四、肺部吸入給藥系統(tǒng)課件

四、肺部吸入給藥系統(tǒng)優(yōu)點：面積,上皮細胞間隙，肺泡、血管和淋巴管，血流速度，無首過破壞、無促進劑系統(tǒng)

限制和要求：沉著部位及重現(xiàn)性、長期毒性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氣霧粒子大小與沉積位置的關(guān)系氣霧粒子沉積位置氣霧粒子大小太大無法進入50μm

口.鼻.咽部10-50咽部.氣氣管3-10

細支氣可能隨呼出氣體飄至大氣不沉積<0.05μmGlossaryinAerosolMMAD

(MeanMassAerodynamicDiameter)themeansizeofparticlesinmicronsthelargertheMMAD,thelargeristhemedianparticlesize

GSD

(GeometricStandardDerviation)therangeofsizesofparticlesinanaerosolthegreatertheGSD,themoreheterodisperseistheaerosolSystemPerformanceRequirementsParticlesize:1-5micrometersLungdeposition

-Amount

-Location

-Moleculartarget

-Efficiency;SideeffectsDose;DoseconsistencyPhysical/Chemicalproperties劑型因素粉霧劑、氣霧劑給藥裝置：計量式吸入器、噴霧器、氣霧器微粉化及其方法：研磨、噴干、超臨界粉碎、攪拌離心穩(wěn)定劑：-干擾素與山梨醇、人血清蛋白和氯化鈉、胰島素與乳糖、檸檬酸鈉和甘露醇、人生長激素〔hGH〕與吐溫20促吸劑：亮丙瑞林/1%甘油或Azone，胰島素/25%癸酸鈉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