拉帕替尼自微乳给药系统的制备与体内外质量评价  

Preparation and quality evaluation of self-microemulsifying drug delivery system for lapatinib in vivo/vitro

作　　者：张强 张雪 符渝昕 程泽能 ZHANG Qiang;ZHANG Xue;FU Yuxin;CHENG Zeneng(School of Pharmacy,Xuzhou Medical University,Xuzhou,221000,Jiangsu,China;Hunan Huize Bio-pharmaceutical Co.,Ltd.,Changsha,410000,Hunan,China;Xiangya School of Pharmaceutical Sciences,Central South University,Changsha,410013,Hunan,China)

机构地区：[1]徐州医科大学药学院,江苏徐州221000 [2]湖南慧泽生物医药科技有限公司,湖南长沙410000 [3]中南大学湘雅药学院,湖南长沙410013

出　　处：《肿瘤药学》2023年第4期427-435,共9页Anti-Tumor Pharmacy

摘　　要：目的制备拉帕替尼自微乳给药系统,进行体外质量评价与大鼠体内药动学性质考察。方法通过检测拉帕替尼在不同辅料中的溶解度,选择合适的辅料绘制伪三元相图,利用星点设计-效应面法优化处方组分,确定最终处方。对制备的拉帕替尼自微乳进行粒径、Zeta电位检测,采用透射电镜观察微观形态,并考察不同介质、不同稀释倍数、不同放置时间对粒径的影响,进行拉帕替尼自微乳与拉帕替尼混悬液体外释放实验与大鼠体内药动学研究。结果最终确定拉帕替尼自微乳处方为玉米油∶油酸∶RH40∶TP=20∶20∶48∶12,平均粒径为(35.88±0.61)nm,Zeta电位为(-2.81±0.25)mV;在不同介质(pH 1.0、pH 4.5、pH 6.8)、不同稀释倍数(1∶50、1∶100、1∶200)下放置6 h,粒径稳定;体外释放48 h,药物累计释放量达70%;大鼠药动学实验结果显示,与拉帕替尼混悬液相比,拉帕替尼自微乳的C_(max)与AUC显著提高。结论拉帕替尼自微乳给药系统性质稳定,改善了药物的溶解度,提高了拉帕替尼在大鼠体内的生物利用度,对拉帕替尼新剂型的研发有一定的参考价值。Objective To prepare a self-microemulsifying drug delivery system of lapatinib,and to evaluate its quality in vitro and pharmacokinetic properties in rats.Methods Detect the lapatinib solubility in different excipients,and select appropriate excipients to complete ternary phase diagram,and optimize the formulation by central composite design-response surface methodology,Detect the particle size,Zeta potential of the prepared lapatinib microemulsion,and observe its microscopic morphology by transmission electron microscope.Examine the effects of different media,dilution ratio and storage time on the particle size of lapatinib microemulsion.The in vitro release test and pharmacokinetics test of lapatinib microemulsion and lapatinib suspension in rats were also performed here.Results The optimized lapatinib microemulsion was composed of corn oil∶oleic acid∶RH40∶TP=20∶20∶48∶12.The mean particle size of lapatinib microemulsion was(35.88±0.61)nm,Zeta potential was(-2.81±0.25)mV.The particle size of lapatinib microemulsion was still stable when diluted at 1∶50,1∶100,1∶200 in pH 1.0,pH 4.5,pH 6.8 medium respectively and placed for 6 h.The total lapatinib release was found to be 70%at the end of 48 h in the in vitro drug release studies.Compared to the lapatinib suspension,the C_(max)and AUC of lapatinib in microemulsion was significantly improved as showed in pharmacokinetic experiments of rats.Conclusion The self-emulsifying drug delivery system of lapatinib was stable.It could improve the solubility of lapatinib and the bioavailability in rats,and could be contribute to the development of new forms of lapatinib.

关 键 词：拉帕替尼 自微乳给药系统 星点设计-效应面法 释放 生物利用度 

分 类 号：R965[医药卫生—药理学]