Chapter 21 Targeted Drug Delivery System (TDDS)掌握靶向给药系统的概念、分类、特点。熟悉靶向制剂的体内外质量评价。了解分子药剂学和细胞生物学技术，了解靶向制剂的药动学基础。熟悉被动靶向制剂中脂质体、纳米粒、微乳等的特点、组成、靶向原理及制备方法、质量评价。了解主动靶向制剂和物理化学靶向制剂的类型、特点.Drug delivery system (DDS) Drug delivery system (DDS) 给药系统给药系统A drug delivery system (DDS) is defined as a formulation or a device that enables the introduction of a therapeutic substance 治疗物治疗物质质in the body and improves its efficacy and safety by controlling the rate, time, and place of release of drugs in the body.This process includes the administration of the therapeutic product, the release of the active ingredients by the product, and the subsequent transport of the active ingredients across the biological membranes to the site of action.Definition Drug delivery system is an interface between the patient and the drug. It may be a formulation of the drug to administer it for a therapeutic purpose or a device used to deliver the drug.Targeted drug delivery system (TDDS)Definition The selective delivery of a drug to a specific region (tissue, cell type) of the body经某种途径给药后，药物通过特殊载体的作经某种途径给药后，药物通过特殊载体的作用，用，特异性地浓集特异性地浓集在靶部位的给药系统。在靶部位的给药系统。The aim of targeted drug delivery is to improve the therapeutic effectiveness of a drug (or treatment) while at the same time improving its safety. Therefore, the aim is to increase the therapeutic index of a drug.6Superiorities of TDDSTraditional drug delivery systems:Medication is distributed throughout the body through the systemic blood circulation;A small portion of the medication reaches the organ to be affected.Superiorities of TDDSTargeted drug delivery: Concentrate the medication in the tissues of interest;Reducing the relative concentration of the medication in the remaining tissues SIDE EFFECTS EFFICACY Target position:an organ or tissuea particular cell typea specific intracellular compartment.特定细胞器内特定细胞器内Classification of TDDS 分类分类Passive targeted drug delivery 被动靶向被动靶向Active targeted drug delivery 主动靶向主动靶向Physicochemical targeted drug delivery 物理化学靶向物理化学靶向Classification of TDDSClassification of TDDS体内靶向性评价体内靶向性评价(1)(1)Relative uptake rate 相对摄取率相对摄取率 R Re e=(AUC=(AUCi i) )p p/(AUC/(AUCi i) )s s (2)(2)Peak concentration ratio 峰浓度比峰浓度比 C Ce e=(Cmax)p/(Cmax)s =(Cmax)p/(Cmax)s (3)(3)Targeting efficiency 靶向效率靶向效率 T Te e=(AUC)=(AUC)targettarget/(AUC)/(AUC)non-targetnon-target 传统的隔室药动学模型不适于评价靶向制剂传统的隔室药动学模型不适于评价靶向制剂Molecular PharmaceuticsMolecular Pharmaceutics从分子水平和细胞水平研究剂型因素对药物疗效的从分子水平和细胞水平研究剂型因素对药物疗效的影响的科学。影响的科学。1)1)药物分子与药物分子与DDSDDS的体内外转运与代谢的体内外转运与代谢2)2)药物分子与载体的相互作用药物分子与载体的相互作用3)3)靶向给药的分子机制靶向给药的分子机制4)4)分子水平的药代动力学研究分子水平的药代动力学研究12Particulate drug carriers 微粒类载体微粒类载体YLiposome 脂质体脂质体YNanoparticles/macroparticles 纳米粒纳米粒/微球微球YMicelles 胶束胶束YEmulsion 乳剂乳剂YDendrimers 树突状物树突状物LIPOSOMES 脂质体脂质体YWhat are LiposomesYAdvantages of LiposomesYClasses of LiposomesYPreparation of LiposomesLiposomes are phospholipid based vesicles comprising of aqueous and lipid compartments. 脂质体是利用脂质体是利用磷脂磷脂双分子层膜所形成的囊泡。双分子层膜所形成的囊泡。 Based on the solubility, a drug can be encapsulated either in the aqueous compartment or in the lipid bilayer.药物分子可被包裹在水相或脂药物分子可被包裹在水相或脂质双层中。质双层中。HydrophilicHydrophobic Phospholipids are amphiphathic in nature, containing a hydro-phobic tail and hydrophilic head.磷脂为两性物质，胆固醇亦属两亲物质，有疏水亲水磷脂为两性物质，胆固醇亦属两亲物质，有疏水亲水两种基团两种基团.Types of the LiposomesImmunoCationicLong Circulating Conventional TargetedDoxil - FDADoxil - FDA批准的第一个批准的第一个纳纳米米药药物物通用名：Doxorubicin Liposomal； 阿霉素脂质体商品名：Doxil（多喜）, Caelyx(楷莱)公司： Sequus Pharmaceuticals 应用： 最初用于治疗卡波氏肉瘤， 后被批准用于卵巢癌治疗 Amphotericin B Liposome1 1）Targeting ability 靶向性和淋巴定向性靶向性和淋巴定向性 2 2）Extended circulation time 长效性长效性 3 3）Good bioacceptability and biocompatibility 细胞亲和性与组织相容性细胞亲和性与组织相容性 4 4）Reduce the toxicity of crude drug 降低药物降低药物毒性毒性5 5）Increase the stability of drug 提高药物稳定性提高药物稳定性 物理和化学稳定性较差（磷脂分子的氧化物理和化学稳定性较差（磷脂分子的氧化) )脂质体的剂型特点脂质体的剂型特点磷脂磷脂+ +胆固醇胆固醇a、磷脂类磷脂类 卵磷脂、脑磷脂、大豆磷脂和人工合成磷脂卵磷脂、脑磷脂、大豆磷脂和人工合成磷脂 中性磷脂、负电荷磷脂、正电荷磷脂、中性磷脂、负电荷磷脂、正电荷磷脂、 长循环磷脂长循环磷脂b b、胆固醇、胆固醇 脂质体“流动性缓冲剂”(fluidity buffer) 调节膜流动性调节膜流动性 制备脂质体的材料制备脂质体的材料Materials: Phospholipids + cholesterol Preparation of liposomePreparation of liposomeNeutral: PC, DPPC, DMPC, DOPENegatively-charged: PA, OG, DCPPositively-charged: SA, DDABCholesterol: fluidity buffer Phospholipids Common components of the liposomesCholesterol Cholesterol acts as a “fluidity buffer”. 胆固醇擦入磷脂双分子层中，改变磷脂中疏水链的胆固醇擦入磷脂双分子层中，改变磷脂中疏水链的流动性。流动性。This adds rigidity刚性刚性 to the lipid bilayers. Preparation methodPreparation methodFilm dispersion method 薄膜法薄膜法High-pressure homogenizer method 高压乳匀法高压乳匀法Reverse phase evaporation vesicle method 逆向蒸发法逆向蒸发法Injection method 注入法注入法Freeze-thawing method 冻融法冻融法Film dispersion methodFilm dispersion method1.Phospholipids and cholesterol were dissolved in organic solvents2.Remove organic solvents by rotary evaporation，to form uniform film3.Add water and keep stirringInjection methodInjection method1.Dissolve phospholipids and cholesterol in organic solvents2.Inject the solvent into phosphate buffer（50-60）3.keep stirring until the o