Pulmonary administration of a dry powder formulation of the antifibrotic drug tilorone reduces silica-induced lung fibrosis in mice

Ville Vartiainen, Janne Raula, Luis M. Bimbo, Jenni Viinamäki, Janne T. Backman, Nurcin Ugur, Esko Kauppinen, Eva Sutinen, Emmi Joensuu, Katri Koli, Marjukka Myllärniemi

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

The aim of this work was to study the antifibrotic effect of pulmonary administration of tilorone to lung fibrosis. L-leucine coated tilorone particles were prepared and their aerosolization properties were analyzed using two dry powder inhalers (Easyhaler and Twister). In addition, the biological activity and cell monolayer permeation was tested. The antifibrotic effect of tilorone delivered by oropharyngeal aspiration was studied in vivo using a silica-induced model of pulmonary fibrosis in mice in a preventive setting. When delivered from the Easyhaler in an inhalation simulator, the emitted dose and fine particle fraction were independent from the pressure applied and showed dose repeatability. However, with Twister the aerosolization was pressure-dependent indicating poor compatibility between the device and the formulation. The formulation showed more consistent permeation through a differentiated Calu-3 cell monolayer compared to pristine tilorone. Tilorone decreased the histological fibrosis score in vivo in systemic and local administration, but only systemic administration decreased the mRNA expression of type I collagen. The difference was hypothesized to result from 40-fold higher drug concentration in tissue samples in the systemic administration group. These results show that tilorone can be formulated as inhalable dry powder and has potential as an oral and inhalable antifibrotic drug
LanguageEnglish
Pages121-128
Number of pages8
JournalInternational Journal of Pharmaceutics
Volume544
Issue number1
Early online date12 Apr 2018
DOIs
Publication statusPublished - 10 Jun 2018

Fingerprint

Tilorone
Drug Compounding
Silicon Dioxide
Powders
Fibrosis
Lung
Dry Powder Inhalers
Pressure
Pulmonary Fibrosis
Collagen Type I
Leucine
Pharmaceutical Preparations
Inhalation
Equipment and Supplies
Messenger RNA

Keywords

  • idiopathic pulmonary fibrosis
  • antifibrotics
  • tilorone
  • dry powder inhaler

Cite this

Vartiainen, Ville ; Raula, Janne ; Bimbo, Luis M. ; Viinamäki, Jenni ; T. Backman, Janne ; Ugur, Nurcin ; Kauppinen, Esko ; Sutinen, Eva ; Joensuu, Emmi ; Koli, Katri ; Myllärniemi, Marjukka . / Pulmonary administration of a dry powder formulation of the antifibrotic drug tilorone reduces silica-induced lung fibrosis in mice. In: International Journal of Pharmaceutics. 2018 ; Vol. 544, No. 1. pp. 121-128.
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Vartiainen, V, Raula, J, Bimbo, LM, Viinamäki, J, T. Backman, J, Ugur, N, Kauppinen, E, Sutinen, E, Joensuu, E, Koli, K & Myllärniemi, M 2018, 'Pulmonary administration of a dry powder formulation of the antifibrotic drug tilorone reduces silica-induced lung fibrosis in mice' International Journal of Pharmaceutics, vol. 544, no. 1, pp. 121-128. https://doi.org/10.1016/j.ijpharm.2018.04.019

Pulmonary administration of a dry powder formulation of the antifibrotic drug tilorone reduces silica-induced lung fibrosis in mice. / Vartiainen, Ville; Raula, Janne; Bimbo, Luis M.; Viinamäki, Jenni ; T. Backman, Janne ; Ugur, Nurcin; Kauppinen, Esko ; Sutinen, Eva; Joensuu, Emmi; Koli, Katri; Myllärniemi, Marjukka .

In: International Journal of Pharmaceutics, Vol. 544, No. 1, 10.06.2018, p. 121-128.

Research output: Contribution to journalArticle

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T1 - Pulmonary administration of a dry powder formulation of the antifibrotic drug tilorone reduces silica-induced lung fibrosis in mice

AU - Vartiainen, Ville

AU - Raula, Janne

AU - Bimbo, Luis M.

AU - Viinamäki, Jenni

AU - T. Backman, Janne

AU - Ugur, Nurcin

AU - Kauppinen, Esko

AU - Sutinen, Eva

AU - Joensuu, Emmi

AU - Koli, Katri

AU - Myllärniemi, Marjukka

PY - 2018/6/10

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N2 - The aim of this work was to study the antifibrotic effect of pulmonary administration of tilorone to lung fibrosis. L-leucine coated tilorone particles were prepared and their aerosolization properties were analyzed using two dry powder inhalers (Easyhaler and Twister). In addition, the biological activity and cell monolayer permeation was tested. The antifibrotic effect of tilorone delivered by oropharyngeal aspiration was studied in vivo using a silica-induced model of pulmonary fibrosis in mice in a preventive setting. When delivered from the Easyhaler in an inhalation simulator, the emitted dose and fine particle fraction were independent from the pressure applied and showed dose repeatability. However, with Twister the aerosolization was pressure-dependent indicating poor compatibility between the device and the formulation. The formulation showed more consistent permeation through a differentiated Calu-3 cell monolayer compared to pristine tilorone. Tilorone decreased the histological fibrosis score in vivo in systemic and local administration, but only systemic administration decreased the mRNA expression of type I collagen. The difference was hypothesized to result from 40-fold higher drug concentration in tissue samples in the systemic administration group. These results show that tilorone can be formulated as inhalable dry powder and has potential as an oral and inhalable antifibrotic drug

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KW - antifibrotics

KW - tilorone

KW - dry powder inhaler

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