依折麦布纳米结构脂质体的工艺制备和生物药剂学研究  

Preparation and Biopharmaceutical Evaluation of Ezetimibe Nanostructured Lipid Carriers

作　　者：张丹 曹思思 彭瑛 谢向阳 陈志龙 ZHANG Dan;CAO Sisi;PENG Ying;XIE Xiangyang;CHEN Zhilong(Department of Pharmacy,General Hospital of Central Theater Command,Wuhan Hubei 430070,China)

机构地区：[1]中部战区总医院药剂科,湖北武汉430070 [2]陆军74集团军医院泌尿外科

出　　处：《联勤军事医学》2023年第11期911-918,943,共9页Military Medicine of Joint Logistics

基　　金：湖北省卫生健康科研立项项目(WJ2021M218)。

摘　　要：目的制备依折麦布纳米结构脂质体(Ezetimibe nanostructured lipid carriers,Eze-NLCs),并评价其在大鼠体内的药物代谢动力学以及对高血脂模型大鼠的降血脂效果。方法以山嵛酸甘油酯(Compritol888ATO)作为固体脂质,丙二醇单辛酸酯(CapmulPG8)作为液体脂质,聚乙二醇-15羟基硬脂酸酯(KolliphorHS15)作为表面活性剂,通过Box-Behnken实验设计优化得到Eze-NLCs最佳处方。评价Eze-NLCs的理化性质,分别考察了Eze-NLCs在pH 1.2、4.5、6.83种介质溶液中体外释药特性;比较大鼠口服Eze混悬剂和Eze-NLCs后的体内药物代谢动力学及药效动力学。结果优化得到Eze-NLCs的处方组成为Compritol888ATO浓度为13mg/ml,CapmulPG8浓度为25mg/ml,KolliphorHS15浓度为10 mg/ml,连续制备3批Eze-NLCs的粒径为(215.62±13.55)nm,包封率为(86.73±2.58)%。在透射电镜下可观察到Eze-NLCs呈类球形,表面光滑,均匀分散。Eze-NLCs在3种pH值介质溶液中均表现为前期药物释放较快,后期药物释放平缓。与大鼠口服Eze混悬剂相比,大鼠口服Eze-NLCs后,其药物达峰时间(tmax)缩短,达峰浓度(Cmax)增加,半衰期(T1/2)延长,药时曲线下面积(areaunderthecure,AUC)增加。Eze-NLCs可显著降低高脂血症大鼠的总胆固醇(totalcholesterol,TC)、甘油三酯(trigly ceride,TG)、高密度脂蛋白胆固醇(high-density lipoprotein cholesterol,HDL-C)水平,升高低密度脂蛋白胆固醇(low-density lipoprotein cholesterol,LDL-C)水平。结论本研究制备的Eze-NLCs,能够显著提高药物的生物利用度,达到更好地调节血脂的作用,对Eze的临床应用具有重要价值。Objective To prepare Ezetimibe nanostructured lipid carriers(Eze-NLCs)and evaluate its pharmacokinetics in rats and its lipid-lowering effects on hyperlipidemia model rats.Methods Using glyceryl behenate(Compritol 888 ATO)as a solid lipid,propylene glycol monooctanoate(Capmul PG 8)as a liquid lipid and solutol HS-15(Kolliphor HS15)as a surfactant,the formulation of Eze-NLCs was optimized through Box-Behnken experimental design.The physicochemical properties of Eze-NLCs were evaluated,and the in vitro drug release characteristics of Eze-NLCs in pH 1.2,4.5 and 6.8 medium solutions were investigated;the in vitro pharmacokinetics and pharmacodynamics of Eze suspension and Eze-NLCs after oral administration in rats were compared.Results The optimized formulation of Eze-NLCs was as followed:Concentration of Compritol 888 ATO was 13 mg/ml,concentration of Capmul PG 8 was 25 mg/ml,concentration of Kolliphor HS15 was 10 mg/ml,and the average particle size of 3 consecutive batches of Eze-NLCs was(215.62±13.55)nm,with an encapsulation efficiency of(86.73±2.58)%.Under transmission electron microscopy,it could be observed that Eze-NLCs were spherical in shape,uniformly dispersed,and had smooth surface.Eze-NLCs exhibited faster drug release in the early stage and slower drug release in the later stage in the 3 pH medium solutions.Compared with the oral administration of Eze suspension in rats,after oral administration of Eze-NLCs,the time to peak(t_(max))of Eze-NLCs shortened,the peak concentration(C_(max))increased,the half-life period(T_(1/2))prolonged,and the area under the cure(AUC)increased.Eze-NLCs significantly reduced the levels of total cholesterol(TC),triglyceride(TG)and high-density lipoprotein cholesterol(HDL-C)in hyperlipidemic rats,while elevated the level of low-density lipoprotein cholesterol(LDL-C).Conclusion Eze-NLCs prepared in this study can significantly improve the bioavailability and achieve better blood lipid regulation,which has important value for the clinical application of Eze.

关 键 词：依折麦布 纳米结构脂质体 高血脂模型 药物代谢动力学 药效动力学 

分 类 号：R969[医药卫生—药理学]