PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: PFD-RP might be an attractive alternative to the current oral PFD therapy with a better safety margin.
PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS:PFD-RP might be an attractive alternative to the current oral PFD therapy with a better safety margin.
Authors: H Taniguchi; M Ebina; Y Kondoh; T Ogura; A Azuma; M Suga; Y Taguchi; H Takahashi; K Nakata; A Sato; M Takeuchi; G Raghu; S Kudoh; T Nukiwa Journal: Eur Respir J Date: 2009-12-08 Impact factor: 16.671
Authors: David Alejandro Lopez-de la Mora; Cibeles Sanchez-Roque; Margarita Montoya-Buelna; Sergio Sanchez-Enriquez; Silvia Lucano-Landeros; Jose Macias-Barragan; Juan Armendariz-Borunda Journal: Int J Med Sci Date: 2015-10-14 Impact factor: 3.738