higher swelling ratio in acidic and basic pH. The formation of microspheres was confirmed by different spectral characterization techniques, and thermal kinetic study indicated the formation of thermally stable microspheres. Cell viability and biocompatibility studies on hepatocellular carcinoma (HepG2) cell showed the polymeric matrix to be biocompatible. In vitro dissolution of optimized formulation (F5) showed releases of 54.09 and 76.37% in 0.1 N HCl after 2 h and phosphate buffer (pH 6.8) up to 8 h, respectively. In vivo performances of prepared microsphere and marketed product of PFD were comparedin rabbit. Tmax (time taken to reach peakplasma concentration) was found to be achieved at 0.83 h, comparedto 0.5 h for Pirfenex with no significant difference complementingthe immediate action, while area under curve was significantly greaterfor optimized formulation (9768 ± 1300 ng h/mL) compared to Pirfenex(4311 ± 110 ng h/mL), complementing the sustained action. Invivo pharmacokinetic study suggested that the prepared microspherecould be a potential candidate for therapeutically effective controlleddelivery of PFD used in dyspnea and cough management due to idiopathicpulmonary fibrosis.