Drug Delivery and Translational Research ( IF 5.7 ) Pub Date : 2021-06-20 , DOI: 10.1007/s13346-021-01012-6 Yuzhu Sun 1 , Dongmei Chen 1, 2 , Ying Zhao 1 , Kaixiang Zhou 1 , Bao Zhang 1 , Haiting Wang 3 , Shuyu Xie 1
|
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 ± 18 nm, a polydispersity index (PDI) of 0.376 ± 0.128, a zeta potential of 2.30 ± 0.44 mV, 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 5 min, 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 50 mg/kg were 4.23 and 13.63 μg/mL, 2.04 and 1.67 h, and 111.36 and 295.80 μg*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.
Graphical abstract
中文翻译：
开发纳米晶混悬剂作为奥芬达唑的有效口服制剂
通过酸碱中和结晶结合超声分散制备奥芬达唑（OFZ）纳米晶混悬液，以克服其口服生物利用度差的挑战。通过单因素实验和以尺寸和外观为指标的正交设计对纳米混悬剂进行筛选和优化。进一步开发了最佳制剂的形态学（差示扫描量热法 (DSC)、X 射线粉末衍射 (XRPD)）性质和药代动力学。结果表明，最佳助溶剂和稳定剂分别为苹果酸和氢化蓖麻油聚氧乙烯醚（HEL-40）。扫描电镜显示奥芬唑纳米晶体为不规则片状，具有相对均匀性。制备的纳米晶体的平均粒径为 431 ± 18 nm，多分散指数 (PDI) 为 0.376 ± 0.128，zeta 电位为 2.30 ± 0.44 mV，沉降系数为 0.993。与 OFZ 原油相比，纳米晶体在不同溶剂中的平衡溶解度显着提高了 2.02-109.99 倍。在 0.5% SDS-PBS (pH 2) 和 0.5% SDS-PBS (pH 8) 溶液中，奥芬达唑纳米晶体在 5 分钟内完全释放，而 OFZ 粗品分别仅释放 60.26% 和 28.31%。药代动力学表明，C 奥芬达唑纳米晶体在 5 分钟内完全释放，而 OFZ 粗品分别仅释放 60.26% 和 28.31%。药代动力学表明，C 奥芬达唑纳米晶体在 5 分钟内完全释放，而 OFZ 粗品分别仅释放 60.26% 和 28.31%。药代动力学表明，COFZ纳米混悬剂和OFZ颗粒在大鼠中以50 mg/kg口服给药后的最大、T max和AUC 0-∞分别为4.23和13.63 μg/mL、2.04和1.67 h、111.36和295.80 μg*h/mL . 与OFZ颗粒相比，奥芬达唑纳米混悬剂的相对生物利用度为265.61%。这些结果表明，纳米混悬剂可能是一种有前途的难溶性OFZ口服制剂。
京公网安备 11010802027423号