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

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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.

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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

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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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Authors and Affiliations

  1. Department of Pharmacokinetics and Pharmacodynamics School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan

    Satomi Onoue, Yoshiki Seto, Masashi Kato, Yosuke Aoki, Yoshiki Kojo & Shizuo Yamada

Authors
  1. Satomi Onoue
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  2. Yoshiki Seto
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  3. Masashi Kato
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  4. Yosuke Aoki
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  5. Yoshiki Kojo
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  6. Shizuo Yamada
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Correspondence to Satomi Onoue.

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Onoue, S., Seto, Y., Kato, M. et al. Inhalable Powder Formulation of Pirfenidone with Reduced Phototoxic Risk for Treatment of Pulmonary Fibrosis. Pharm Res 30, 1586–1596 (2013). https://doi.org/10.1007/s11095-013-0997-4

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  • DOI: https://doi.org/10.1007/s11095-013-0997-4

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