Department of Pharmacokinetics and Pharmacodynamics School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Pharm Res. 2013 Jun;30(6):1586-96. doi: 10.1007/s11095-013-0997-4. Epub 2013 Feb 21.
Orally-taken pirfenidone (PFD), an idiopathic pulmonary fibrosis drug, often causes severe phototoxicity. Present study aimed to develop a respirable powder formulation for PFD (PFD-RP) to minimize phototoxic risk.
Photochemical properties of PFD were examined using a reactive oxygen species (ROS) assay and photostability testing. PFD-RP was characterized with a focus on photostability, in vitro inhalation performance, and the efficacy in antigen-sensitized rats. Pharmacokinetic studies were conducted after oral and intratracheal administration of PFD formulations.
Although PFD solution exhibited photodegradation under simulated sunlight (250 W/m²), both PFD powder and PFD-RP were photochemically stable. Laser diffraction and cascade impactor analyses on PFD-RP suggested its high dispersion and fine in vitro inhalation performance. Inhaled PFD-RP (300 μg-PFD/rat) could suppress antigen-evoked pulmonary inflammation in rats as evidenced by decreases in recruited inflammatory cells and neutrophilia-related biomarkers in the lung. Exposure of PFD to light-exposed tissues (skin and eye) after intratracheal administration of PFD-RP at a pharmacologically effective dose (300 μg-PFD/rat) was 90-130-fold less than that of the oral PFD dosage form at a phototoxic dose (160 mg/kg).
PFD-RP might be an attractive alternative to the current oral PFD therapy with a better safety margin.
口服吡非尼酮（PFD）是一种特发性肺纤维化药物，常导致严重的光毒性。本研究旨在开发一种可吸入粉末制剂（PFD-RP）以最小化光毒性风险。
使用活性氧（ROS）测定法和光稳定性测试来检查 PFD 的光化学性质。PFD-RP 的特征在于光稳定性、体外吸入性能以及在抗原致敏大鼠中的疗效。进行了口服和气管内给予 PFD 制剂后的药代动力学研究。
尽管 PFD 溶液在模拟阳光下（250 W/m²）表现出光降解，但 PFD 粉末和 PFD-RP 均具有光化学稳定性。对 PFD-RP 的激光衍射和级联撞击器分析表明其具有高分散性和良好的体外吸入性能。吸入 PFD-RP（300 μg-PFD/大鼠）可抑制抗原诱发的大鼠肺部炎症，表现为肺部募集的炎症细胞和嗜中性粒细胞相关生物标志物减少。与口服 PFD 剂型在光毒性剂量（160 mg/kg）下相比，在气管内给予 PFD-RP 的治疗剂量（300 μg-PFD/大鼠）后，PFD 暴露于光照射组织（皮肤和眼睛）的暴露量少 90-130 倍。
PFD-RP 可能是当前口服 PFD 治疗的一种有吸引力的替代方法，具有更好的安全性。
