阿立哌唑微粒的制备及其体外释药研究  

Preparation and in vitro release of aripiprazole microparticles

作　　者：李聘 李红鑫 吴茜 孙常胜 吴婧楠 薛婉莹 郭杏梅 孙腾跃 蔡程科[1] 王洪飞 LI Pin;LI Hongxin;WU Qian;SUN Changshengi;WU Jingnan;XUE Wanying;GUO Xingmei;SUNTengyue;CAI Chengke;WANG Hongfei(School of Traditional Chinese Medicine,Beijing University of Chinese Medicine,Beijing 102488,China;Beijing Quantum Hi-tech Pharmaceutical Technical Co.,Ltd,Beijing 102200,China)

机构地区：[1]北京中医药大学中药学院,北京102488 [2]北京量子高科制药科技有限公司,北京102200

出　　处：《药物评价研究》2021年第4期703-710,共8页Drug Evaluation Research

基　　金：国家科技重大专项项目(2011ZX09201-201);北京市科技计划专项研发项目(Z16010101390)。

摘　　要：目的采用快速膜乳化-溶剂挥发法制备不含载体辅料的阿立哌唑微粒,并对其体外释药行为进行评价。方法采用快速膜乳化-溶剂挥发法制备阿立哌唑微粒,将主药于室温条件下超声溶解于有机溶剂中作为油相。将聚乙烯醇(PVA)于磁力搅拌且加热的条件下溶解于去离子水中,并趁热用0.45μm的微孔滤膜真空抽滤,得续滤液,作为水相。油相与水相经磁力搅拌混合均匀后得初乳液,将初乳液倒入快速不锈钢膜乳化装置,氮气加压,过膜,收集乳液。将乳液与固化液混合后固化至无有机溶剂气味,离心洗涤,冷冻干燥即得到阿立哌唑微粒冻干粉。以微粒粒径、跨距及表观形态为指标,采用单因素考察法对有机溶剂、水相PVA浓度、阿立哌唑质量浓度、油水相体积比、固化液pH值、过膜次数、固化方式进行考察,并初步确定最优制备条件;采用直接释药法测定并比较阿立哌唑原料药与微粒在不同时间点的累积释放率,并对其释放行为进行数学模型拟合。结果经过单因素考察,确定阿立哌唑微粒的制备工艺条件为:有机溶剂二氯甲烷,水相PVA浓度3%,药物质量浓度7 mg/mL,油水相体积比1∶1,固化液3%PVA溶液(pH 8.5),四级串联不锈钢膜乳化器过膜1次,机械搅拌固化。阿立哌唑微粒平均D_(10)、D_(50)、D_(90)及跨距分别为2.03、4.38、8.09μm、1.39;扫描电镜下呈现较为均匀的薄片状;差示扫描量热法显示其结晶程度降低;平均药物质量分数为99.27%。阿立哌唑微粒在48 h时累积释放率可达100.17%,体外释放符合Logistic方程,而原料药在48 h时仅释放47.17%,释放符合一级方程。结论快速膜乳化法可用于提高难溶性药物的溶出速度,具有广阔的应用前景。Objective To prepare aripiprazole microparticles without carrier excipients by rapid membrane emulsification-solvent evaporation method and evaluate their drug release behavior in vitro.Methods Aripiprazole microparticles were prepared by rapid membrane emulsification and solvent evaporation method.The main drug was dissolved in good solvent as oil phase by ultrasound at room temperature.The polyvinyl alcohol(PVA)was dissolved in deionized water under the condition of magnetic stirring and heating,and the filtrate was obtained by vacuum pumping with a 0.45μm microporous filter membrane as the aqueous phase.After the oil phase and water phase were mixed uniformly by magnetic stirring,the primary emulsion was obtained.The primary emulsion was poured into the rapid stainless steel membrane emulsifying device.The nitrogen was pressurized,the film is passed,and the emulsion was collected.The emulsion was mixed with the curing solution and cured until there was no odor of organic solvent.Then the emulsion was centrifugally washed and freeze-dried to obtain the freeze-dried powder of aripiprazole microparticles.Taking the particle size,span and apparent morphology as indexes,the the organic solvent,aqueous PVA concentration,aripiprazole mass concentration,volume ratio of oil to water,pH value of curing solution,times of membrane crossing and curing method were investigated by single factor method,and the optimal preparation conditions were preliminarily determined;The cumulative release rates of aripiprazole and its microparticles at different time points were measured and compared by direct release method,and the release behavior was fitted by mathematical model.Results After single factor investigation,the preparation conditions of aripiprazole microparticles were determined as follows:organic solvent methylene chloride,aqueous phase PVA concentration of 3%,drug mass concentration of 7 mg/mL,oil-water phase volume ratio of 1∶1,curing liquid of 3% PVA solution(pH 8.5),fourstage series stainless steel membrane emulsi

关 键 词：快速膜乳化 溶剂挥发法 阿立哌唑 微粒 体外释放 

分 类 号：R94[医药卫生—药剂学]