肺部给药疫苗装置的研究进展(英文).docxVIP

1、RecentdevelopmentinaerosoldevicesforpulmonaryvaccinedeliveryLUDong-meiA，(OfficeofGenericDrugs,CenterofDrugEvaluationandResearch,FoodandDrugAdministration,Rockville,MD20855,USA)SUMMARYThisreviewwilldiscussaerosoldevicetechnologiesavailablefbrpulmonaryvaccinedeliveries.Thepossibilitiesofadoptingaeroso

2、l-generationforthepurposeofpulmonaryimmunizationaredescribed.Aerosol-generationsystemsmightofferadvantagesinrespecttovaccinestabilityandantigenicity.Thenoninvasive,relativelysafeandlow-costnetofpulmonarydeliverymayprovidegreatbenefitstothepublichealthvaccinationcampaign.KEYWORDSAerosols；Vaccines；Neb

3、ulizereandvaporizers；Powder；InhalationPulmonaryimmunizationisapotentialalternativetoconventionalparenteraldeliveryapproaches.Mostcommonpathogensenterthebodyviamucousmembranesinthenose,lungsandgastrointestinaltract.Respiratoryviralandbacterialinfectionsareamajorcauseofmorbidityandmortalityworldwide&q

4、uot;.Manypathogensutilizetherespiratorytractasaportalofentryintothebody").Lungsarehighlyvascularized,havealargeabsorptivesurfaceandcontainmucosa-associatedlymphoidtissues.Theexistenceoftheantigenpresentingcells(APC,includingalveolarmacrophageanddendriticcells)145andbronchus-associatedlymphoidti

5、ssue(BALT)inthelungsfacilitatetheelicitationofthehumoralandcell-mediatedimmunity.Therefore,pulmonaryaerosolvaccinationcouldbeapotentiallypowerfulwaytorapidlyimmunizethepopulation,inducingprotectionbyexposingairwaystovaccines.Thisrouteofvaccineadministration,whichfollowsthenaturalrouteofinfection,may

6、bestmimictheinductionofimmunityintherespiratorytractbypathogensandmayleadtomoregeneralsystemicimmunity'”.Therearemanyfactorstobeconsideredforsuccessfulpulmonaryvaccinedeliveries,includingavailableaerosoltechnologies,formulations,stabilityuponstorageandafterdeliveryintothelungsandsafetyuponandpos

7、t-delivery.Tliisreviewpaperwouldfocusonpulmonaryimmunizationdeliverysystemsfbrvaccinations.1AerosoldevicetechnologyavailableforpulmonarydeliveryofvaccinesManyaerosolexposuremethodshavebeenusedtovaccinateanimalmodels.Intratrachealinstillationandinsufflationallowsdirectdeliveryofliquidsandpowderstothe

8、lungs.Animalexposuretoaerosolshasbeenachievedthrougharangeofexposurechambers(wholebodyandnose-onlychambers).Forclinicaltrials,aerosolvaccinedeliveryrequiresdeliverydevicesaswellasformulationsinwhichtheantigensareincorporated.Thesiteandefficiencyofdepositionofaerosolizedparticlesintherespiratorytract

9、iscriticallyinfluencedbytheirparticlesize(definedasaerodynamicdiameter),sizedistribution,particleshapeanddensity8.Iftheaerodynamicparticlesizeis>5jxm,inertialimpactionistheprimarymechanismfordepositionoftheparticlesintheupperandcentralairways.TheparticlesW3pun,whichhavenotdepositedbyimpaction,dep

10、ositinthelowerairwaysbysedimentation.Relativelylowvelocities,alongwithlongerresidencetimes,inthelowerairwaysfavorthedepositionofsubmicronsizeparticles(<1jim)bythediffusionprocess.Diffusionandsedimentationarethemajormechanismsofdepositioninthelowerairwaysofthelungs.Sinceparticlesthataresubjecttodi

11、ffusionhavelittlemass,thismechanismisnotconsideredimportantfbrtherapeuticorvaccineaerosolpurpose.Aerosolvaccinationusuallydependsonthetargetpathogenandthesitesoftheinductiveimmunity.Largerparticles(>5jim)areneededforthevaccinationtopreventupperrespiratoryinfectionsbyrespiratoryvirusesorbacteria(f

12、orexample,BordetellapertussisandChlamydiapneumoniae9)andsmallerparticles(W3pim)fbrlowerrespiratorytractinfections(Streptococcuspneumoniae,Bacillusanthracisastheexamples19).Thesizedistributioninfluencesthemassdepositedinthetargetareaofthelungs,whicharethesitesoftheinductiveimmunity.Theaerosoldelivery

13、deviceplatforms-inhalers,canbeclassifiedintothreemajorcategories:nebulizer,pressurizedmetered-doseinhaler(pMDI)anddrypowderinhaler(DPI).ThecharacteristicsofthedevicesandsuitabilityforthepulmonaryvaccinedeliveriesarelistedinTable1.1.1NebulizersTwotypesofnebulizersarecommerciallyavailable：airjetandult

14、rasonicnebulizers.Generallyairjetnebulizerscangeneratesmallerparticlesizes(massmedianaerodynamicdiameter2-5jim),whichmoreeasilypenetratetothesmallairways.NebulizershaveliveredthanwithMDIandDPIdevices；disposablesomeadvantages:constantoutputcandeliveraerosolsnebulizersareinexpensive.However,treatments

15、usingofmostsolutionsandprovidelargedoseswithverylittlethesenebulizersaretime-consumingandinefficient,patientco-ordinalionorskill；largerdosescanbede-resultinginthewasteofactiveingredients.Table1ComparisonofaerosoldeliverydevicesDeviceplatformFeatureAdvantagesDisadvantagesSuitabilityforvaccinedelivery

16、Nebulizer(1)Aqueousbase(dissolved)(2)Pumpisneeded(1)Pediatric,geriatricandemergencyusepredominately(2)Continuousdelivery,longtreatmenttime(3)Patientscaninhalewithmultiplebreathewhensinglebreathdosingisimpractical(1)Bulky,inconvenientandcomplextouse(2)Drugwastage(3)Pronetomicrobiologicalcontamination

17、(1)Aqueousbaseisfriendlytovaccines(2)Potentialissueonpotency-lossofantigensorvaccinepathogensinnebulizationprocedurepMDl(1)Propellantused(2)Metcred-valveindevice(3)Solution,suspensionformulation(1)Portable(2)Remainingproductuncon-taminated(3)Accuratedosemetering(4)Cosolvent,surfactantcanbeused(5)Pro

18、tectpackeddrug/vac-cinefromlight(6) Highrespirablefraction(7) Inexpensive(8) Maturetechnology(1)Poorhand-mouthcoordinationisftur(2)Propellanttransitionfromchloroflurocarbon(CFG)tohydmfluoroalkanc(HFA)(3)ColdFreoneffectduetopropellantevaporationPropellantisnotveryfriendlytothevaccinepathogensorvaccin

19、eantigensDPI(1)Canhavebuilt-inmeteredd瞒ccounter(2) Nopropellant(3) Reservoirordos<-cartridge(4) Single-doseunitswithcombinationofdevicesareavailable(1)PotentialStabilityadvantage(2) Accuratedose(3) Highdosecarrjingcapacity(4) Activedevicecanimprovethecoordinationbetweendosingandinhalation(1) Devi

20、ceismoivcomplicated(2) Fewexcipientcanbeusedinformulation(generallyonlylactose)GoodpotentialforvaccinedeliveryAdvancesintechnologyhaveledtonovelnebulizersthatreducewasteandimprovedeliveryefficiency.Anenhanceddelivery*design,PariLCStar(Pari,Germany),increasesaerosoloutputbydirectingauxi-liaryairandca

21、usingmoregeneratedaerosoltobesweptoutofthenebulizerforinhalationBreath-actuatednebulizers,e.g.AeroEclipse(TrudellMedicalInternational,London,ON,Canada)andHalolite(Medic-AidLimited,WestSussex,UK)haverecentlybeendeveloped.TheAeroEclipsecontrolsanactuatorpistontoproduceaerosolininspirationandatrestposi

22、tioninpatient*sexpiration101.TheHalolitemonitorsapatient§breathingpatterninthefirstthreebreathsandthentargetstheaerosoldeliveryintothefirst50%ofeachinhalation.Thisensurestheaerosolsaredeliveredtothepatientduringinspirationonly,therebyeliminatingdruglossduringexpiration1u.Anumberofme-tered-dosel

23、iquidinhalers,includingAERx(Aradigm,Hayward,CA,USA),AeroDose(AeroGen,Sunnyvale,CA,USA)andRespimat(BoehringerIngelheim,Ingelheim,Germany),havebeendevelopedtoproducefineaerosolsintherespirablerangebyforcingthedrugsolutionthroughanarrayofnozzleswith30%-75%oftheemitteddosebeingdepositedinthelungs”-”AKIT

24、Ainhalationsystems(Activaero,Germany),combinedwithjetnebulizerfromPari,canactivelycontrolinhalationvolumeandflowrateprogrammedonanindividualizedSmartCard,whichrecordsalltheeventsofAKITA.Theelectronicallycontrolledinhalationisbasedontherapeuticanddosingrequirementsandcanbeadjustedtothepatients'in

25、dividualconditions,4Pulmonaryvaccinationstudieshavebeenperformedbynebulizationofliveattenuatedpathogens,suchastularemia，measles'"，,BCG，andRubella1201.Recently,thenebulizedimmunizationonchickens,usingQueenslandV4andUlster2CstrainsofNewcastlediseaseviruswith60secondexposurelimebyultrasonicneb

26、ulizer,providedprotectionsagainstthevirulentchallenges21.Theonlysuccessfulclinicalcaseofpulmonaryvaccinationonalargescale,withcharacterizationofaerosoldevicetechnology,isapulmonarymeaslesimmunizationstudydeliveredbynebulization.Measlesvaccinewasdeliveredviathe*ClassicalMexicanDeviceM.Measlesvaccinat

27、ionviapulmonaryaerosoldeliveryhasconsiderableappeal.Approximately4millionchildreninMexicowereexposedtomeaslesvaccineaerosolsandahighrateofsuccessfulpreventionwasachieved22.Nebulizationdeliversvaccineaerosolstothelowerrespiratorytract.However,thereispotency-lossproblem.Itwasreportedcomplex-moleculesw

28、erefrequentlydegradedbytheshearforceofjetnebulization1231.Stabilityofmeaslesvaccinewasdeterminedduringnebulizationviathe*classicalMexicandevice".Therewasa71%lossofvaccinepotencyafterthenebulizerwasruncontinuouslyfor20minutes.Thelossinviralpotencywasintheorderofonethirdwhenthenebulizerwasruninth

29、ecyclesof30secondsonand10secondsoffi24j.Immunitymaybeelicitedevenwhenthenumberofviablepathogensinthelungsislow.However,thereproducibilityissueofvaccinedoseinthevaccinemasscampaigncouldnotbeneglected.1.2Pressurizedmetered-doseinhalers(pMDI)pMDIsrepresentthemajorityofpharmaceuticalaerosolproducts.They

30、arecomprisedofdrugformulationfilledorpackedunderpressurealongwiththeenergysource,aliquefiedpropellant,inacanisterequippedwithvalve,tometeraccurateandprecisedoses,andactuator.Apre-determinedvolumeofnonaqueousliquidisdischargedperactuationtooffertheprecisedosedeliveryondemand.pMDIsdeliveronlyasmallfra

31、ctionofthedrugdosetothelungs(10%-20%ofemitteddose).Thereisacoldpropellanteffectduetotheevaporationofpropellantwhentheaerosolsimpactonthebackofthethroat,whichcanbeamelioratedbytheuseofaspacer.Poorhand-mouthcoordinationisanotherobstacleintheoptimaluseofapMDI.Recently,thebreath-actuatedpMDIshavebeendev

32、elopedtoeliminateco-ordinationdifficultiesbyfiringinresponsetothepatient'sinspiratoryflow.TheAutohaler(3MPharmaceuticals,Minnesota,USA),increasedlungdepositionfrom7.2%withaconventionalMDIto20.8%ofthedoseusingthebreath-activatedpMDI251.LatelyAccentiaBiopharmaceuticals(Tampa,Florida)launchedanewbr

33、eath-activated,dose-countinginhaler(MDTurbo)'").Thisdevicehelpstocoordinatethepress-and-breatheactionneededforproperuseofaninhalerapartfromcountingtheremainingdosesintheinhaler.Insulair(TheBang&OulfsenMedicom,Denmark),builtonpMDItechnology,isdesignedforusewithliquiddrugformulationsinclu

34、dingthetreatmentofdiabetes.ThecompanyalsohasdevelopedAstnair,apMDIforasthmaandCOPD.Thisunitrequires50%lessforcethanconventionalinhalerstoreleaseasingledoseFewvaccineshavebeendeliveredviapropellant-drivenmetereddoseaerosols.Thehydrophobicpropellantisnotafriendlyenvironmentformostofthevaccinestrainsor

35、aqueoussolubleantigenproteins.UsuallysurfactantsorcosolventsmaybeneededforpMDIvaccineformulation.BrownetaldeliveredStreptococcussuisbacteriaintotherespiratorytractofswineinthepresenceofsurfactantsusingliquefieddimethyletheraspropellant271.About6%-12%ofbacteriaweredeliveredtothedeeplungs.Afteraerosol

36、izalion,only17%38%ofthecell-wallpmteinswereassociatedwiththebacteriaand30%-50%ofantigenicityintherespirablebacteriawasretainedafteractuation.ThisreportdemonstratedthatsmallparticleaerosolsofthebacteriavaccinefrompMDIcanbegenerated,butwithsignificantlossofantigenicity27*.1.3Drypowderinhalers(DPI)Thee

37、mergenceofnoveldrypowderinhalers(DPls)wasdrivenlargelybytheMontrealprotocoltoeliminatechlorofluorocarbons(CFCs)fromtraditionalpMDIs.ThereareawiderangeofDPIdevicesonthemarket,fromsingle-dosedevicesAerolizer(Novartis,Basel,Switzerland)andHandihaler(BoehringerIngelheim,Ingelheim,Germany)tomultiunitdose

38、devicesprovidedinablisterpackDiskhalerandDis-kus(GlaxoSmithKine,Middlesex,UK)orreservoirtypesystemTurbuhaler(Astrazeneca,London,UK)J28.Generally,inertcarriersareneededfordispersionofsmallparticlesofactiveingredients.Lactoseiscommonlyused.Aerosolsarecreatedbydirectingtheairthroughloosepowders.Thelung

39、depositionvaries12%-40%emitteddoseamongdifferentDPIs.Insufficientdeaggregationoftheactiveingredientfromcoarsecarrierparticlescontributestothelowactiveingredientdeposition.ActiveDPIsarebeinginvestigatedtoreducepatients*inspiratoryefforttodispersethefineparticles.Aspirair(Veclura,Wiltshire,UK)istrigge

40、redbyapatient'sinhalation.Thisinhalergeneratesanaerosolplumesignificantlyslowerthanthemostavailableinhalers.Therefore,theuseofAspirairreducestheamountofdrugthatisunintentionallydepositedinthemouthandthroat,andsubsequentlyswallowedratherthanreachingthelungs'291.Spiros(Durapharmaceuticals,SanD

41、iego,CA)usesabattery-drivenpropellertoaidthedispersionofpowders.InhancePulmonaryDeliverySystem(Nektar,SanCarlos,CA)usescompressedairtoaerosolizethepowderandthenconvertsitintoastandingcloudinaholdingchamber.Thismakesthegenerationofaerosolindependentofpatients1inspiratoryeffort.ThiswasthedeviceforPfiz

42、er*sinhaledinsulinproduct,Exubera,whichwasoutofmarketin2008.TheConixDPI(3MPharmaceuticals,Minnesota,USA)isdesignedwithapatentedreverse-flowcyclonetechnologythateffectivelyusesthepatient'sinhalationtoaerosolizethedrug.Asthepatientinhales,airisdrawnintothecyclonechamber,whereavortexisestablished.A

43、tthebottomofthechamber,theairflowreversesdirectionandtravelsupthroughthecircularoutlet.Theswirlingairflowdeaggregatesandaerosolizesfine,respirableparticlesfromlargerparticles(lactose)Itofferssingleandmultiple-doseapplications.TaperDPIbythesamecompanyusesauniquedesignthatstoresAPIonamicro-stmeturedca

44、rriertape.Itcombinespatient-friendlydesignandactiveaerosolizationinthismulti-doseDPI.TheMicroDoseelectronicDPI(MicroDoseThera-peutx,Inc.,Monmouth,NJ),consistsofahigh-frequencypiezotransducerandotherelectromechanicalelements.TheMicroDoseinhalerachievessuperiordosedeliveryefficiencythatispatientflowra

45、te,orientation,andcoordination-independent.MicroDosecandeliverbothsmallandlargemoleculesforlocalorsystemicdeliveryL"LInadditiontothegeneraladvantagesofdrypowdervaccination,auniquefeatureinrespectofimmunologyisthat,thealveolarantigen-presentingcells(APC)(especiallymacrophagesand/ordendriticcells

46、)arephagocyticandrespondtosmall-sizeparticulatesbyelicitingcell-mediatedandhumoralimmunity.Theseparticulatescouldbewholevaccinestrains,subunitproteinsorDNAsformulatedinparticulates.Drypowderaerosolvaccinationhasbeeninusetoimmunizehumansandanimals.Intheearly1960s,Russianinvestigatorsuseddryvaccinesof

47、attenuatedbacterialstrainstoimmunizeexperimentalanimalsagainstplague,tularemia,brucellosisandanthrax301.Largeparticleaerosolsofalive,temperature-sensitiverecombinantinfluenzavirusweregeneratedbyspinning-topaerosolgeneratortoimmunizethemice31.Thesedrypowderparticlesofinfluenzavirusprovided89%survival

48、afterchallenge.ThedrypowdervaccinesofaninfluenzasubunitvaccinepowderinducedsignificantlyhigherIgGtitresinmiceandremainedstableforatleast3yearsat20PulmonaryimmunizationofguineapigswithDiphtheriaCRM-197Antigenasnanoparticleaggregatedrypowderssignificantlyenhancedlocalandsystemicimmuneresponsesinthelun

49、gswithoutusingtraditionaladjuvants”.Theaerosoldeliveryofspray-driednanoparticlesofBacilleCalmette-GuOrin(BCG)effectivelyinducedimmunityagainstMycobacteriumtuberculosisinguineapigsM|.Drypowderaerosoldeliveryoftheantigensinpoly(lactic-co-glycolicacid)(PLGA)particlesagainsttuberculosiswasabletoreduceth

50、eextentofgranulomaandnecrosisgrowthinlungandspleenuponmycobac-tierialchallenge35.DrypowdermeaslesformulationwasinitiallysuggestedfordeliverybySpirosinhalers'祐.Theyaredurable,handheldandcouldbeeithersingleormultidoseinhalers.ThedeliveryefficacyofSpirostechnologywasdemonstratedbypulmonaryimagingwi

51、thradiolabelledalbuterolsulfate.Scintigraphyresultsshoweduniformdepositionofradiolabelleddrugthroughoutthetracheobronchialregionandsignificantanduniformdepositioninthealveolarregion371.Thestudiesperformedwithnebulizedmeaslesvaccineprovideevidencethattheaerosolvaccinetothelungsneednotbegreaterthanthe

52、currentlyacceptedminimumsubcutaneousdoseof1000TCIDqtissuecultureID)Theestimatedmeaslesvaccineconcentrationscouldvaryfrom3%to40%inlactosedependingonTCIDfromdifferentmanufactures.Thisformulationblendingisinthegoodrangeofmixturewithinertlactosefordispersion.AnoveldrypowderinhalertPuffHaler(AktivDry,Col

53、orado)wasadaptedforuseinevaluatingtheutilityofcottonratstostudythevaccinationsfollowinginhalationofthedrypowdermeaslesvaccines.Itwasfoundthattheviralreplicationwasconfinedtothelungs.Hieinhalationdeliveryresultedinanimmuneresponsecomparabletothatfollowinginjection138Athermostablediypowderformulationo

54、fliveattenuatedmeaslesvaccinewasdeveloped.Itcanremainaspowderthrougliouttheshippingandimmunizationprocess,eliminatingtheneedforreconstitution.Linetal39showedthatinarhesusmacaquemodel,asingledoseofvaccinationwitheitheroftwodry-powderinhalers,PuflHalerandSolovent(BDTechnologies,NorthCarolina),wassafea

55、ndprovideddurableprotectiveimmunityfrommeasleswithnoobservedadverseeffects.Recently,aclinicaltrialbySerumInstituteofIndialimitedtoassessthesafetyofameaslesdrypowdervaccineadministeredbytwo击fferentdevices：PufihalerandSoloventdevices,wasconductedinMarch20240'.Drypowdermeaslesvaccinationhasthegreat

56、potentialforsuccessfulmassvaccinalioncam->aign.Thisshedsthelightonthefuturedrypowdervaccinationmarket.2ConclusionsAerosolvaccinationisanoninvasive,nonlrauma-ticmethodofantigendeliverythatavoidstheriskoftransmittingdiseasesandotherblood-borneagentsthroughimproperinjectionpractices.Besidessmall-sca

57、lehumanvaccinationtrialsintheSovietUnion,themeaslesvaccineistheonlysuccessfuluseofthepulmonaryimmunizationonalargescale.OneDPIpul-monarymeaslesvaccineclinicaltrialwasinitializedinMarch2012.Sofarthereisnopulmonaryvaccineapprovedbyanyregulatoryagencyyet.However,fromthetechnologicalpointofview,theproof

58、ofconceptforpulmonaryimmunizationhasbeendemonstratedtoprotectagainstinfectiousdiseasesandbioterrorismattack,especiallyforairbornepathogens.Deliverydeviceselectionwouldchangethedepositionpatternandreducetheundesirablesideeffects.Appropriateselectionofdeliverydevicesfortherespiratorydeliveryofvaccines

59、wouldhavebroadbenefitsforthewelfareofmankind.References1WoodlandDL,RandallTD.Anatomicalfeaturesofanti-viralimmunityintherespiratorytractJ.SeminImmunol,2004,16(3)：163-170.2JBrandtzaegP.Humoralimmune-responsepatternsofhumanmucosae：inductionandrelationtobacterialrespirator),tractinfectionsJ.JInfectDis,1992,165(Suppl1)：SI67-S176.3BreimanRE,ButlerJC,MclnnesPM.Vaccinestopreventrespiratoryinf