Department of Clinical Medicine, Division of Pulmonary Medicine, University of Helsinki, Finland; Research Programs Unit, Translational Cancer Biology, University of Helsinki, Finland.
Department of Applied Physics, Aalto University School of Science, Finland.
Int J Pharm. 2018 Jun 10;544(1):121-128. doi: 10.1016/j.ijpharm.2018.04.019. Epub 2018 Apr 12.
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.
本研究旨在探讨肺部给予曲尼司特治疗肺纤维化的抗纤维化作用。采用 L-亮氨酸包被曲尼司特颗粒，并使用两种干粉吸入器（Easyhaler 和 Twister）分析其气溶胶化特性。此外，还测试了其生物学活性和细胞单层渗透性。采用二氧化硅诱导的小鼠肺纤维化模型，在预防性给药条件下，通过口咽吸入途径给予曲尼司特，研究其体内抗纤维化作用。在吸入模拟器中，从 Easyhaler 给药时，发射剂量和细颗粒分数与所施加的压力无关，且具有剂量重现性。然而，用 Twister 时，气溶胶化与压力相关，表明装置与配方之间的兼容性差。与原曲尼司特相比，该制剂在分化的 Calu-3 细胞单层中的渗透性更一致。曲尼司特在体内全身和局部给药时均能降低组织学纤维化评分，但只有全身给药能降低 I 型胶原 mRNA 的表达。推测这是由于全身给药组组织样本中的药物浓度高 40 倍所致。这些结果表明，曲尼司特可制成吸入干粉，具有作为口服和吸入性抗纤维化药物的潜力。
