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1、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)给药系统,A drug delivery system(DDS)is defined as a formulation or a device that enables the introducti
2、on of a therapeutic substance 治疗物质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 trans
3、port 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 de
4、livery 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用，特异性地浓集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.Ther
5、efore,the aim is to increase the therapeutic index of a drug.,6,Superiorities of TDDS,Traditional 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 TDDS,Targe
6、ted 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,Classification of TDDS 分类,P
7、assive targeted drug delivery 被动靶向Active targeted drug delivery 主动靶向Physicochemical targeted drug delivery 物理化学靶向,Classification of TDDS,体内靶向性评价,(1)Relative uptake rate 相对摄取率 Re=(AUCi)p/(AUCi)s(2)Peak concentration ratio 峰浓度比 Ce=(Cmax)p/(Cmax)s(3)Targeting efficiency 靶向效率 Te=(AUC)target/(AUC)non-tar
8、get,传统的隔室药动学模型不适于评价靶向制剂,Molecular Pharmaceutics,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。药物分子与DDS的体内外转运与代谢药物分子与载体的相互作用靶向给药的分子机制分子水平的药代动力学研究,12,Particulate drug carriers 微粒类载体,Liposome 脂质体Nanoparticles/macroparticles 纳米粒/微球Micelles 胶束Emulsion 乳剂Dendrimers 树突状物,LIPOSOMES 脂质体,What are LiposomesAdvantages of Liposom
9、esClasses of LiposomesPreparation of Liposomes,Liposomes are phospholipid based vesicles comprising of aqueous and lipid compartments.脂质体是利用磷脂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质双层中。,Hydrophilic,Hydrop
10、hobic,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，有疏水亲水两种基团.,Types of the Liposomes,Immuno,Cationic,Long Circulating,Conventional,Targeted,Doxil-FDA批准的第一个纳米药物,通用名：Doxorubicin Liposomal；阿霉素脂质体商品名：Doxil（多喜）,Caelyx(楷莱)公司：Sequus Pharmace
11、uticals 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 Liposome,1）Targeting ability 靶向性和淋巴定向性 2）Extended circulation time 长效性 3）Good bioacceptability and biocompatibility 细胞亲和性与组织相容性 4）Reduce the toxicity of crude drug 降低药物毒性5）Increase the stability of drug 提高药物稳定性 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,磷脂+胆固醇a、磷脂
12、类 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、长循环磷脂b、胆固醇 脂质体“流动性缓冲剂”(fluidity buffer)调节膜流动性,制备脂质体的材料,Materials:Phospholipids+cholesterol,Preparation of liposome,Neutral:PC,DPPC,DMPC,DOPENegatively-charged:PA,OG,DCPPositively-charged:SA,DDAB,Cholesterol:fluidity buffer,Phospholipids,Common components of the
13、 liposomes,Cholesterol,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流动性。This adds rigidity刚性 to the lipid bilayers.,Preparation method,Film dispersion method 薄膜法High-pressure homogenizer method 高压乳匀法Reverse phase evaporation vesicle method 逆向蒸发法Injection method 注入法Freeze-thawing meth
14、od 冻融法,Film dispersion method,Phospholipids and cholesterol were dissolved in organic solventsRemove organic solvents by rotary evaporation，to form uniform filmAdd water and keep stirring,Injection method,Dissolve phospholipids and cholesterol in organic solventsInject the solvent into phosphate buf
15、fer（50-60）keep stirring until the organic solvent is removed,1、Morphology,particle size and distribution 形态、粒径及其分布2、Entrapment efficiency and loading capacity 载药量和包封率 包封率=脂质体中的药量/（介质中的药量+脂质体中的药量）100%3、Leakage rate 渗漏率 渗漏率=（储存一定时间后渗漏到介质中的药量/储存前包封的药量）100%4Distribution in vivo 药物体内分布,脂质体制剂的质量评价,Nanopar
16、ticles 纳米粒,Colloidal particles ranging in size between 1 and 1000nm are known as nanoparticles 由天然或合成的高分子载体材料制成的、粒度在纳米数量级（1-1000nm）的固态胶体微粒,Nanocapsule纳米囊属药库膜壳型，由聚合材料外壳和液状核构成，药物主要溶解在液状核中，这种纳米囊主要适于包裹脂溶性药物。,Nanosphere 纳米球属基质骨架型，属于实心的球或微粒，药物吸附在其表面或包裹、溶解在其内部。,Advantages of NP delivery,Physical stability
17、物理稳定性好Belongs to colloid system 属胶体系统，较混悬型微球制剂容易给药Extended therapeutic time 长效Uptake by RES 被动到达肝脏、脾脏和骨髓Ligand-modified nanoparticle 可主动靶向分布于其他器官Enhanced permeability 改变药物对生物膜的透过性，有利于药物的胞内靶向传输,白蛋白纳米粒,Hydrophobic drugs,e.g.,Paclitaxel,docetaxel,rapamycin etc.,Albumin,Mean size=50-150 nm,cryo-TEM,Conc
18、entration dependent dissociation into individual drug-bound albumin molecules,Active drug in nanoparticle is in non-crystalline,amorphous,readily bioavailable state,Taxol,Abraxane(nab-paclitaxel)is a solvent-free nano version of Taxol(cremophor-based paclitaxel),Contents:Paclitaxel 6 mg/mlCremophor
19、537 mg/mlEthanol 396 mg/ml,Contents:100 mg paclitaxel900 mg albuminNo Surfactants/Solvents,Abraxane received FDA Approval January,2005for metastatic breast cancer,Abraxane,Nanomaterials 纳米粒的载体材料,Biodegradable 生物可降解Biocompatible 生物相容性Low toxicity,天然高分子材料半合成高分子材料合成高分子材料,壳聚糖 Chitoson,一种天然的聚阳离子多糖具有优良的生物
20、相容性和生物降解性已经广泛的应用于医疗领域,34,聚乳酸,聚乳酸-乙醇酸,PLA PLGA,乳酸,丙交酯,乙醇酸,乙交酯,36,Polymerization method 聚合法 Dispersion method 分散法,NP preparation：物理分散法/化学反应法,micelle polymerizationemulsion polymerizationinterfacial polymerization,emulsion dispersion salting-out dispersionsolvent evaporation,Sonication,Preparation of N
21、anoparticles,Evaporation,乳化-溶剂蒸发法,38,Result,39,Appearance of INS-PLC-NPs before and after lyophilization,冻干前,冻干品,冻干后,Characterization of INS-PLC-NPs before and after lyophilization,40,Therapeutic effect in diabetic rats after s.c.injection(n=5),3 Days,41,界面缩聚法 Interfacial polymerization,如氰基丙烯酸酯的单体在O
22、H-离子的作用下，发生聚合反应，可生成聚氰基丙烯酸酯纳米粒。,米托蒽醌聚氰基丙烯酸正丁酯毫微粒,nanoparticle drug molecule NP loaded with drug,Mitoxantrone polybutyl cyanoacrylate nanoparticles,图 米托蒽醌毫微粒的扫描电镜照片,Tumor inhibition effects,Overall survival of HCC patients treated with DHAD-PBCA-NP or DHAD injection,治疗108例原发性肝癌效果（华西医院、四川省肿瘤医院、重庆市肿瘤医院、
23、广西医科大学肿瘤医院）,In vivo distribution of NP,Nanoparticles will usually be taken up by the liver,spleen and other parts of the RES depending on their surface characteristicsNanoparticles with more hydrophobic surfaces will preferentially be taken up by the liver,followed by the spleen and lungsParticles w
24、ith longer circulation times,and hence greater ability to target to the site of interest,should be 100 nm or less in diameter and have a hydrophilic surface in order to reduce clearance by macrophages.,Microemulsion 微乳,Microemulsions are clear,stable,isotropic liquid mixtures of oil,water and surfac
25、tant,frequently in combination with a co-surfactant.由适当比例的表面活性剂，助表面活性剂，水和油自发形成的各向同性、外观透明或半透明、热力学稳定的分散体系,In contrast to ordinary emulsions,microemulsions form upon simple mixing of the components and do not require the high shear conditions generally used in the formation of ordinary emulsions.The tw
26、o basic types of microemulsions are direct(oil dispersed in water,o/w)and reversed(water dispersed in oil,w/o).,Difference between Microemulsions and emulsions,50,Advantages of microemulsion based drug delivery,spontaneous formation 自发形成，不需外界提供能量ease of manufacturing and scale-upthermodynamic stabil
27、ity 热力学稳定，长期放置或离心不分层 improved drug solubilization and bioavailability 提高难溶性药物的溶解度，促进药物吸收，提高其生物利用度,Oil,Formulating Microemulsions,Co-surfactant,Water,O/Wmicroemulsion,W/Omicroemulsion,52,Method of microemulsion preparation,Microfluidization,加水滴定法加油滴定法加乳化剂滴定法交替加入法,微乳的形成不需要外界做功，是体系内各组分达到适当的配比时自发形成的。,Li
28、posomePolymeric nanoparticles/macroparticlesBlock copolymer micellesEmulsionDendrimers,Classes of particulate drug carriers,Passive targeted drug delivery 被动靶向Active targeted drug delivery 主动靶向Physicochemical targeted drug delivery 物理化学靶向,Classification of TDDS,Passive targeted drug delivery,Passive
29、 targeting relies on the natural distribution pattern of the drug or drug-carrier systemParticle size,Surface characters 粒径大小 表面特征,Less than 7m:removed from the blood by macrophages 巨噬细胞 of the RES 网状内皮系统 when administered systemicallyLarger than 7m:target drug to lungNanoparticles less than 50 nm:a
30、ccumulate in bone marrow 骨髓 slowly,广泛应用于肿瘤靶向治疗中的一种靶向机制：EPR effect(enhanced permeability and retention)增强的血管通透性和存留量 increased permeability of endothelial barriers in tumor blood vessels;the lack of effective lymphatic drainage from the tumor.,EPR效应（大分子物质和微粒在肿瘤组织具有的高通透性和滞留效应）,被动靶向,Passive targeted dru
31、g delivery 被动靶向Active targeted drug delivery 主动靶向Physicochemical targeted drug delivery 物理化学靶向,Classification of TDDS,Active targeted drug delivery,Active targeting employs a deliberately modified drug or drug carrier molecule capable of recognizing and interacting with a specific cell tissue or org
32、an in the body 经特殊分子修饰的药物或药物载体，可将药物定向地运送到靶区浓集发挥药效。Modification of the carrier system may include incorporation of antigen-specific antibodies 抗体,or attachment of cell receptor-specific ligands 配体,Active particulate Drug Carriers,Mechanism for active target delivery of drug-loaded particulates,On bin
33、ding to the receptors,the ligandparticle complex could be internalized into the cell.,Major targeting ligands for drug delivery,根据肝细胞表面过量表达去唾液酸糖蛋白受体，能够特异性地结合半乳糖残基，对胆固醇分子进行半乳糖修饰。,半乳糖修饰的胆固醇脂质体,不同半乳糖密度的胆固醇衍生物,不同链长的胆固醇衍生物,Xun Sun,et al.J of Drug Targeting.2005,13:121-128.J of Drug Targeting.2010,18:520-
34、535,A549 cells,HepG2 cells,配体分子结构对Gal-LPD转染率的影响,Targeting Moiety,Antigen binding fragments,66,Prodrug,Definition:A pharmacologically inactive chemical entity that when metabolized or chemically transformed by a mammalian system is converted into a pharmacologically active substance.,母体药物经化学衍生而成的物质，在
35、体内经酶或化学反应再生成母体药物，发挥治疗作用,Improve patient acceptability(decrease pain on injection)Alter and improve absorption Alter biodistribution Alter metabolism Alter elimination,Why use prodrugs?,Metabolism(enzyme dependant)Chemical Methods(non-dependant):Hydrolysis 水解 Decarboxylation 脱羧 NOT patient dependant!
36、Stability/Storage issues,Conversion of Prodrugs,Principals for the design of prodrug,Prodrug should be:Inactive and nontoxic Easily synthesizable Chemically stable outside site of action Bioreversible(parent drug must be regenerated in vivo),Target mechanism of prodrug,Erythromycin红霉素 is a very bitt
37、er substance easily destroyed at acidic pH Propionate ester is to increase lipid solubility for improved absorption Ester must be hydrolyzed for antibacterial activity Lauryl sulfate salt十二烷基硫酸盐 absorption not affected by food,less bitter after taste and is acid stable,Functional Groups in Prodrugs,
38、Azo Prodrugs 偶氮前体药物,Bacterial reductases reductive cleavage Occurs in colon discourages small intestine systemic absorption Concentrates the drug at the desired site of action,柳氮磺胺吡啶,73,Key Lab of Drug Targeting and drug delivery systems,Sichuan University靶向药物及释药系统教育部重点实验室四川大学华西药学院,14-Succinate lyso
39、zyme conjugate for the renal delivery of triptolide(雷公藤）,Renal disease and systemic disease caused by renal disease are frequently occurred and difficult to treat all over the world.Its reported that the incidence of kidney disease was up to 9.6%in China,and more than 90%of patients know very little
40、 about their disease.The incidence of End Stage Renal Disease(ESRD)in China:1/10000 in 1994 3/10000 in 2002,Renal Disease,Triptolide:A potent C3 suppressantand immunosuppresant with severe toxicity,雷公藤Tripterygium Tilfordii Hook F.,Tripterygium Tilfordii Hook F.卫茅科,疗效明确制剂以多甙片为主副作用大主要有效成分：雷公藤内酯醇,The
41、characteristics of lysozyme as carrier for renal drug targeting Selective disposition in kidney Biodegradable Containing reactive functional groups None-antigenic,Administrated FITC+TP by i.v.,Administrated TPS-LZM labeled FITC by i.v.,T P,TPS-LZM,Mechanism for renal targeting-megalin mediated site
42、specific delivery,Passive targeted drug delivery 被动靶向Active targeted drug delivery 主动靶向Physicochemical targeted drug delivery 物理化学靶向,Classification of TDDS,Physicochemical targeted preparations,Physicochemical targeting refers to delivery systems that release a drug only when exposed to a specific m
43、icro-environment,such as a change in pH or temperature,or the use of external magnetic field.应用某些物理化学方法可使靶向制剂在特定部位发药效。如磁性材料、pH敏感，热敏感,热敏性脂质体,Thermo-sensitive liposome 通过在处方中添加特殊的脂质材料，使脂质体在高于生理温度几度的环境中发生脂质膜的相转变，最终释放出药物。,Key concepts:According to the principles of targeting preparations,Targeted Drug D
44、elivery Systems can be divided into passive target-oriented preparation,active target-oriented preparations and physical target-oriented preparations.Molecular pharmaceutics is a subject that studies the relationship between dosage form and drug therapeutic effect at molecular and cellular levels.,L
45、iposome is a kind of lipid micelles consisting of an aqueous core enclosed in one or more phospholipids layers.It is formed by phospholipids along with appropriate additives suspended in water.Advantages associated with liposome as drug carriers include:(i)excellent cytocompatibility and histocompat
46、ibility;(ii)minimizing toxicity of drugs;(iii)enhancing stability of drugs;(iv)triggering drug targeting,etc.,Nanoparticles are solid colloidal particles measuring in one dimension between 1-1000 nm.They are made from natural polymers or some alternative materials such as solid lipids.Microemulsions are thermodynamically stable,isotropic,transparent or semitransparent mixtures of oil,water,surfactant and consurfactant.The size of the micro-emulsion droplets can be varied from 10 to100 nm.,
