Advertisement

Pharmaceutical Research

, Volume 30, Issue 6, pp 1586–1596 | Cite as

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

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

inhalation photostability phototoxicity pirfenidone pulmonary 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

Notes

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.

References

  1. 1.
    Hisatomi K, Mukae H, Sakamoto N, Ishimatsu Y, Kakugawa T, Hara S, et al. Pirfenidone inhibits TGF-ss1-induced over-expression of collagen type I and heat shock protein 47 in A549 cells. BMC Pulm Med. 2012;12:24.PubMedCrossRefGoogle Scholar
  2. 2.
    Iyer SN, Gurujeyalakshmi G, Giri SN. Effects of pirfenidone on transforming growth factor-beta gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis. J Pharmacol Exp Ther. 1999;291:367–73.PubMedGoogle Scholar
  3. 3.
    Lasky J. Pirfenidone. IDrugs. 2004;7:166–72.PubMedGoogle Scholar
  4. 4.
    Schaefer CJ, Ruhrmund DW, Pan L, Seiwert SD, Kossen K. Antifibrotic activities of pirfenidone in animal models. Eur Respir Rev. 2011;20:85–97.PubMedCrossRefGoogle Scholar
  5. 5.
    Corbel M, Lanchou J, Germain N, Malledant Y, Boichot E, Lagente V. Modulation of airway remodeling-associated mediators by the antifibrotic compound, pirfenidone, and the matrix metalloproteinase inhibitor, batimastat, during acute lung injury in mice. Eur J Pharmacol. 2001;426:113–21.PubMedCrossRefGoogle Scholar
  6. 6.
    Hilberg O, Simonsen U, du Bois R, Bendstrup E. Pirfenidone: significant treatment effects in idiopathic pulmonary fibrosis. Clin Respir J. 2012;6:131–43.PubMedCrossRefGoogle Scholar
  7. 7.
    Richeldi L, Yasothan U, Kirkpatrick P. Pirfenidone. Nat Rev Drug Discov. 2011;10:489–90.PubMedCrossRefGoogle Scholar
  8. 8.
    Taniguchi H, Ebina M, Kondoh Y, Ogura T, Azuma A, Suga M, et al. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J. 2010;35:821–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Carter NJ. Pirfenidone: in idiopathic pulmonary fibrosis. Drugs. 2011;71:1721–1732.Google Scholar
  10. 10.
    Steinand KR, Scheinfeld NS. Drug-induced photoallergic and phototoxic reactions. Expert Opin Drug Saf. 2007;6:431–43.CrossRefGoogle Scholar
  11. 11.
    Onoue S, Seto Y, Gandy G, Yamada S. Drug-induced phototoxicity; an early in vitro identification of phototoxic potential of new drug entities in drug discovery and development. Curr Drug Saf. 2009;4:123–36.PubMedCrossRefGoogle Scholar
  12. 12.
    Seto Y, Inoue R, Ochi M, Gandy G, Yamada S, Onoue S. Combined use of in vitro phototoxic assessments and cassette dosing pharmacokinetic study for phototoxicity characterization of fluoroquinolones. AAPS J. 2011;13:482–92.PubMedCrossRefGoogle Scholar
  13. 13.
    Onoue S, Aoki Y, Kawabata Y, Matsui T, Yamamoto K, Sato H, et al. Development of inhalable nanocrystalline solid dispersion of tranilast for airway inflammatory diseases. J Pharm Sci. 2011;100:622–33.PubMedCrossRefGoogle Scholar
  14. 14.
    Onoue S, Sato H, Kawabata Y, Mizumoto T, Hashimoto N, Yamada S. In vitro and in vivo characterization on amorphous solid dispersion of cyclosporine A for inhalation therapy. J Control Release. 2009;138:16–23.PubMedCrossRefGoogle Scholar
  15. 15.
    Onoueand S, Tsuda Y. Analytical studies on the prediction of photosensitive/phototoxic potential of pharmaceutical substances. Pharm Res. 2006;23:156–64.CrossRefGoogle Scholar
  16. 16.
    Misaka S, Sato H, Yamauchi Y, Onoue S, Yamada S. Novel dry powder formulation of ovalbumin for development of COPD-like animal model: Physicochemical characterization and biomarker profiling in rats. Eur J Pharm Sci. 2009;37:469–76.PubMedCrossRefGoogle Scholar
  17. 17.
    Onoue S, Kawamura K, Igarashi N, Zhou Y, Fujikawa M, Yamada H, et al. Reactive oxygen species assay-based risk assessment of drug-induced phototoxicity: Classification criteria and application to drug candidates. J Pharm Biomed Anal. 2008;47:967–72.PubMedCrossRefGoogle Scholar
  18. 18.
    Onoue S, Hosoi K, Wakuri S, Iwase Y, Yamamoto T, Matsuoka N et al. Establishment and intra-/inter-laboratory validation of a standard protocol of reactive oxygen species assay for chemical photosafety evaluation. J Appl Toxicol:in press (2012). doi: 10.1002/jat.2776.
  19. 19.
    Onoue S, Takahashi H, Kawabata Y, Seto Y, Hatanaka J, Timmermann B, et al. Formulation design and photochemical studies on nanocrystal solid dispersion of curcumin with improved oral bioavailability. J Pharm Sci. 2010;99:1871–81.PubMedGoogle Scholar
  20. 20.
    Matsudaand Y, Masahara R. Photostability of solid-state ubidecarenone at ordinary and elevated temperatures under exaggerated UV irradiation. J Pharm Sci. 1983;72:1198–203.CrossRefGoogle Scholar
  21. 21.
    Onoue S, Hashimoto N, Yamada S. Dry powder inhalation systems for pulmonary delivery of therapeutic peptides and proteins. Expert Opin Ther Patents. 2008;18:429–42.CrossRefGoogle Scholar
  22. 22.
    Suarezand S, Hickey AJ. Drug properties affecting aerosol behavior. Respir Care. 2000;45:652–66.Google Scholar
  23. 23.
    Labirisand NR, Dolovich MB. Pulmonary drug delivery. Part I: physiological factors affecting therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol. 2003;56:588–99.CrossRefGoogle Scholar
  24. 24.
    Pesci A, Ricchiuti E, Ruggiero R, De Micheli A. Bronchoalveolar lavage in idiopathic pulmonary fibrosis: what does it tell us? Respir Med. 2010;104 Suppl 1:S70–3.PubMedCrossRefGoogle Scholar
  25. 25.
    Beeh KM, Beier J, Kornmann O, Buhl R. Neutrophilic inflammation in induced sputum of patients with idiopathic pulmonary fibrosis. Sarcoidosis Vasc Diffuse Lung Dis. 2003;20:138–43.PubMedGoogle Scholar
  26. 26.
    Tzortzaki EG, Tsoumakidou M, Makris D, Siafakas NM. Laboratory markers for COPD in “susceptible” smokers. Clin Chim Acta. 2006;364:124–38.PubMedCrossRefGoogle Scholar
  27. 27.
    Onoue S, Misaka S, Kawabata Y, Yamada S. New treatments for chronic obstructive pulmonary disease and viable formulation/device options for inhalation therapy. Expert Opin Drug Deliv. 2009;6:793–811.PubMedCrossRefGoogle Scholar
  28. 28.
    Seto Y, Aoki Y, Inoue R, Kojo Y, Kato M, Onoue S, et al. Development of dry powder inhaler system for reducing phototoxic risk. In: Oku N, editor. DDS conference, vol. 20. Shizuoka: Biomedical Research Press; 2011. p. 41–6.Google Scholar

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

Personalised recommendations