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

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.

Respiratory Tract Deposition and Distribution Pattern of Microparticles in Mice Using Different Pulmonary Delivery Techniques

“…Vartiainen et al used aspiration to administer silicon dioxide to induce pulmonary fibrosis, after which they used aspiration to deliver tilorone as a therapy to treat fibrosis. The authors observed a significant reduction in the histological fibrosis score with the aspiration delivery method [ 34 ]. Further, Chakravarthy et al have used the aspiration technique to deliver formulations to the lungs and target the alveolar macrophages [ 35 ].…”

Inhaled nano-based therapeutics for pulmonary fibrosis: recent advances and future prospects

“…Nanoparticles offer new possibilities for improving drug release properties and obtaining optimal results in the treatment of inflammatory lung diseases by modifying the physical properties of the inhaled drug delivery carriers, such as particle size, shape, density, surface charge and other surface modifications [ 79 , 80 ]. Vartiainen et al [ 81 ] fabricated a dry powder nanoparticle formulation that contained 29.4% of tilorone, 9.6% of leucine and 61.0% of mannitol for silica-induced PF treatment. The formulation promoted more stable penetration through the monolayer of lung cells.…”

Traditional Chinese medicine combined with pulmonary drug delivery system and idiopathic pulmonary fibrosis: Rationale and therapeutic potential

“…There have been some clinical applications to treat IPF by PDDS in western medicine. For example, Rasool [ 134 ] prepared an ultrasonic nebulizer of pirfenidone, and Vartiainena with l -leucine coated tilorone dry particles [ 135 ], which all provide the basis for the treatment of IPF.…”