Molecular Pharmaceutics and Drug Delivery Division, College of Pharmacy, The University of Texas at Austin, 2409 University Avenue, Austin, TX 78712, USA.
Molecular Pharmaceutics and Drug Delivery Division, College of Pharmacy, The University of Texas at Austin, 2409 University Avenue, Austin, TX 78712, USA.
Int J Pharm. 2021 Jun 15;603:120701. doi: 10.1016/j.ijpharm.2021.120701. Epub 2021 May 12.
In this work, we have developed and tested a dry powder form of niclosamide made by thin-film freezing (TFF) and administered it by inhalation to rats and hamsters to gather data about its toxicology and pharmacokinetics. Niclosamide, a poorly water-soluble drug, is an interesting drug candidate because it was approved over 60 years ago for use as an anthelmintic medication, but recent studies demonstrated its potential as a broad-spectrum antiviral with pharmacological effect against SARS-CoV-2 infection. TFF was used to develop a niclosamide inhalation powder composition that exhibited acceptable aerosol performance with a fine particle fraction (FPF) of 86.0% and a mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of 1.11 µm and 2.84, respectively. This formulation not only proved to be safe after an acute three-day, multi-dose tolerability and exposure study in rats as evidenced by histopathology analysis, and also was able to achieve lung concentrations above the required IC levels for at least 24 h after a single administration in a Syrian hamster model. To conclude, we successfully developed a niclosamide dry powder inhalation that overcomes niclosamide's limitation of poor oral bioavailability by targeting the drug directly to the primary site of infection, the lungs.
在这项工作中，我们开发并测试了一种通过薄膜冷冻（TFF）制成的尼氯硝唑干粉形式，并通过吸入将其施用于大鼠和仓鼠，以收集有关其毒理学和药代动力学的数据。尼氯硝唑是一种水溶性差的药物，是一种很有前途的候选药物，因为它在 60 多年前就被批准用于驱虫药物，但最近的研究表明，它具有广谱抗病毒作用，对 SARS-CoV-2 感染具有药理作用。TFF 用于开发尼氯硝唑吸入粉末制剂，其具有可接受的气溶胶性能，细颗粒分数（FPF）为 86.0%，质量中值空气动力学直径（MMAD）和几何标准偏差（GSD）分别为 1.11µm 和 2.84。这种配方不仅在大鼠的急性三天多剂量耐受性和暴露研究中通过组织病理学分析证明是安全的，而且在单次给药后至少 24 小时内，在叙利亚仓鼠模型中能够达到高于所需 IC 水平的肺部浓度。总之，我们成功地开发了一种尼氯硝唑干粉吸入剂，通过将药物直接靶向感染的主要部位肺部，克服了尼氯硝唑口服生物利用度差的局限性。
