Novel Approach to Pre-Exposure Prophylaxis (PrEP) of COVID-19: Development of S-892216 Long-Acting Injectable Suspension

[5-(3-Chloro-4-fluorophenyl)-3-(5-chloropyridin-3-yl)-6-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl] acetonitrile (S-892216) is a small-molecule compound developed by Shionogi & Co., Ltd. as a 2nd-generation 3CLpro inhibitor against severe acute respiratory syndrome coronavirus 2. In this study, we evaluated the feasibility of developing a long-acting injectable suspension formulation of S-892216 for the future development of a coronavirus disease 2019 pre-exposure prophylaxis medicine for immunocompromised patients. We found that the S-892216 drug substance had a low solubility, suitable for long-acting injectable suspension development. The developed S-892216 injectable suspension showed prolonged plasma exposure in both rats and beagle dogs when formulated as a nanosuspension. Selecting polysorbate 20 as a stabilizer enabled the manufacturing of the nanosuspension with less wet-milling time than that required for poloxamer P338. The developed injectable suspension was stable for 12 months at 5 and 25°C/60% relative humidity after terminal sterilization by gamma irradiation. Thus, the developed injectable suspension shows potential for further development for human use.