目的 采用PEG化壳聚糖制备葫芦素B纳米混悬剂（cucurbitacin B nanosuspensions，CuB-NPs），考察CuB-NPs冻干粉口服吸收生物利用度。方法 反溶剂-高压均质法制备CuB-NPs，单因素实验结合Box-Behnken设计-效应面法（Box- Behnken design-response surface methodology，BBD-RSM）优化CuB-NPs处方。测定粒径、多分散指数（polydispersity index，PDI）及ζ电位等，透射电子显微镜（transmission electron microscope，TEM）观察CuB-NPs微观形态。采用5%乳糖作为冻干保护剂制备冻干粉，X射线粉末衍射（X-ray powder diffraction，XRPD）法分析晶型，透析法考察CuB-NPs冻干粉在pH 2.0和pH 7.4磷酸盐缓冲液（PBS）中的释药行为。ig给予SD大鼠葫芦素B和CuB-NPs冻干粉，测定血药浓度，计算口服相对吸收生物利用度。结果 CuB-NPs最佳处方工艺：葫芦素B与PEG化壳聚糖用量比例为1.95∶1，均质压力为100 MPa，均质次数为11次。CuB-NPs粒径为（265.71±13.46）nm，PDI值为0.116±0.012，ζ电位为（33.14±1.39）mV。CuB-NPs微观形态为球形，葫芦素B在CuB-NPs冻干粉中结晶度下降。CuB-NPs在pH 2.0和pH 7.4 PBS中2 h溶出度均大于90%，溶解度提高至58.58倍。药动学显示，新制备CuB-NPs和加速条件下储存6个月后相对生物利用度分别为4.87倍和4.48倍，药动学参数之间无显著性差异。结论 CuB-NPs提高了葫芦素B的溶解度及溶出度，稳定性良好，有效促进了口服吸收。

Objective To prepare cucurbitacin B nanosuspensions (CuB-NPs) with PEGylated chitosanas stabilizer, and oral bioavailability of its lyophilized powder was also investigated. Methods Antisolvent-high pressure homogenization method was used to prepare CuB-NPs. Single factor experiments combined with Box-Behnken design-response surface methodology (BBD-RSM) was used to gain optimal prescriptions of CuB-NPs. Particle size, polydispersity index (PDI) value and ζ potential were determined, morphology was observed by transmission electron microscope (TEM). Lyophilized powder was prepared with 5% lactose as lyophilized protective agent, crystal form of CuB-NPs lyophilized powder was analyzed by X-ray powder diffraction (XRPD). Release behavior of CuB-NPs lyophilized powder in pH 2.0 and pH 7.4 phosphate buffers was investigated by dialysis method. SD rats were given cucurbitine B and CUP-NPS lyophilized powder by instillation, concentration of cucurbitacin B was determined, and its relative bioavailability was also calculated. Results Optimal formulation of CuB-NPs: ratio of cucurbitacin B to PEGylated chitosan was 1.95:1, homogenization pressure was 100 MPa and homogenization times were 11. Particle size, PDI value and ζ potential were (265.71 ± 13.46) nm, 0.116 ± 0.012, and (33.14 ± 1.39) mV, respectively. Morphology of CuB-NPs was spherical, crystallinity of cucurbitacin B decreased in lyophilized powder of CuB-NPs. Cumulative release rate was more than 90% within 2 h in pH 2.0 and pH 7.4 phosphate buffer, and the solubility increased to 58.58 times. Pharmacokinetic results showed that relative bioavailability of CuB-NPs (newly prepared) and CuB-NPs (accelerated storage for 6 months) were 4.87 times and 4.48 times, respectively. There was no significant difference in pharmacokinetic parameters between the two samples of CuB-NPs. Conclusion CuB-NPs increased solubility and dissolution of cucurbitacin B, its storage stability was good, and effectively promoted oral absorption.

R283.6

国家重大科技专项（2018ZX09200109-002-009）；上海市科委项目（21S21903400）