Inhalable Powder Formulation of Pirfenidone with Reduced Phototoxic Risk for Treatment of Pulmonary Fibrosis
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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.
Key wordsinhalation photostability phototoxicity pirfenidone pulmonary fibrosis
analysis of variance
area under concentration versus time curve
area under moment curve
bronchoalveolar lavage fluid
electrospray ionization mass spectrometry
mean residence time
reactive oxygen species
scanning electron microscopy
ultra performance liquid chromatography
Acknowledgments AND DISCLOSURES
Authors are grateful to Shionogi&Co., Ltd. for kindly providing pirfenidone. This work was supported in part by a Grant-in-Aid for Young Scientists (B) (No. 22790043; S. Onoue) from the Ministry of Education, Culture, Sports, Science, and Technology and a Health Labour Sciences Research Grant from The Ministry of Health, Labour, and Welfare, Japan.
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