四、肺部吸入给药系统课件

四、肺部吸入给药系统优点：面积,上皮细胞间隙，肺泡、血管和淋巴管，血流速度，无首过破坏、无促进剂系统

限制和要求：沉着部位及重现性、长期毒性Inhalationtherapy

(

Historicalperspective)1955,Metered-doesinhaler(MDI)developedbyGeorgeMaison1956marketed,FDAapprovalMay,1974,Sugarloafconferencemilestoneintheclinicaluseofaerosolizeddrugtherapy1980s-1990s,developmentanddeliveryofdrugformulationadditionaldevice,↓oropharyngeallossdrypowderinhaler2000Non-CFCpropellantmedicationsotherthanpulmonarydisease

Inhalationtherapy

(

Historicalperspective)InhalationforairwaydiseaseLungTotalsurface80M2Majorcontactbetweenbody&environmentHostdefensemechanismhasevolvedtocopewithnoxiousinhaledsubstancesAfewkeyprocessesinasthmapathogenesisaresurfaceprocessesBenefitsofinhalationrouteforairwaydiseaseLunghasmorepotentialsurfaceareaformolecularexchangewithblood&rapidabsorptionActionviaabsorptionthroughtracheobronchialmucosalungparenchymal(alveolar-capillary)topicallyreactwithreceptorinairwaybothMacromoleculesandAirwayMacromoleculesairwaysurface(3.0M2)nearlyimpermeablelungperiphery(alveoli,80-100M2)dopermeateComparisonoftherapeuticratio

usingthreeroutesofadministrationofahypothetical

drugforequivalenttherapeuticbenefits

IVOralInhaledunitsavailable1005010toexerteffectreachingtargettissue211reachingothertissues98499therapeuticratio1/491/491/9(effectivedrug/drugactingatothertissue)InhalabledrugforsystemictherapyEfficientlydelivertothelungperipheryReproducibletherapeuticdrugdoseAccommodateflexibledosingStableformulationatroomTemp.DevicemustbeportableandeasytouseInhalabledrugindustrytodayAtleast5companiesAeroGenAlkermesAradigmcorporationDurapharmaceuticalsInhaleTherapeuticSystemsKnowndevelopinginhalableproteinsAventisBeringα-1proteinaseinhibitorforemphysemaBiogenAVONEX(IFNβ-1a)forMSPfizer,AventisPharmainhalableinsulinMedicalconditionsthatcouldbenefitsfrompulmonarydeliveryPainPanicandanxietyAnaphylaxisCardiacarrhythmiaOtherCVconditionsDiarrheaNauseaandvomitingNicotinewithdrawalUrinaryincontinenceSpasmInsomniaMacromoleculecandidatesforpulmonarydeliveryInsulinGrowthhormoneAnti-obesitypeptidesPTHOsteoporosispeptideDiabetespeptidesHumancalcitoninInterferonsSomatostatinLHRHanalogsVaccinesAntibioticsILsandantagonistsImmunesuppressionpeptidesNervegrowthfactorsCSFEPOFactorIXα1-proteinaseinhibitorClinicalindicationsforvariousdrugsbyaerosoltotheairwayAsthmasteroidbronchodilatorscromolynInfluenza,RSVRibavirinPneumocystispentamidineFungalinfectionamphotericinCysticfibrosisantibioticsDynaseImmunizationvaccinesSarcoidosissteroidDMinsulinClinicalefficacyinaerosoltherapyDependsHowfartheaerosolwillpenetrateintracheobronchialtreeHowmuchwillbedepositedintracheobronchialtreePulmonarydeliveryisaffectedby...PhysicalpropertiesofthedrugsubstanceParticlesize,density,shape,staticelectricityetc.Therequiredaerodynamicsizerangeis0.5-5µmDeliverydeviceDosedeliveryandaerosolisationefficacyPatientinspirationprofilePeakflowrate,timetopeakandtotalvolume(Pato)physiologyoftherespiratorytractParticlesize,characteristics0.5-5um,uniformAerosolproducing(delivery)systemslow-movingfineparticulatecloudeasytouseInhalationpatternlaminaflowisbetterDegreeofairwaynarrowingAerosolDefinition:Suspensionofveryfineparticlesofliquidorsolidinagasvaryinshape,density,orsizeheterodisperseormonodisperseMechanismsofAerosolDepositionImpaction(>5μm)resultfrominertiadepositionwhentheycollidewithasurfaceSedimentation(1-5μm)duetogravityoccurswhentheaerosolloseinertiaDiffusion(<3μm)Brownianmovement气雾粒子大小与沉积位置的关系气雾粒子沉积位置气雾粒子大小太大无法进入50μm

口.鼻.咽部10-50咽部.气气管3-10

細支气可能隨呼出气体飘至大气不沉积<0.05μmGlossaryinAerosolMMAD

(MeanMassAerodynamicDiameter)themeansizeofparticlesinmicronsthelargertheMMAD,thelargeristhemedianparticlesize

GSD

(GeometricStandardDerviation)therangeofsizesofparticlesinanaerosolthegreatertheGSD,themoreheterodisperseistheaerosolSystemPerformanceRequirementsParticlesize:1-5micrometersLungdeposition

-Amount

-Location

-Moleculartarget

-Efficiency;SideeffectsDose;DoseconsistencyPhysical/Chemicalproperties剂型因素粉雾剂、气雾剂给药装置：计量式吸入器、喷雾器、气雾器微粉化及其方法：研磨、喷干、超临界粉碎、搅拌离心稳定剂：-干扰素与山梨醇、人血清蛋白和氯化钠、胰岛素与乳糖、柠檬酸钠和甘露醇、人生长激素〔hGH〕与吐温20促吸剂：亮丙瑞林/1%甘油或Azone，胰岛素/25%癸酸钠OtherFactorstoConsiderPatientcomplianceissuesOnceperdaydosingReduceddosingTaste;Taste-maskingSafety;Lock-outfeaturesBreathactuationDosecounters;DoseindicatorsDosesperunitSamplesCosts;TimelinesDevelopmentManufacturingDetectionofthefateofinhaleddrugRadiolabeledaerosolstudiesInhaledradiolabelledparticles,followedbygammascintigraphyCharcoalingestionmethodsinhaleddrugissimultaneouslyadministratedwithcharcoalwhichblockoralabsorptionTimedurinaryexcretionsurrogatesoflungbioavailabilitybiphasicrenalexcretionfollowedinhaleddrugHowtodeliverdrugsforsystemictherapyviainhalationGoal:TargetthelungperipheryMethod:adequatesize:1-3um(≦2um)breathingpattern:slow,deepinhalationbetterdeliverydeviceTraditionaldeliverydeviceMDI,DPI,Nebulizer:forairwaydiseasenottodeliverdrugsintolungperipheryacceptableforlargetherapeuticwindowandpotentdrug(5-20ug)inconsistentdosereproducibilitynotabletodelivermostmacromoleculeslowsystemicefficiencyanddrugmassperpuffpoorformulationstabilityanddosereproducibilityMeteredDoseInhalers(MDIs)Canister(holdsformulation)MeteringvalvePlasticmouthpieceSprayofficeAdvantagesofMeteredDoseInhalersConsistentdosingWidedoserangeperactuationwithnobulkingagentsSelf-containedpowersourceDoseisindependentofinspirationeffortEasytouse;SimilarmethodofoperationCompact;PortableDurableSealedtoenvironment;LongshelflifeRelativelyinexpensivetomanufactureWhydrypowderinhalersareneeded?DonotcontainozonedepletingCFCpropellantsNocoldfreoneffectpresentInspiration-actuationco-ordinationnotneededHighlungdepositionRelativesimpletoformulateHFA’sarenotdirectlyanalternativeforCFC’sSomeDPIformulationissues...Manipulationofparticle-particleadhesionFineparticle(<5µm)aerosolisationElectrostatics-moisturecontent-capillaryforceOtherphysicalcharacteristicsoftheparticlesMaintainingphysicalstabilityandflowpropertiesoftheinhalationpowderDelivereddoseconsistency-bulkingagent(s)Conventionalorderedmixture-carrier