Pharmaceutical Research

, Volume 30, Issue 6, pp 1586–1596

Inhalable Powder Formulation of Pirfenidone with Reduced Phototoxic Risk for Treatment of Pulmonary Fibrosis

  • Satomi Onoue
  • Yoshiki Seto
  • Masashi Kato
  • Yosuke Aoki
  • Yoshiki Kojo
  • Shizuo Yamada
Research Paper

DOI: 10.1007/s11095-013-0997-4

Cite this article as:
Onoue, S., Seto, Y., Kato, M. et al. Pharm Res (2013) 30: 1586. doi:10.1007/s11095-013-0997-4

Abstract

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.

Key words

inhalationphotostabilityphototoxicitypirfenidonepulmonary fibrosis

Abbreviations

8-MOP

8-methoxypsoralen

ANOVA

analysis of variance

AUC

area under concentration versus time curve

AUMC

area under moment curve

BALF

bronchoalveolar lavage fluid

EPO

eosinophil peroxidase

ESI-MS

electrospray ionization mass spectrometry

FQ

fluoroquinolones

HPMC

hydroxypropyl methylcellulose

MPO

myeloperoxidase

MRT

mean residence time

OVA

ovalbumin

PBS

phosphate-buffered saline

ROS

reactive oxygen species

RP

respirable powder

SEM

scanning electron microscopy

TMBZ

3,3′,5,5′-tetramethylbenzidine

UPLC

ultra performance liquid chromatography

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Satomi Onoue
    • 1
  • Yoshiki Seto
    • 1
  • Masashi Kato
    • 1
  • Yosuke Aoki
    • 1
  • Yoshiki Kojo
    • 1
  • Shizuo Yamada
    • 1
  1. 1.Department of Pharmacokinetics and Pharmacodynamics School of Pharmaceutical SciencesUniversity of ShizuokaShizuokaJapan