Therapeutically Effective Controlled Release Formulation ofPirfenidone from Nontoxic Biocompatible Carboxymethyl PullulanPoly(vinyl alcohol) Interpenetrating Polymer Networks

摘要

The present study was conducted to developtherapeutically effective controlled release formulation ofpirfenidone (PFD) and explore the possibility to reduce thetotal administered dose and dosing regimen. For this purpose,pH-sensitive biomaterial was prepared by inducing carboxymethyl group on pullulan by Williamson ether synthesisreaction, and further, interpenetrating polymeric networkmicrospheres were prepared by glutaraldehyde-assistedwater-in-oil (w/o) emulsion cross-linking method, whichshowed higher swelling ratio in acidic and basic pH. Theformation of microspheres was confirmed by different spectralcharacterization techniques, and thermal kinetic studyindicated the formation of thermally stable microspheres.Cell viability and biocompatibility studies on hepatocellularcarcinoma (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 vivoperformances of prepared microsphere and marketed product of PFD were compared in rabbit. Tmax (time taken to reach peakplasma concentration) was found to be achieved at 0.83 h, compared to 0.5 h for Pirfenex with no significant differencecomplementing the immediate action, while area under curve was significantly greater for optimized formulation (9768 ± 1300ng h/mL) compared to Pirfenex (4311 ± 110 ng h/mL), complementing the sustained action. In vivo pharmacokinetic studysuggested that the prepared microsphere could be a potential candidate for therapeutically effective controlled delivery of PFDused in dyspnea and cough management due to idiopathic pulmonary fibrosis.