1、,哈尔滨医科大学药学院唐景玲 副教授,纳米技术改善难溶性药物口服吸收,The Stages of Drug Discovery and Development,Oral drug absorption,The Biopharmaceutics Classification System (BCS) as defined by the FDA after Amidon et al.,Dosage Form Development Strategies,A few common strategies to overcome impacts of low solubility on product
2、development: Salt formation or prodrug Cyclodextrin inclusion Solid dispersion Particle size reduction Lipid-based drug delivery,Particle size reduction,Particle size reductionPatent,Nanocrystal technology Elan corporation,The new formulation overcame the drugs relative insolubility by reducing the
3、particle size to less than 200nm, and subsequently coating the active compound with GRAS (Generally Regarded As Safe) surface stabilizers.,Particle size reductionPatent,Dissocubes SkyepharmaNanoedge Baxter aqueous mediaNanopure Pharmasol GmbHnon-aqueous media (PEG) orwater-ethanol mixtures, isotonic
4、 water-glycerol mixtures,Appearance of solid PEG nanocrystal dispersionmilled to a fine powder,Amphotericin B nanosuspension in liquid PEG 400 (left), as solid dispersion in solidified PEG1000 (middle) and in form of milled solid PEG 1000 yielding a powder (right),Capsules directly filled with hot P
5、EG nanosuspension (upper) and with granulated solidified PEG nano-suspension (lower),Controlled-flow cavitation (CFC) Five Star technologies,Particle size reductionPatent,Technology controls the location, size, density, and intensity of bubbles in the cavitation zone to create optimum nanoparticles.
6、”,Particle size reductionPatent,Crititech Crititech Inc. and Lawronce KS Particle Formation Using Supercritical Carbon Dioxide,Particle size reductionProducts,Dissocubes,20mL:800mg5mL:625mg,Particle size reductionLimitations and Future challenges,More suitable for the drug of BCS Nanoparticles aggre
7、gation during the storageShortage of the equipment for formulation optimizationShortage of the methods for in vitro evaluation for nanoparticles,Definition of Lipid-baseddelivery systems,Lipid-based delivery systems includes: simple oil solutions complex mixtures of oils surfactants, co-surfactants
8、cosolvents,self-emulsifying drug delivery systems (SEDDS)self-microemulsifying drug delivery systems (SMEDDS),The Lipid Formulation Classification System,Schematic representation of the critical steps in oral drug absorption and the possible influences of lipid-based formulations.,2011.08.05,上市剂型,提高
9、难溶性有效成分的溶出度,新剂型优点,提高口服生物利用度,工艺简单 、服用方便,本课题的研究将为大量有前景的难溶性药物，特别是难溶性中药口服制剂的研究提供参考,五仁醇（五味子乙醇提取物）,2011.08.05,五仁醇主要成分溶解度的测定,药物溶解度在辅料中得到了极大提高,通过观察溶解后溶液的颜色及外观来判断溶解的程度,209倍,36倍,7倍,41倍,172倍,31倍,106倍,18倍,2011.08.05,伪三元相图的绘制,油酸：5%35% 吐温20：60%70% Transcutolp：5%25%均一、透明，略有乳光.,2011.08.05,五仁醇自乳化制剂最终处方的确定及制备,处方,制备方法
10、,混匀后的辅料,五仁醇,40 C温度以内,超声完全混合,药物完全溶解,装胶囊,2011.08.05,五仁醇自乳化制剂与市售胶囊的含量测定,自乳化制剂中五味子醇甲的含量低于市售制剂，五味子乙素的含量高于市售制剂,含药乳液平均粒径为241 nm，粒度分布较均匀,五仁醇自乳化制剂粒度测定：,2011.08.05,五仁醇自乳化制剂溶出度的测定,五味子醇甲自乳化制剂 ()，市售制剂 (),市售制剂的五味子醇甲15 min可达93%，而自乳化制剂中可达到100%,五味子乙素自乳化制剂 ()，市售制剂 (),自乳化制剂中五味子乙素45分溶出达到71.3%,而市售制剂中五味子乙素一直未检测到,2011.08.
11、05,五味子醇甲药-时曲线 SEDDS () or commercial capsules (),五味子乙素-药时曲线 SEDDS () or commercial capsules (),五仁醇大鼠血浆平均药物浓度经时变化曲线,2011.08.05,染料木素,2011.08.05,最优处方,制备工艺,搅拌 50 min,旋转蒸发,3235 C 7585 r/min,0.8 m 滤膜,不断搅拌,2011.08.05,不同批号的染料木素纳米粒的包封率、载药量的测定,三种批号的染料木素纳米粒包封率均在50%以上。包封率及载药量都比较稳定，制备方法可靠。,2011.08.05,染料木素纳米粒的质量评价,染料木素纳米粒电镜图,染料木素纳米粒粒径图,2011.08.05,染料木素纳米粒溶出度测定,图3 纳米粒制剂与普通胶囊中染料木素溶出度测定结果,染料木素制成纳米粒后，溶出度较普通胶囊有明显的提高。且纳米粒中染料木素的溶出速率明显高于普通胶囊。,2011.08.05,大鼠血浆平均药物浓度经时变化曲线,图6 口服染料木素纳米粒与染料木素混悬剂后大鼠血浆中药-时曲线,2011.08.05,Thank you！,
