Abstract
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.
Highlights
Coronavirus disease 2019 (COVID-19), which is caused by a new type of coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading rapidly worldwide
The ratio of nafamostat mesylate (NFM) to lecithin was fixed at 1:1 in the stability test in the bronchoalveolar lavage fluid (BALF), Figure 5, and the ratio of mannitol was varied at 1:1:0, 1:1:10, 1:1:50 to 1:1:100 (w/w)
We found that the higher the proportion of mannitol, the higher the yield, and the same was found for the smaller particle sizes and lower span values (Table 1)
Summary
Coronavirus disease 2019 (COVID-19), which is caused by a new type of coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading rapidly worldwide. According to the World Health Organization (WHO 2020), approximately 70 million people have been infected with COVID-19 worldwide, and the death toll has reached 2.3 million in about. SARS-CoV-2 is an RNA virus that requires two steps to enter the human host. The S2 protein is cleaved by transmembrane serine protease 2 (TMPRSS2), cathepsin, or other proteases. This S20 cleavage is called priming, which aids the virus in fusing with the human cell membrane. These fusions lead to the formation of endosomes, aiding the viral RNA to penetrate the cell. The RNA of the virus that has penetrated the cell is replicated, and, eventually, the virus propagates
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