Preparation and in vitro/in vivo evaluation of aprepitant nano/micron suspension for long-acting sustained-release subcutaneous injection

A long-acting, sustained-release suspension of aprepitant (APT) nano/micron subcutaneous injection was prepared to enhance the bioavailability of APT, achieve a long-acting, sustained-release effect, and improve suitability for patients with vomiting, thereby improving the anti-vomiting effect of APT. APT nano suspension (APT-NPs, 64.65 ± 2.54 nm; PDI = 0.135 ± 0.007; Zeta potential = −28.27 ± 0.91 mV) and micron suspension (APT-MPs, 1.94 ± 0.14 μm, Zeta potential = −44.50 ± 0.85 mV) were prepared by high-pressure homogenization and antisolvent precipitation methods, respectively. Crystal characterisation confirms that APT-NPS retains part of the APT structure, whereas the crystalline state of APT-MPS has undergone alteration. APT-NPs showed a 1.8-fold increase in solubility (17.12 μg/mL) and a cumulative release (72 h) of 85.12 ± 2.33% compared to APT-MPs (56.60 ± 1.40%). The subcutaneous injection of the nano/micron suspension was non-irritating, and APT-NPs demonstrated comparable efficacy and a longer duration of action compared to APT-MPs, administered via gavage, and Orkoping. A single subcutaneous injection into rats resulted in a sustained release for 21 d, and the relative bioavailability of APT-NPs and APT-MPs was approximately 460% and 190%, respectively. It indicates that the smaller the particle size, the higher the bioavailability of APT. This study mechanistically validates particle size engineering as a strategic approach to develop long-lasting antiemetic formulations. These findings validate that a smaller particle size improves the bioavailability and solubility of APT, providing a new strategy for developing clinically long-acting antiemetic formulations.