Exploitation of nanocrystal suspension as an effective oral formulation for oxfendazole.

Abstract

An oxfendazole (OFZ) nanocrystal suspension was prepared by acid-base neutralization and crystallization combined with ultrasonic dispersion to overcome the challenge of its poor oral bioavailability. The nanosuspensions were screened and optimized by single-factor experiments and an orthogonal design using size and appearance as indices. The morphology (differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD)) properties and pharmacokinetics of the best formulation were further developed. The results showed that the best cosolvent and stabilizer were malic acid and hydrogenated castor oil polyoxyethylene ether (HEL-40), respectively. Scanning electron microscopy demonstrated that the oxfendazole nanocrystals are irregular sheets with relative uniformity. The prepared nanocrystals have an average particle diameter of 431 ± 18nm, a polydispersity index (PDI) of 0.376 ± 0.128, a zeta potential of 2.30 ± 0.44mV, and a sedimentation coefficient of 0.993. The equilibrium solubility of nanocrystals in different solvents was significantly improved by 2.02-109.99-fold compared to OFZ crude. In 0.5% SDS-PBS (pH 2) and 0.5% SDS-PBS (pH 8) solution, oxfendazole nanocrystals were completely released within 5min, while the OFZ crude only released 60.26% and 28.31%, respectively. The pharmacokinetics showed that the Cmax, Tmax, and AUC0-∞ of OFZ nanosuspension and OFZ granules in rats after oral dosage at 50mg/kg were 4.23 and 13.63μg/mL, 2.04 and 1.67h, and 111.36 and 295.80μg*h/mL, respectively. The relative bioavailability of the oxfendazole nanosuspension was 265.61% compared to the OFZ granules. These results showed that the nanosuspension might be a promising oral formulation for the hardly soluble OFZ.