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 Sugarloafconferencemilestoneintheclinicaluseofaerosolizeddrugtherapy 1980s 1990s developmentanddeliveryofdrugformulationadditionaldevice oropharyngeallossdrypowderinhaler2000Non CFCpropellantmedicationsotherthanpulmonarydisease Inhalationtherapy Historicalperspective Inhalationforairwaydisease LungTotalsurface80M2Majorcontactbetweenbody environmentHostdefensemechanismhasevolvedtocopewithnoxiousinhaledsubstancesAfewkeyprocessesinasthmapathogenesisaresurfaceprocesses Benefitsofinhalationrouteforairwaydisease Lunghasmorepotentialsurfaceareaformolecularexchangewithblood rapidabsorptionActionviaabsorptionthroughtracheobronchialmucosalungparenchymal alveolar capillary topicallyreactwithreceptorinairwayboth MacromoleculesandAirway Macromoleculesairwaysurface 3 0M2 nearlyimpermeablelungperiphery alveoli 80 100M2 dopermeate Comparisonoftherapeuticratiousingthreeroutesofadministrationofahypotheticaldrugforequivalenttherapeuticbenefits IVOralInhaledunitsavailable1005010toexerteffectreachingtargettissue211reachingothertissues98499therapeuticratio1 491 491 9 effectivedrug drugactingatothertissue Inhalabledrugforsystemictherapy EfficientlydelivertothelungperipheryReproducibletherapeuticdrugdoseAccommodateflexibledosingStableformulationatroomTemp Devicemustbeportableandeasytouse Inhalabledrugindustrytoday Atleast5companiesAeroGenAlkermesAradigmcorporationDurapharmaceuticalsInhaleTherapeuticSystems Knowndevelopinginhalableproteins AventisBering 1proteinaseinhibitorforemphysemaBiogenAVONEX IFN 1a forMSPfizer AventisPharmainhalableinsulin Medicalconditionsthatcouldbenefitsfrompulmonarydelivery PainPanicandanxietyAnaphylaxisCardiacarrhythmiaOtherCVconditionsDiarrhea NauseaandvomitingNicotinewithdrawalUrinaryincontinenceSpasmInsomnia Macromoleculecandidatesforpulmonarydelivery InsulinGrowthhormoneAnti obesitypeptidesPTHOsteoporosispeptideDiabetespeptidesHumancalcitoninInterferonsSomatostatinLHRHanalogs VaccinesAntibioticsILsandantagonistsImmunesuppressionpeptidesNervegrowthfactorsCSFEPOFactorIX 1 proteinaseinhibitor Clinicalindicationsforvariousdrugsbyaerosoltotheairway AsthmasteroidbronchodilatorscromolynInfluenza RSVRibavirinPneumocystispentamidineFungalinfectionamphotericin CysticfibrosisantibioticsDynaseImmunizationvaccinesSarcoidosissteroidDMinsulin Clinicalefficacyinaerosoltherapy DependsHowfartheaerosolwillpenetrateintracheobronchialtreeHowmuchwillbedepositedintracheobronchialtree Pulmonarydeliveryisaffectedby PhysicalpropertiesofthedrugsubstanceParticlesize density shape staticelectricityetc Therequiredaerodynamicsizerangeis0 5 5 mDeliverydeviceDosedeliveryandaerosolisationefficacyPatientinspirationprofilePeakflowrate timetopeakandtotalvolume Pato physiologyoftherespiratorytract Particlesize characteristics0 5 5um uniformAerosolproducing delivery systemslow movingfineparticulatecloudeasytouseInhalationpatternlaminaflowisbetterDegreeofairwaynarrowing Aerosol Definition Suspensionofveryfineparticlesofliquidorsolidinagasvaryinshape density orsizeheterodisperseormonodisperse MechanismsofAerosolDeposition Impaction 5 m resultfrominertiadepositionwhentheycollidewithasurfaceSedimentation 1 5 m duetogravityoccurswhentheaerosolloseinertiaDiffusion 3 m 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50 m口 鼻 咽部10 50咽部 气管 支气管3 10細支气管 肺泡管 肺泡0 5 3可能隨呼出气体飘至大气不沉积 0 05 m GlossaryinAerosol MMAD MeanMassAerodynamicDiameter themeansizeofparticlesinmicronsthelargertheMMAD thelargeristhemedianparticlesizeBestsize0 5 5umGSD GeometricStandardDerviation therangeofsizesofparticlesinanaerosolthegreatertheGSD themoreheterodisperseistheaerosol SystemPerformanceRequirements Particlesize 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 OtherFactorstoConsider PatientcomplianceissuesOnceperdaydosingReduceddosingTaste Taste maskingSafety Lock outfeaturesBreathactuationDosecounters DoseindicatorsDosesperunitSamplesCosts TimelinesDevelopmentManufacturing Detectionofthefateofinhaleddrug RadiolabeledaerosolstudiesInhaledradiolabelledparticles followedbygammascintigraphyCharcoalingestionmethodsinhaleddrugissimultaneouslyadministratedwithcharcoalwhichblockoralabsorptionTimedurinaryexcretionsurrogatesoflungbioavailabilitybiphasicrenalexcretionfollowedinhaleddrug Howtodeliverdrugsforsystemictherapyviainhalation Goal TargetthelungperipheryMethod adequatesize 1 3um 2um breathingpattern slow deepinhalationbetterdeliverydevice Traditionaldeliverydevice MDI DPI Nebulizer forairwaydiseasenottodeliverdrugsintolungperipheryacceptableforlargetherapeuticwindowandpotentdrug 5 20ug inconsistentdosereproducibilitynotabletodelivermostmacromoleculeslowsystemicefficiencyanddrugmassperpuffpoorformulationstabilityanddosereproducibility MeteredDoseInhalers MDIs AdvantagesofMeteredDoseInhalers ConsistentdosingWidedoserangeperactuationwithnobulkingagentsSelf containedpowersourceDoseisindependentofinspirationeffortEasytouse SimilarmethodofoperationCompact PortableDurableSealedtoenvironment LongshelflifeRelativelyinexpensivetomanufacture Whydrypowderinhalersareneeded DonotcontainozonedepletingCFCpropellantsNocoldfreoneffectpresentInspiration actuationco ordinationnotneededHighlungdepositionRelativesimpletoformulateHFA sarenotdirectlyanalternativeforCFC s SomeDPIformulationissues Manipulationofparticle particleadhesionFineparticle 5 m aerosolisationElectrostatics moisturecontent ca