PEG化壳聚糖葫芦素B纳米混悬剂的制备及其冻干粉药动学评价  

Preparation of cucurbitacin B nanosuspensions with PEGylated chitosan and pharmacokinetics evaluation of its lyophilized powder

作　　者：李瑞华 吴书凯 孙丽 张国民 LI Ruihua;WU Shukai;SUN Li;ZHANG Guomin(Puyang Medical College,Puyang 457000,China;Puyang Quality&Technology Supervision Inspection and Testing Center,Puyang 457000,China;Shanghai Institute of Traditional Chinese Medicine,Shanghai 201401,China)

机构地区：[1]濮阳医学高等专科学校,河南濮阳457000 [2]濮阳市质量技术监督检验测试中心,河南濮阳457000 [3]上海市中药研究所,上海201401

出　　处：《中草药》2024年第15期5050-5060,共11页Chinese Traditional and Herbal Drugs

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

摘　　要：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(BoxBehnken 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p H2.0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)m V。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 andζpotential 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 andζpotential 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.

关 键 词：葫芦素B 纳米混悬剂 PEG化壳聚糖 Box-Behnken设计-效应面法 溶出度 药动学 口服生物利用度 

分 类 号：R283.6[医药卫生—中药学]