纳米效应对难溶性药物阿瑞匹坦体内外性质的影响  

Influences of Nanometer Effects on the Characters of Water-Insoluble Drug Aprepitant in Vivo and in Vitro

作　　者：张晓燕[1] 李倩[1,2] 孙建绪[1] 曲昌海[3] 郑爱萍[1] 

机构地区：[1]军事医学科学院毒物药物研究所药物制剂研究室,北京100850 [2]天津中医药大学,天津300193 [3]北京中医药大学,北京10029

出　　处：《中国药学杂志》2014年第14期1226-1232,共7页Chinese Pharmaceutical Journal

基　　金：国家重大新药创制科技重大专项(2011ZXJ09103-09B;2014ZX09J14103-01A);国家重大新药创制科技重大专项综合性新药研究开发技术大平台资助项目(2012ZX09301003-001-009)

摘　　要：目的研制阿瑞匹坦口服纳米制剂,并通过对其体内外性质的评价,考察纳米效应对难溶性药物的影响。方法制备粒径约为0.2、1和20μm的阿瑞匹坦,粒度及表面电位分析仪测量粒径及Zeta电位;HPLC测定20和0.2μm阿瑞匹坦在4种介质中的溶解度;采用溶出度测定第二法,对自制制剂与市售制剂进行不同介质中的溶出度对比研究;对20、1和0.2μm 3种粒径阿瑞匹坦在空腹及进食的条件下的口服生物利用度进行对比研究,并比较自制制剂与市售制剂的体内行为。结果制备的纳米晶体平均粒径为224.5 nm,Zeta电位-22.1 mV;0.2和20μm的阿瑞匹坦在pH 1.2、pH 4.5、pH 6.8的介质和水中的溶解度比值分别为3.30、70.77、48.25和110.44,表明水难溶性药物阿瑞匹坦纳米化后溶解度显著提高;自制与上市制剂在4种介质中的溶出度相似因子f2均>50,即自制与市售制剂的体外溶出行为基本一致;禁食条件下,0.2μm粒径的纳米晶体混悬液生物利用度较20和1μm粒径分别提高了2.05和1.43倍;进食条件下20和1μm粒径的生物利用度为禁食条件下1.79和1.21倍,而0.2μm粒径为0.95倍,说明阿瑞匹坦纳米化后可以消除食物效应;自制与市售纳米混悬液在SD大鼠体内具有生物等效性。结论运用纳米晶体技术制备阿瑞匹坦口服微丸胶囊,可以显著性提高难溶性药物的溶解度和体外溶出度,从而改善其口服吸收速度和程度;同时可降低食物对口服吸收的影响,消除食物效应。OBJECTIVE To develop nano-formulations of aprepitant for oral administration, and investigate the influence of nanmeter effect for indissolvable drug by evaluation of the characters in vitro and in vivo. METHODS Aprepitant with the particle size about 0.2 and 1 μm was prepared by medium grinding method, and about 20 μm was prepared by jet milling method. The particle sizes and surface potential were determined by Malvern Zetasizer, and the solubility of aprepitant in water, pH 1.2 HCl, pH 4. 5 acetate buffer and pH 6. 8 phosphate buffer were determined by high-performance liquid chromatography method. Dissolution curves in several mediums were studied and compared. The oral bioavallability of aprepitant with particle size about 20, 1 and 0.2 μm were studied under fasting and the fed state respectively, and then the in vivo behavior were compared. RESULTS The particle sizes of nanocrystals prepared by medium grinding method were uniform, with average particle size of 224. 5 nm and Zeta potential of -22. 1 inV. The solubility ratios of aprepitant with different size, 0.2 and 20 p,m, was 3.30, 70.77,48.25 and 110.44 respectively in the above medium with pH value of 1.2, 4. 5, 6.8 and water. It indicated that nanocrystalization could significantly improve the solubility of water-insoluble drugs. Similarity factors of the dissolution curves in several mediums of homemade and contrast preparation were all greater than 50, which represented the similar dissolution behavior in vitro. Under the fasting state, the bioavailability of nanocrystals suspension with particle sizes of 0. 2 μm was increased by 2. 05 times and 1.43 times respectively compared with the sizes of 20 and 1 μm. And compared with fasting conditions, the bioavailability of aprepitant with particle sizes of 20 and 1 p,m was about 1.79 times and 1.21 times under the fed state, while the same comparation was 0. 95 times of the 0. 2 μm particle size. It＇ s indicated that nanocrystalization could reduce the food effects. And in our experiments, the bi

关 键 词：阿瑞匹坦 纳米晶体 溶解度 溶出度 生物利用度 食物效应 

分 类 号：R944[医药卫生—药剂学]