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

Autor: Vartiainen V; Department of Clinical Medicine, Division of Pulmonary Medicine, University of Helsinki, Finland; Research Programs Unit, Translational Cancer Biology, University of Helsinki, Finland. Electronic address: ville.vartiainen@helsinki.fi., Raula J; Department of Applied Physics, Aalto University School of Science, Finland., Bimbo LM; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, United Kingdom; Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Finland., Viinamäki J; Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Finland., Backman JT; Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Finland., Ugur N; Department of Applied Physics, Aalto University School of Science, Finland., Kauppinen E; Department of Applied Physics, Aalto University School of Science, Finland., Sutinen E; Department of Clinical Medicine, Division of Pulmonary Medicine, University of Helsinki, Finland., Joensuu E; Research Programs Unit, Translational Cancer Biology, University of Helsinki, Finland., Koli K; Research Programs Unit, Translational Cancer Biology, University of Helsinki, Finland., Myllärniemi M; University of Helsinki and Helsinki University Hospital, Heart and Lung Center and HUH Diagnostics, Pulmonary Medicine, Finland.
Jazyk: angličtina
Zdroj: International journal of pharmaceutics [Int J Pharm] 2018 Jun 10; Vol. 544 (1), pp. 121-128. Date of Electronic Publication: 2018 Apr 12.
DOI: 10.1016/j.ijpharm.2018.04.019
Abstrakt: 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.
(Copyright © 2018 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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