Novel inhalable powder formulation of pirfenidone with sustained release properties to improve pulmonary deposition

Abstract

The aim of this study was to develop a new respirable powder (RP) formulation of pirfenidone (PFD) with sustained release properties to ameliorate the pharmacokinetic drawbacks of the previously-developed PFD-RP on rapid elimination from the lung after insufflation. Based on screenings using several polymers, Kollidon® SR was chosen to produce a solid dispersion of PFD with sustained release properties (SRSD/PFD), and an RP formulation of SRSD/PFD (SRSD/PFD-RP) was prepared. Characteristics of SRSD/PFD-RP were examined in terms of biopharmaceutical, pharmacological, and phototoxic properties. In laser diffraction analysis, SRSD/PFD-RP could be dispersed to SRSD/PFD and lactose carrier particles, and SRSD/PFD in SRSD/PFD-RP had suitable particle sizes for inhalation. Insufflated SRSD/PFD-RP (0.03 mg-PFD/rat) showed a prolonged elimination half-life and mean residence time of PFD since these values were approximately 3.7-fold higher than those of insufflated PFD-RP (0.3 mg-PFD/rat: a pharmacologically-effective dose). Insufflated SRSD/PFD-RP (0.03 mg-PFD/rat) showed a similar anti-inflammatory potential in the lung of antigen-evoked lung inflammatory models compared with insufflated PFD-RP (0.3 mg-PFD/rat). Obvious skin phototoxicity was negligible after insufflation of SRSD/PFD-RP (0.03 mg-PFD/rat). In conclusion, SRSD/PFD-RP would be an attractive dosage form for an inhalation system of PFD and contribute to PFD medication for idiopathic pulmonary fibrosis with high efficacy and safety.