Development of Nafamostat Mesylate Immediate-Release Tablet by Drug Repositioning Using Quality-by-Design Approach

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.

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Materials

The active pharmaceutical ingredient (API), nafamostat mesylate, was purchased from Kukjeon (Anyang, Gyeonggi-do, Korea). Microcelac was supplied by Meggle (Wasserburg am Inc., Upper Bavaria, Germany). Crospovidone was supplied by BASF (Carl-Bosch-Str.38; Ludwigshafen, Germany). Hydroxypropyl cellulose was purchased from Nippon Soda (Chiyoda-ku, Tokyo, Japan). Sodium stearyl fumarate was purchased from JRS Pharma (Holzmuhle 1, Rosenberg, Germany). The following reagents were used throughout the study: microcrystalline cellulose (Heweten 102, JRS Pharma, Rosenberg, Germany), lactose (Pgarmatose 200M, DFE Pharma, Goch, Germany), mannitol (Pearlitol 200SD, Roquette Pharma, Lestrem, France), dicalcium phosphate dihydrate (Innophos, Cranbury, NJ, USA), pregelatinized starch (Starch 1500, Colorcon, Shanghai, China), hydroxypropyl methylcellulose (METHOCEL, Colorcon, Shanghai, China), sodium starch glycolate (GLYCOLYS, Roquette, Lestrem, France), magnesium stearate (Faci Asia Pacific Pty Ltd., Jurong Island, Singapore), and croscarmellose sodium (VIVASOL, JRS Pharma, Rosenberg, Germany). All other chemicals were of analytical reagent grade and were purchased commercially.

Kim, H.-A.; Kim, J.-E. Development of Nafamostat Mesylate Immediate-Release Tablet by Drug Repositioning Using Quality-by-Design Approach. Pharmaceutics 2022, 14, 1219. https://doi.org/10.3390/pharmaceutics14061219