第21章靶向给药系统课件

Chapter21TargetedDrugDeliverySystem(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.Drugdeliverysystem(DDS)给药系统Adrugdeliverysystem(DDS)isdefinedasaformulationoradevicethatenablestheintroductionofatherapeuticsubstance

治疗物质inthebodyandimprovesitsefficacyandsafetybycontrollingtherate,time,andplaceofreleaseofdrugsinthebody.Thisprocessincludestheadministrationofthetherapeuticproduct,thereleaseoftheactiveingredientsbytheproduct,andthesubsequenttransportoftheactiveingredientsacrossthebiologicalmembranestothesiteofaction.DefinitionDrugdeliverysystemisaninterfacebetweenthepatientandthedrug.Itmaybeaformulationofthedrugtoadministeritforatherapeuticpurposeoradeviceusedtodeliverthedrug.Targeteddrugdeliverysystem(TDDS)DefinitionTheselectivedeliveryofadrugtoaspecificregion(tissue,celltype)ofthebody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。Theaimoftargeteddrugdeliveryistoimprovethetherapeuticeffectivenessofadrug(ortreatment)whileatthesametimeimprovingitssafety.Therefore,theaimistoincreasethetherapeuticindexofadrug.6SuperioritiesofTDDSTraditionaldrugdeliverysystems:Medicationisdistributedthroughoutthebodythroughthesystemicbloodcirculation;Asmallportionofthemedicationreachestheorgantobeaffected.SuperioritiesofTDDSTargeteddrugdelivery:Concentratethemedicationinthetissuesofinterest;ReducingtherelativeconcentrationofthemedicationintheremainingtissuesSIDEEFFECTSEFFICACYTargetposition:anorganortissueaparticularcelltypeaspecificintracellularcompartment.特定细胞器内ClassificationofTDDS

分类Passivetargeteddrugdelivery被动靶向Activetargeteddrugdelivery主动靶向Physicochemicaltargeteddrugdelivery物理化学靶向ClassificationofTDDS体内靶向性评价(1)Relativeuptakerate

相对摄取率

Re=(AUCi)p/(AUCi)s

(2)Peakconcentrationratio

峰浓度比

Ce=(Cmax)p/(Cmax)s(3)Targetingefficiency

靶向效率

Te=(AUC)target/(AUC)non-target

传统的隔室药动学模型不适于评价靶向制剂MolecularPharmaceutics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12Particulatedrugcarriers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WhatareLiposomesAdvantagesofLiposomesClassesofLiposomesPreparationofLiposomesLiposomesarephospholipidbasedvesiclescomprisingofaqueousandlipidcompartments.

脂质体是利用磷脂双分子层膜所形成的囊泡。

Basedonthesolubility,adrugcanbeencapsulatedeitherintheaqueouscompartmentorinthelipidbilayer.药物分子可被包裹在水相或脂质双层中。HydrophilicHydrophobic

Phospholipidsareamphiphathicinnature,containingahydro-phobictailandhydrophilichead.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.TypesoftheLiposomesImmunoCationicLongCirculating

Conventional

TargetedDoxil®-FDA批准的第一个纳米药物通用名：DoxorubicinLiposomal；阿霉素脂质体商品名：Doxil（多喜）,Caelyx(楷莱)公司：SequusPharmaceuticals应用：最初用于治疗卡波氏肉瘤，后被批准用于卵巢癌治疗

AmphotericinBLiposome1）Targetingability

靶向性和淋巴定向性

2）Extendedcirculationtime长效性

3）Goodbioacceptabilityandbiocompatibility

细胞亲和性与组织相容性

4）Reducethetoxicityofcrudedrug降低药物毒性5）Increasethestabilityofdrug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”(fluiditybuffer)

调节膜流动性

制备脂质体的材料Materials:Phospholipids+cholesterolPreparationofliposomeNeutral:PC,DPPC,DMPC,DOPENegatively-charged:PA,OG,DCPPositively-charged:SA,DDABCholesterol:fluiditybufferPhospholipidsCommoncomponentsoftheliposomesCholesterolCholesterolactsasa“fluiditybuffer”.胆固醇擦入磷脂双分子层中，改变磷脂中疏水链的流动性。Thisaddsrigidity刚性

tothelipidbilayers.

PreparationmethodFilmdispersionmethod薄膜法High-pressurehomogenizermethod高压乳匀法Reversephaseevaporationvesiclemethod

逆向蒸发法Injectionmethod注入法Freeze-thawingmethod冻融法FilmdispersionmethodPhospholipidsandcholesterolweredissolvedinorganicsolventsRemoveorganicsolventsbyrotaryevaporation，toformuniformfilmAddwaterandkeepstirringInjectionmethodDissolvephospholipidsandcholesterolinorganicsolventsInjectthesolventintophosphatebuffer（50-60℃）keepstirringuntiltheorganicsolventisremoved1、Morphology,particlesizeanddistribution

形态、粒径及其分布2、Entrapmentefficiencyandloadingcapacity

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、Leakagerate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%4．Distributioninvivo

药物体内分布

脂质体制剂的质量评价Nanoparticles纳米粒Colloidalparticlesranginginsizebetween1and1000nmareknownasnanoparticles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。AdvantagesofNPdeliveryPhysicalstability物理稳定性好Belongstocolloidsystem属胶体系统，较混悬型微球制剂容易给药Extendedtherapeutictime长效UptakebyRES被动到达肝脏、脾脏和骨髓Ligand-modifiednanoparticle可主动靶向分布于其他器官Enhancedpermeability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Hydrophobicdrugs,e.g.,Paclitaxel,docetaxel,rapamycinetc.AlbuminMeansize=50-150nmcryo-TEMConcentrationdependentdissociationintoindividualdrug-boundalbuminmoleculesActivedruginnanoparticleisinnon-crystalline,amorphous,readily

bioavailablestateTaxolAbraxane(nab-paclitaxel)isasolvent-free‘nano’versionofTaxol(cremophor-basedpaclitaxel)Contents:Paclitaxel6mg/mlCremophor537mg/mlEthanol396mg/mlContents:100mgpaclitaxel900mgalbuminNoSurfactants/SolventsAbraxanereceivedFDAApprovalJanuary,2005formetastaticbreastcancerAbraxaneNanomaterials纳米粒的载体材料Biodegradable生物可降解Biocompatible生物相容性Lowtoxicity

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相容性和生物降解性已经广泛的应用于医疗领域甲壳类动物甲壳素壳聚糖34聚乳酸聚乳酸-乙醇酸PLAPLGA乳酸丙交酯乙醇酸乙交酯36Polymerizationmethod

聚合法

Dispersionmethod

分散法

NPpreparation：物理分散法/化学反应法micellepolymerizationemulsionpolymerizationinterfacialpolymerization

emulsiondispersionsalting-outdispersionsolventevaporationSonicationPreparationofNanoparticlesEvaporation乳化-溶剂蒸发法38Result39AppearanceofINS-PLC-NPsbeforeandafterlyophilization冻干前冻干品冻干后CharacterizationofINS-PLC-NPsbeforeandafterlyophilization40Therapeuticeffectindiabeticratsafters.c.injection(n=5)3Days41界面缩聚法Interfacialpolymerization如氰基丙烯酸酯的单体在OH-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nanoparticledrugmoleculeNPloadedwithdrugMitoxantronepolybutylcyanoacrylatenanoparticles图米托蒽醌毫微粒的扫描电镜照片TumorinhibitioneffectsOverallsurvivalofHCCpatientstreatedwithDHAD-PBCA-NPorDHADinjection

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、广西医科大学肿瘤医院）InvivodistributionofNPNanoparticleswillusuallybetakenupbytheliver,spleenandotherpartsoftheRESdependingontheirsurfacecharacteristicsNanoparticleswithmorehydrophobicsurfaceswillpreferentiallybetakenupbytheliver,followedbythespleenandlungsParticleswithlongercirculationtimes,andhencegreaterabilitytotargettothesiteofinterest,shouldbe100nmorlessindiameterandhaveahydrophilicsurfaceinordertoreduceclearancebymacrophages.Microemulsion微乳Microemulsionsareclear,stable,isotropicliquidmixturesofoil,waterandsurfactant,frequentlyincombinationwithaco-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Incontrasttoordinaryemulsions,microemulsionsformuponsimplemixingofthecomponentsanddonotrequirethehighshearconditionsgenerallyusedintheformationofordinaryemulsions.Thetwobasictypesofmicroemulsionsaredirect(oildispersedinwater,o/w)andreversed(waterdispersedinoil,w/o).DifferencebetweenMicroemulsionsandemulsions50Advantagesofmicroemulsionbaseddrugdeliveryspontaneousformation自发形成，不需外界提供能量easeofmanufacturingandscale-upthermodynamicstability热力学稳定，长期放置或离心不分层improveddrugsolubilizationandbioavailability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OilFormulatingMicroemulsionsCo-surfactantWaterO/WmicroemulsionW/Omicroemulsion52MethodofmicroemulsionpreparationMicrofluidization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。LiposomePolymericnanoparticles/macroparticlesBlockcopolymermicellesEmulsionDendrimersClassesofparticulatedrugcarriersPassivetargeteddrugdelivery被动靶向Activetargeteddrugdelivery主动靶向Physicochemicaltargeteddrugdelivery物理化学靶向ClassificationofTDDSPassivetargeteddrugdelivery

Passivetargetingreliesonthenaturaldistributionpatternofthedrugordrug-carriersystemParticlesize,Surfacecharacters粒径大小表面特征Lessthan7µm:removedfromthebloodbymacrophages

巨噬细胞oftheRES

网状内皮系统whenadministeredsystemicallyLargerthan7µm:targetdrugtolungNanoparticleslessthan50nm:accumulateinbonemarrow

骨髓slowly广泛应用于肿瘤靶向治疗中的一种靶向机制：EPReffect(enhancedpermeabilityandretention)增强的血管通透性和存留量

increasedpermeabilityofendothelialbarriersintumorbloodvessels;thelackofeffectivelymphaticdrainagefromthetumor.血管壁间隙较宽，结构完整性较差，淋巴回流缺失实体瘤组织血管丰富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）Smoothmusclelayer内皮间隙致密、结构完整

被动靶向Passivetargeteddrugdelivery被动靶向Activetargeteddrugdelivery主动靶向Physicochemicaltargeteddrugdelivery物理化学靶向ClassificationofTDDSActivetargeteddrugdelivery

Activetargetingemploysadeliberatelymodifieddrugordrugcarriermoleculecapableofrecognizingandinteractingwithaspecificcelltissueororganinthebody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。Modificationofthecarriersystemmayincludeincorporationofantigen-specificantibodies抗体,orattachmentofcellreceptor-specificligands配体ActiveparticulateDrugCarriersMechanismforactivetargetdeliveryofdrug-loadedparticulatesOnbindingtothereceptors,theligand–particlecomplexcouldbeinternalizedintothecell.Majortargetingligandsfordrugdelivery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XunSun,etal.JofDrugTargeting.2005,13:121-128.JofDrugTargeting.2010,18:520-535

A549cellsHepG2cells配体分子结构对Gal-LPD转染率的影响TargetingMoietyAntigenbindingfragments66ProdrugDefinition:Apharmacologicallyinactivechemicalentitythatwhenmetabolizedorchemicallytransformedbyamammaliansystemisconvertedintoapharmacologicallyactivesubstance.母体药物经化学衍生而成的物质，在体内经酶或化学反应再生成母体药物，发挥治疗作用Improvepatientacceptability(decreasepainoninjection)AlterandimproveabsorptionAlterbiodistributionAltermetabolismAltereliminationWhyuseprodrugs?Metabolism(enzymedependant)ChemicalMethods(non-dependant):Hydrolysis水解

Decarboxylation脱羧

NOTpatientdependant!Stability/StorageissuesConversionofProdrugsPrincipalsforthedesignofprodrugProdrugshouldbe:InactiveandnontoxicEasilysynthesizableChemicallystableoutsidesiteofactionBioreversible(parentdrugmustberegeneratedinvivo)TargetmechanismofprodrugErythromycin红霉素

isaverybittersubstanceeasilydestroyedatacidicpHPropionateesteristoincreaselipidsolubilityforimprovedabsorption

Estermustbehydrolyzedforantibacterialactivity

Laurylsulfatesalt十二烷基硫酸盐–absorptionnotaffectedbyfood,lessbitteraftertasteandisacidstableFunctionalGroupsinProdrugsAzoProdrugs偶氮前体药物Bacterialreductases

reductivecleavageOccursincolon

discouragessmallintestinesystemicabsorptionConcentratesthedrugatthedesiredsiteofaction柳氮磺胺吡啶

73KeyLabofDrugTargetinganddrugdeliverysystems,SichuanUniversity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-Succinatelysozymeconjugatefortherenaldeliveryoftriptolide(雷公藤）Renaldiseaseandsystemicdiseasecausedbyrenaldiseasearefrequentlyoccurredanddifficulttotreatallovertheworld.It’sreportedthattheincidenceofkidneydiseasewasupto9.6%inChina,andmorethan90%ofpatientsknowverylittleabouttheirdisease.TheincidenceofEndStageRenalDisease(ESRD)inChina:1/10000in19943/10000in2002

RenalDiseaseTriptolide:ApotentC3suppressantandimmunosuppresantwithseveretoxicity雷公藤TripterygiumTilfordiiHookF.TripterygiumTilfordiiHookF.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：

雷公藤内酯醇溶菌酶作为肾靶向的药物载体Thecharacteristicsoflysozymeascarrierforrenaldrugtargeting

SelectivedispositioninkidneyBiodegradableContainingreactivefunctionalgroupsNone-antigenicAdministratedFITC+TPbyi.v.AdministratedTPS-LZMlabeledFITCbyi.v.TPTPS-LZM雷公藤内酯醇和前体药物给药半小时后的体内分布Mechanismforrenaltargeting-megalinmediatedsitespecificdeliveryPassivetargeteddrugdelivery被动靶向Activetargeteddrugdelivery主动靶向Physicochemicaltargeteddrugdelivery物理化学靶向ClassificationofTDDSPhysicochemicaltargetedpreparationsPhysicochemicaltargetingreferstodeliverysystemsthatreleaseadrugonlywhe