Kim Hyeon-A, Kim Joo-Eun
Department of Pharmaceutical Engineering, Catholic University of Daegu, Hayang-Ro 13-13, Gyeongsan City 38430, Korea.
Pharmaceutics. 2022 Jun 8;14(6):1219. doi: 10.3390/pharmaceutics14061219.
We aimed to develop nafamostat mesylate immediate-release tablets for the treatment of COVID-19 through drug repositioning studies of nafamostat mesylate injection. Nafamostat mesylate is a serine protease inhibitor known to inhibit the activity of the transmembrane protease, serine 2 enzyme that affects the penetration of the COVID-19 virus, thereby preventing the binding of the angiotensin-converting enzyme 2 receptor in vivo and the spike protein of the COVID-19 virus. The formulation was selected through a stability study after manufacturing by a wet granulation process and a direct tableting process to develop a stable nafamostat mesylate immediate-release tablet. Formulation issues for the selected processes were addressed using the design of experiments and quality-by-design approaches. The dissolution rate of the developed tablet was confirmed to be >90% within 30 min in the four major dissolutions, except in the pH 6.8 dissolution medium. Additionally, an in vivo pharmacokinetic study was performed in monkeys, and the pharmacokinetic profiles of nafamostat injections, oral solutions, and tablets were compared. The half-life during oral administration was confirmed to be significantly longer than the reported literature value of 8 min, and the bioavailability of the tablet was approximately 25% higher than that of the oral solution.
我们旨在通过甲磺酸萘莫司他注射液的药物重新定位研究，开发用于治疗新冠肺炎的甲磺酸萘莫司他速释片。甲磺酸萘莫司他是一种丝氨酸蛋白酶抑制剂，已知可抑制跨膜蛋白酶丝氨酸2酶的活性，该酶会影响新冠病毒的渗透，从而在体内阻止血管紧张素转换酶2受体与新冠病毒刺突蛋白的结合。通过湿法制粒工艺和直接压片工艺制备后，经稳定性研究选择制剂，以开发出稳定的甲磺酸萘莫司他速释片。使用实验设计和质量源于设计的方法解决所选工艺的制剂问题。所开发片剂在四种主要溶出介质中30分钟内的溶出率被确认为>90%，但在pH 6.8溶出介质中除外。此外，在猴子身上进行了体内药代动力学研究，并比较了萘莫司他注射液、口服溶液和片剂的药代动力学特征。口服给药期间的半衰期被确认为明显长于报道的文献值8分钟，且片剂的生物利用度比口服溶液高约25%。
