Progesterone (PG) is an essential sex hormone with a variety of important biological functions, but its insolubility leads to low bioavailability of most water-based formulations. What is more, the commercial oil-based formulations often cause severe side effects after long-term injection due to poor tissue absorption of oil. Herein, we report an aseptic bottom-up method utilizing emulsion freeze-drying technology that produces size-controllable, highly bioavailable, and water-based PG nanocrystal injection. The key factors that can determine the features of nanocrystals were investigated, including solvents, water-to-oil ratio, drug concentrations, type of surfactants, temperature in freeze-drying process, and lyoprotectants. Mechanisms of crystal growth formation process for PG nanocrystals were also analyzed theoretically. The prepared water-based PG nanocrystal suspension injection (PG/NSI) not only showed quick dissolution behaviors but also had significantly improved bioavailability in vivo. Therefore, this method can effectively control the size of nanocrystals, enhance bioavailability of insoluble drugs, and produce aseptic water-based nanocrystals that can be directly used for injection. Moreover, this method can also be used to prepare nanocrystals with the desired size under aseptic conditions for other poorly water-soluble drugs.
Keywords: PG nanocrystal; bottom-up method; emulsion freeze-drying; insoluble drugs; size control and aseptic.