Coronavirus disease 2019 (COVID-19), caused by a new strain of coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading rapidly worldwide. Nafamostat mesylate (NFM) suppresses transmembrane serine protease 2 and SARS-CoV-2 S protein-mediated fusion. In this study, pharmacokinetics and lung distribution of NFM, administered via intravenous and intratracheal routes, were determined using high performance liquid chromatography analysis of blood plasma, lung lumen using bronchoalveolar lavage fluid, and lung tissue. Intratracheal administration had higher drug delivery and longer residual time in the lung lumen and tissue, which are the main sites of action, than intravenous administration. We confirmed the effect of lecithin as a stabilizer through an ex vivo stability test. Lecithin acts as an inhibitor of carboxylesterase and delays NFM decomposition. We prepared inhalable microparticles with NFM, lecithin, and mannitol via the co-spray method. The formulation prepared using an NFM:lecithin:mannitol ratio of 1:1:100 had a small particle size and excellent aerodynamic performance. Spray dried microparticles containing NFM, lecithin, and mannitol (1:1:100) had the longest residual time in the lung tissue. In conclusion, NFM-inhalable microparticles were prepared and confirmed to be delivered into the respiratory tract, such as lung lumen and lung tissue, through in vitro and in vivo evaluations.

中文翻译：

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共喷雾干燥甲磺酸萘莫司他与卵磷脂和甘露醇作为可吸入微粒用于靶向肺部递送：大鼠体内的药代动力学和肺部分布


2019 年冠状病毒病 (COVID-19) 由一种名为严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的新冠状病毒株引起，正在全球范围内迅速传播。 Nafamostat mesylate (NFM) 抑制跨膜丝氨酸蛋白酶 2 和 SARS-CoV-2 S 蛋白介导的融合。在这项研究中，通过静脉内和气管内途径给药的 NFM 的药代动力学和肺部分布是通过血浆、使用支气管肺泡灌洗液的肺腔和肺组织的高效液相色谱分析来确定的。与静脉内给药相比，气管内给药具有更高的药物递送和在作为主要作用部位的肺腔和组织中更长的残留时间。我们通过离体稳定性测试证实了卵磷脂作为稳定剂的效果。卵磷脂充当羧酸酯酶抑制剂并延迟 NFM 分解。我们通过共喷雾法制备了含有 NFM、卵磷脂和甘露醇的可吸入微粒。采用NFM:卵磷脂:甘露醇比例为1:1:100制备的制剂具有较小的粒径和优异的空气动力性能。含有NFM、卵磷脂和甘露醇（1:1:100）的喷雾干燥微粒在肺组织中的残留时间最长。总之，通过体外和体内评估，制备了NFM可吸入微粒并确认其可输送到呼吸道，例如肺腔和肺组织。