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Development of an Improved Inhalable Powder Formulation of Pirfenidone by Spray-Drying: In Vitro Characterization and Pharmacokinetic Profiling

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Abstract

Purpose

Previously, a respirable powder (RP) formulation of pirfenidone (PFD) was developed for reducing phototoxic risk; however, PFD-RP demonstrated unacceptable in vitro inhalation performance. The present study aimed to develop a new RP system of PFD with favorable inhalation properties by spray-drying method.

Methods

Spray-dried PFD (SD/PFD) was prepared by spray-drying with L-leucine, and the physicochemical properties and efficacy in an antigen-sensitized airway inflammation model were assessed. A pharmacokinetic study was also conducted after intratracheal and oral administration of PFD formulations.

Results

Regarding powder characterization, SD/PFD had dimpled surface with the mean diameter of 1.793 μm. In next generation impactor analysis, SD/PFD demonstrated high in vitro inhalation performance without the need of carrier particles, and the fine particle fraction of SD/PFD was calculated to be 62.4%. Insufflated SD/PFD (0.3 mg-PFD/rat) attenuated antigen-evoked inflammatory events in the lung, including infiltration of inflammatory cells and myeloperoxidase activity. Systemic exposure level of PFD after insufflation of SD/PFD at the pharmacologically effective dose was 600-fold lower than that after oral administration of PFD at the phototoxic dose.

Conclusion

SD/PFD would be suitable for inhalation, and the utilization of an RP system with SD/PFD would provide a safer medication compared with oral administration of PFD.

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Abbreviations

AUC0-inf :

Area under the concentration versus time curve

BALF:

Bronchoalveolar lavage fluid

C max :

Maximum concentration

EF:

Emitted fraction

FPF:

Fine particle fraction

HPLC:

High performance liquid chromatography

ICH:

The International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for human use

IPF:

Idiopathic pulmonary fibrosis

MPO:

Myeloperoxidase

MRT:

Mean residence time

NGI:

Next generation impactor

OVA:

Ovalbumin

OVA-RP:

Respirable powder formulation of ovalbumin

PBS:

Phosphate buffered saline

PFD:

Pirfenidone

PFD-RP:

Respirable powder formulation of pirfenidone

RP:

Respirable powder

SD/PFD:

Spray-dried pirfenidone

SEM:

Scanning electron microscopy

t 1/2 :

Elimination half-life

TMBZ:

3,3′,5,5′-tetramethylbenzidine

UPLC/ESI-MS:

Ultra-performance liquid chromatography equipped with electrospray ionization mass spectrometry

VMD:

Volume median diameter

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was supported by Grant-in-Aid for Young Scientists (B) from the Ministry of Education, Science, Sports and Culture, Japan. Sharon Shui Yee Leung was supported by Faculty of Pharmacy postdoctoral fellowship at the University of Sydney.

Author information

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

    Yoshiki Seto, Gen Suzuki & Satomi Onoue

  2. Advanced Drug Delivery Group, Faculty of Pharmacy, University of Sydney, Sydney, NSW, 2006, Australia

    Sharon Shui Yee Leung & Hak-Kim Chan

Authors
  1. Yoshiki Seto
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  2. Gen Suzuki
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  3. Sharon Shui Yee Leung
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  4. Hak-Kim Chan
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  5. Satomi Onoue
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Corresponding author

Correspondence to Satomi Onoue.

Electronic supplementary material

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Supplementary Fig. 1

The timeline for the pharmacological experiment for evaluating the anti-inflammatory effects of insufflated SD/PFD. i.p.: intraperitoneal; and i.t.: intratracheal administration. (GIF 23 kb)

High resolution image (TIF 577 kb)

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Seto, Y., Suzuki, G., Leung, S.S.Y. et al. Development of an Improved Inhalable Powder Formulation of Pirfenidone by Spray-Drying: In Vitro Characterization and Pharmacokinetic Profiling. Pharm Res 33, 1447–1455 (2016). https://doi.org/10.1007/s11095-016-1887-3

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  • DOI: https://doi.org/10.1007/s11095-016-1887-3

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