Seto Yoshiki, Suzuki Gen, Leung Sharon Shui Yee, Chan Hak-Kim, Onoue Satomi
Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan.
Advanced Drug Delivery Group, Faculty of Pharmacy, University of Sydney, Sydney, NSW, 2006, Australia.
Pharm Res. 2016 Jun;33(6):1447-55. doi: 10.1007/s11095-016-1887-3. Epub 2016 Mar 14.
Previously, a respirable powder (RP) formulation of pirfenidone (PFD) was developed for reducing phototoxic risk; however, PFD-RP demonstrated unacceptable in vitro inhalation performance. The present study aimed to develop a new RP system of PFD with favorable inhalation properties by spray-drying method.
Spray-dried PFD (SD/PFD) was prepared by spray-drying with L-leucine, and the physicochemical properties and efficacy in an antigen-sensitized airway inflammation model were assessed. A pharmacokinetic study was also conducted after intratracheal and oral administration of PFD formulations.
Regarding powder characterization, SD/PFD had dimpled surface with the mean diameter of 1.793 μm. In next generation impactor analysis, SD/PFD demonstrated high in vitro inhalation performance without the need of carrier particles, and the fine particle fraction of SD/PFD was calculated to be 62.4%. Insufflated SD/PFD (0.3 mg-PFD/rat) attenuated antigen-evoked inflammatory events in the lung, including infiltration of inflammatory cells and myeloperoxidase activity. Systemic exposure level of PFD after insufflation of SD/PFD at the pharmacologically effective dose was 600-fold lower than that after oral administration of PFD at the phototoxic dose.
SD/PFD would be suitable for inhalation, and the utilization of an RP system with SD/PFD would provide a safer medication compared with oral administration of PFD.
先前已开发出一种用于降低光毒性风险的吡非尼酮（PFD）可吸入粉剂（RP）制剂；然而，PFD-RP在体外吸入性能方面表现不佳。本研究旨在通过喷雾干燥法开发一种具有良好吸入特性的新型PFD-RP系统。
用L-亮氨酸通过喷雾干燥制备喷雾干燥的PFD（SD/PFD），并评估其理化性质以及在抗原致敏气道炎症模型中的疗效。在气管内和口服给予PFD制剂后还进行了药代动力学研究。
关于粉末特性，SD/PFD表面有凹痕，平均直径为1.793μm。在下一代撞击器分析中，SD/PFD在无需载体颗粒的情况下表现出较高的体外吸入性能，计算得出SD/PFD的细颗粒分数为62.4%。吹入SD/PFD（0.3mg-PFD/大鼠）可减轻肺部抗原诱发的炎症反应，包括炎性细胞浸润和髓过氧化物酶活性。在药理有效剂量下吹入SD/PFD后PFD的全身暴露水平比在光毒性剂量下口服PFD后低600倍。
SD/PFD适合吸入，与口服PFD相比，使用含SD/PFD的RP系统将提供更安全的用药方式。
