Inhalable nanoparticulate powders for respiratory delivery - 图文

Nanomedicine:Nanotechnology,Biology,andMedicine

11(2015)1189–1199

ReviewArticle

nanomedjournal.com

Inhalablenanoparticulatepowdersforrespiratorydelivery

PriyaMuralidharana,MonicaMalapita,EvanMallorya,

DonHayesJr.b,c,HeidiM.Mansoura,d,e,f,?

bTheUniversityofArizona,CollegeofPharmacy,SkaggsPharmaceuticalSciencesCenter,Tucson,AZ,USA

TheOhioStateUniversityCollegeofMedicine,DepartmentsofPediatricsandInternalMedicine,LungandHeart-LungTransplantPrograms,Columbus,

OH,USA

cTheOhioStateUniversityCollegeofMedicine,TheDavisHeartandLungResearchInstitute,Columbus,OH,USA

dTheUniversityofArizona,TheBIO5ResearchInstitute,Tucson,AZ,USAeTheUniversityofArizona,InstituteoftheEnvironment,Tucson,AZ,USA

fTheUniversityofArizona,NationalCancerInstituteComprehensiveCancerCenter,Tucson,AZ,USA

Received8September2014;accepted15January2015

aAbstract

Nanoparticlesareextensivelystudiedfordrugdeliveryandareprovingtobeeffectiveindrugdeliveryandthediagnosticfield.Drugdeliverytolungshasitsadvantagesoverotherroutesofadministration.Inhalablepowdersconsistingofnanoparticlesaregainingmuchinterestinrespiratoryresearchandclinicaltherapy.Particleengineeringtechniqueisakeyfactortodevelopinhalableformulationsthatcansuccessfullydeliverdrugwithimprovedtherapeuticeffectandenhancedtargeting.Inhalablenanoparticlesinthesolid-statedrypowdersfortargetedpulmonarydeliveryofferuniqueadvantagesandareanexcitingnewareaofresearch.Nasaldeliveryofinhalablenanoparticulatepowdersisgainingresearchattentionrecently,particularlyinvaccineapplications,systemicdrugdeliveryinthetreatmentofpain,andnon-invasivebraintargeting.Fundamentalaspectsandrecentadvancementsalongwithfutureprospectsofinhalablepowdersconsistingofnanoparticlesinthesolid-stateforrespiratorydeliveryarepresented.

FromtheClinicalEditor:Theadvanceinnanotechnologyhasenabledthedesignofnewdrugdeliverysystemsthroughinhalation,whichhasmanyadvantagesovertraditionaldeliverysystems.Thiscomprehensivereviewdescribesanddiscussesthecurrentstatus,drugdesignandmodificationfortargeteddeliveryandchallengesoftheuseofnanoparticlesintherespiratorytract.?2015ElsevierInc.Allrightsreserved.

Keywords:Pulmonarynanomedicine;Solid-state;Drypowderinhaler;Particleengineeringdesign;Inhalationpowders;Lung/nasal

Systemicdeliveryofdrugsthroughinhalation(oralandnasal)isanattractivealternativefororalorparenteraldrugdelivery.Drugdeliverytolungsthroughinhalationhasadvantagessuchashighbioavailability,1rapidonsetofaction2duetoitslargesurfaceareaforabsorption,2,3self-administration,4improvedpatientcompliance,1non-invasivenature,2limiteddrugdegradation,andhighsolutepermeability.2Pulmonaryroutehasbeenusedforlocaldeliveryofdrugslikeantibiotic,protein,peptide,chemotherapeutics,interferon,3antitrypsin,3proteaseinhibitors,3deoxyribonucleases,3vaccinesandmanymore.Animportantconsiderationinpulmonary

Funding:TheauthorsacknowledgeTheCollegeofPharmacyGraduateFellowship(TheUniversityofArizona,Tucson,AZ,USA)awardedtoP.M.andfederalfundingtoH.M.M.fromtheNationalInstitutesofHealthNIAID(HHSN2272201000033I,HHSN27200002A65).

?Correspondingauthorat:TheUniversityofArizona,CollegeofPharmacy,SkaggsPharmaceuticalSciencesCenter,Tucson,AZ,USA.

E-mailaddress:mansour@pharmacy.arizona.edu(H.M.Mansour).http://dx.doi.org/10.1016/j.nano.2015.01.007

1549-9634/?2015ElsevierInc.Allrightsreserved.

deliveryisaerosolizationofthedrug.Deliveryofdrugtothelungshastogothroughphysicalobstructionandphysiologicalobstructionwhichincludesthemultiplebifurcationofrespiratorytractandtheinnateimmunologicalresponse.However,inhalationisnotnew,inhaledfumigationwasknowninthefirstcenturyandantisepticaerosoltherapywaspopularinmid-20thcentury.5Particlesdepositintherespiratorytrackbyvirtueoftheirsize,shapeandsurfaceproperties.1Therearethreemainmechanismsbywhichparticlesdepositinrespiratorytract:impaction,sedimentationand/ordiffusion.6Particlesdepositinthemidanddeeplungregionswhentheaerodynamicparticlesizeis≤5μm,1,6,7whichiswherenanoparticleshaveanicheinadvancedpulmonarydrugdelivery.Nanoparticlescanbeusedfortargeteddelivery,8sustaineddeliveryanddeeplungdeliveryofdrugsandtherapeutics.Arecentterm,“nanoperiodicproperty”,hasbeenintroducedbyKannanetal,whichrelatesnanoparticlebehaviortoitsinvivobehavior.9Particlesize,shape,surfacechemistry,flexibility/rigidity,architectureandelementalcompositionhavebeenidentifiedas“criticalnanoscale

Pleasecitethisarticleas:MuralidharanP,etal,Inhalablenanoparticulatepowdersforrespiratorydelivery.Nanomedicine:NBM2015;11:1189-1199,http://dx.doi.org/10.1016/j.nano.2015.01.007

1190P.Muralidharanetal/Nanomedicine:Nanotechnology,Biology,andMedicine11(2015)1189–1199

designparameters(CNDP)”whichcanbeusedtocontrolandengineerparticlestooptimizepharmacokinetics,6pharmacodynamicsandsite-specificdiseasetargeting.Nanotechnologyiscurrentlyrevolutionizingdrugdeliveryespeciallyininhalationdrugdelivery.Thisreviewdiscussestheuseofnanoparticlesasdrypowdersforrespiratorydeliveryofdrugs.

Inhalablepowdersforlungdelivery

Particledepositioninthelungdepends10,11predominantlyonitspropertiesincludingparticlesize,sizedistribution,10,11particlemorphology,1011surfacemorphology,10hygroscopicity,11electricalchargeanddensity.11Otherfactorsincludethediseasedstateandbreathingpattern.11Thegeometricdiameterofaparticleislessinfluentialthanaerodynamicdiameter.Hence,theUnitedStatesPharmacopeia(USP)Chapterb601N12definesmassmedianaerodynamicdiameter(MMAD).MMADmeansthat50%ofparticlesintheaerodynamicsizedistribution,basedonmass,lieaboveandbelowthatdiameter.5Largerparticlesdepositintheairwayduetoinertialimpaction13-16,14,17andsedimentationwhilesmallerparticlesdepositbydiffusionCiliatedcolumnarepitheliumintheupperairwaysecretesmucuswhichisathickgellayer.Theprimaryfunctionofthemucosallayeristoprotectthelungsbytrappingandremovingforeignparticlesbythemucociliaryescalatorwhichcausestrappedparticlestobecoughedupoutofthelungs.Particlesreachingthedeeplungalveolarregionmaybesusceptibletoclearancebyalveolarmacrophagesbyphagocytosisdependingonthesurfacechemistryoftheparticles.9Toevademucociliarytrappingandclearance,theinhaledparticleshouldeitherbeofsmallsizetobeinhaledpasttheupperlungregionorhavetheappropriatesurfacechemistrytoavoidadhesiontothemucosallayerand/ormucopentration.Useofhydrophilicandneutrallychargedpolymershelpsinescapingmucusadhesion.Lungphagocytosiscanbesignificantforparticlesofgeometricdiameter(dg)1μm≤dg≥2μm,dependentonthesurfacechemistry18oftheparticles,anddecreasesforparticlessmallerandlarger.DensesurfacechargeandlowmolecularweightPEGylatednanoparticlescanpenetratethemucus.19Infectedairwayshavecompromisedmucociliaryclearanceandarevulnerabletobacterialbiofilmformation,whichishighlyresistanttoantibioticsandrequiresadditionaldosethroughconventionalroutesofadministration.Inhalationofantibioticforpulmonaryinfectionhasbeenprovenclinicallytobemoreeffectivethanotherroutesofadministration.Nanoparticlesinthesizerangeof200nmareeffectiveinmucuspenetration.20Creatingnanoparticlestoexhibitbiphasicreleaseprofilewillgivehighinitialburstfollowedbysustainedreleaseofantibiotictomaintain20sufficientdrugconcentrationtoinhibitbiofilmgrowth.AdditionallyPEGylatedliposomalformulationshaveprovedtobeeffectiveinmucuspenetrationandescapingpulmonaryandimmuneclearance.21Nasaldeliveryofnanoparticles

Nasalrouteisachoiceforvaccinedeliveryduetoeaseofdeliverythroughnose,highvascularityinnose,largesurface

areaforabsorptionandlowenzymaticdegradation.22Inhalablepowderformulationsfornasaldeliveryenhancesystemicbioavailabilityandaresuperiortoliquidformulations.Advan-tagesofdrypowdersalsoincludeincreasedchemicalstability,norequirementforpreservatives,andfeasibilityofadministeringrelativelylargeamountsofdrug.23Improvednasaldeliveryofvaccinesthroughnanoparticlesmaybeeffectiveatpromotingimproveduptakeofparticlesbythenasal-associatedlymphoidtissue(NALT)system.24Nanoparticleslargerthan20nmwillcrossmucosalmembranesthroughthetransmucosalrouteusingendocytosis,24carrier-mediatedorreceptor-mediatedtransportprocesses.Thereisnosignificantdifferenceinimmuneresponsebetweennanoandmicroparticles.25Mucoadhesioniskeytonasaldeliveryofdrugs.Chenetalformulatedliposomesofbovineserumalbumincoated26withpolymertoincreasebioavailabilityandmucoadhesion.Theliposomesweremadeofsoyphosphatidylcholine(SPC)andphospholipiddimyristoylphosphatidylglycerol(DMPG)coatedwithalginate,chitosanortrimethylchitosan(TMC).Polymercoatingresultedinincreasedsizeofliposome.However,mucoadhesionpropertyofchitosanandTMCparticlesincreasedcomparedtoalginatecoatedanduncoatedparticles.26Dehghanetalformulatedapolymericnanospherenasalvaccineforinfluenzawhichentersthebodythroughtheinhalationroute.27Inthestudy,theyprepareddrynanoparticlepowdersofinfluenzavaccineswithtwootherimmunoadjuvantsusingchitosanasthecarrier.Theformulationdemonstratedthatthevaccinestructureandcharacteristicsofchitosandidnotchangeaftertheformulation.Theparticleshadasizeof581.1±32.6nmwithmucoadhesivepropertiesofchitosanthatmakesitsuitablefornasaldeliveryofvaccine.27Drypowderchitosannanospheresmaybeanappropriatedeliverysystemfornasalimmunizationofinfluenza,duetothenanosizerange,theabilityforchitosantoadheretomucosalmembranes,andsuitablereleaseprofile.27AnotherstudyonnasalvaccinedeliverywasconductedbyWangetalwheretheyformulatedanthraxvaccinefordrypowdernasaldelivery.28Vaccinationatthesiteofentrycanbemoreeffectivethanthesystemicroute,simplybecausethepathogenscanbeencounteredandneutralizedatentrybeforeitgetsintothesystemiccirculation.28Thenasalrouteispreferredforitsmucouslayer,hencenasalproductsshouldbemucoadhesive.Inhalablenasalpowdersaregainingpopularityasnewvaccinedeliverybyvirtueoftheirstabilitycomparedtoliquidformulationsthatrequirerefrigerationorpreservatives.27,28AreportbyWangetalinvestigatedanasalformulationcomposedofrecombinantprotectiveantigen,compound48/80mastcellactivatorasamucosaladjuvant,andtrehalose.28Theparticlesizewas~25μmandthevaccinemaintaineditsstructuralintegritythroughoutprocessing.28Invivostudyoftheformulation,inrabbitsshowedthevaccinescompetencetoneutralizeanthraxlethaltoxin.28Theyalsofoundthatthedrypowdervaccinewaseffectiveevenafter2.5yearsofstorageatroomtemperaturewhichwillalleviatethecoldchainshippingproblemforvaccine.28Anin-situgelformingdrypowderformulationwasdevelopedbyVelasquezetalusingnoroviruslikeparticleswithmucoadhesivepolymerGelSite?.22Invivostudyoftheformulationshowedthatthevaccineinducedhigherantigenresponsethanliquidpreparation.22P.Muralidharanetal/Nanomedicine:Nanotechnology,Biology,andMedicine11(2015)1189–11991191

DrypowderinhalersandnanoparticulatepowdersforinhalationTheoverallanatomyandphysiologyofthepulmonarysystemarecomplicatedandthedynamicpulmonaryclearancemechanismspresentchallengesfordrugdeliverythroughthisroute.Despitethesepotentialchallenges,therearefourclinicallysuccessfulpulmonaryinhalationpharmaceuticaldosageformsbasedondeviceclasses;namely,nebulizers(nebs),pressurizedmetereddoseinhalers(pMDIs),drypowderinhalers(DPIs),andsoft-mistinhalers(SMIs).NebulizersproduceliquidaerosolsbyanexternalpowersupplyanddonotcontainanypropellantunlikepMDIs.Nebulizersrequireanexternalpowersourceandowingtoitssizeisrestrictedtoclinicalsettings29andin-houseusefornichepatientpopulations(i.e.youngchildrenandtheelderly),whilepMDIoffersportabilityandpatientconvenience.However,propellanteffectsontheenvironment,solubilityandcompatibilitychallengesofdrugwithpropellant29andphysicohemicalstabilitychallengesarecommon.DPIscancontainrespirablepowdereddrugorrespirablepowdereddrugblendedwithanon-respirablecarrier.TherearemanyuniqueadvantagesofDPIs.30-33Powdereddrugoffersanadvantageespeciallyfordeliveryofpoorlywater-solubledrug,andproteinandpeptidedrugswhichcannotwithstandthesheargeneratedduringinhalation.34However,thechoiceofnon-respirablecarrieriscriticalforDPIformulation.Lactoseisthecarrierofchoiceowingtoitshistoricalprecedence,largesupply,andFDAapprovalforDPIuse.However,patientlactoseintolerance,patientlactoseallergies,andreducingsugarchemicalpropertyleadingtochemicaldegradationissuesbytheMaillardreactionwithcertainpulmonarydrugsarelimitationsofthelactosecarrier.Hence,othernon-respirablecarriershavebeenstudied(someofwhichareapprovedoutsidetheUnitedStates)includingnon-reducingsugars(e.g.mannitol35andtrehalose),glucose,sodiumchloride,erythritol,sorbitol,raffinose,xylitol,dextrose,maltitolandmaltoseaspotentialcarriersthatcanbeusedforDPI.36Afrezza?,whichisinhalablerecombinantinsulincontainsTechno-sphere?particlesformedwithexcipientcarrierfumaryldiketopi-perazine(FDKP)powderwhichselfassemblesthroughhydrogenbondinginmildlyacidicenvironmenttoformmicrospheres.

DPIsoffermanyadvantagesincludingencapsulatingability,21longtermstability,21nohand-lunginhalationcoordination,34,37noliquidpropellant,37modifiedpharmacokinetics,38anextendedreleaseprofile,38improvedtolerability,38reducedtoxicity,38easytouse,39andnoninvasiveness.39Basedonthemechanismsofparticledispersionandaerosolization,theDPIdevicesarefurthercategorizedaspassiveoractivedevices.ApassiveDPIdevicedependsonthepatient'sinspiratoryflowtosupplytheenergyrequiredforpowderdispersion.Variationinpatient'sinspiratoryflowcanvarythequantityofdrugdeliveredwhichmightleadtooverdosingorunderdosing.Incontrast,anactiveDPIdevicedoesnotdependonapatient'sinspiratoryflow.TheDPIdevicethatwasusedinExubera?wasthefirstactivedeviceusedinanFDA-approvedpharmaceuticalinhalationproduct.However,theproductdidn'tlastlonginthemarketduetootherreasons.DependingonthedrugdispensingmethodDPIdevicesareclassifiedintothreetypesnamelyunitdose,multidose(i.e.powderreservoir),andmulti-unitdoseDPIdevices.AunitdoseDPIdevicerequiresthepatienttoinsertaninhalationgradecapsule(i.e.gelatinorhydroxypropylmethylcellulose)containingthepreweigheddrugpowderpriortoeachactuation.Uponactuation,thecapsulebreaksapartorispin-holedbythedeviceandreleasesthepowderforaerosolization.Multidosereservoirdevicecontainsapowderbedofdrugordrug/lactosemonohydrateblendwhichissampledbythedevicemeteringsystemwitheachactuationbypatient.Amulti-unitdoseDPIdeviceispre-loadedwithmultipleunitdoseprefilledcapsulescontainingpowder.

DPIisarapidlygrowingsectorofthepulmonaryinhalationpharmaceuticalmarketwhichisevidentbytheincreasingnumberofsuccessfulproductsinthemarket.RecentFDAapprovalofAfrezza?,theinhaledinsulinwillinvitemoreresearchandgrowthintoinhalationtherapy.40DPIscanhavetwopotentialproblemsconcerningrelativelylowfineparticlefraction(FPF)andemitteddose(ED)whichcanbeattributedtoinsufficientparticledispersionbythepatientorDPIdevice,aerosoldispersioninefficiency,orthepowderformulationitself.FPFisthefractionofinhaledparticlesthataresmallerthanacertainaerodynamicdiameter,andEDistheproportionofinitialdosethatisdeliveredoutofthedevice,asdescribedinUSPChapterb601N.12Theemergingtechnologiesinovercomingtheseproblemswillbediscussedindetailinthisarticle.

Theimprovedformulationshavemadeitpossibletodeliversmall(micro/nanosize)particlestothelungs,yetduetolowinertiatheseparticlescanbeexhaledfromlungandfailtodepositinthelungs.Hence,toenablebetterdeliverytheyareusuallyformulatedwithalargenon-respirablecarrierwhichaddsbulktothepowderandhelpsinefficientmeteringofthedose.Onactuation,thedrugparticlesalongwiththecarriergetsdispersedintopatientsmouthbutonlytherespirabledrugparticleswillreachtherespiratorytract.Thelargenon-respirablecarrierparticleseparatesfromthedrugparticlebyshearormechanicalforcesanditgetsdepositedontheoropharynxandisswallowedintothegastrointestinal(GI)tract.Theseparationoftheseparticlesdependsontheinterparticularforces.

TheinterparticulateinterfacialinteractionsthatimpactDPIaerosoldispersionarevanderWaalsforces,electrostaticforces,andcapillaryforces.41Theseforcesareimportantforaerosoliza-tionofpowderfromthedeviceduringdeliveryandseparationofdrugfromthecarrierparticles.Interparticularforcesvarywithmaterialsusedandthewayitisprocessed.41Interparticulateforcescanbealteredbytheparticlesize,particlesizedistribution,surfacemorphology(i.e.surfaceroughness),particleshape,9,41elastic/plasticdeformity,drug/carrierratioanddrug/fineratio.Xuetalreviewedparticleinteractionsindrypowderinhalerindetail,thearticleisrecommendedforfurtherreading.41Thedifferencesbetweenmicroparticlesandnanoparticlesextendbeyondjustthesize.Nanoparticlescanhavehigherdrugloadingcapacity,5uselesspolymers,5canbettercrosspermeability38barriers,5increasedcellularuptake,38longerlungretentionandinairwaynanoparticleshavebetterchancesofmucuspenetration.Nanoparticlesingeneralhavelargersurfaceareatovolumeratios.Thisimprovesdissolutionpropertieswhereindecreasedparticlesize37increasessolubilityandintracel-lulardrugdeliverypotential.Owingtosmallersize,nanopar-ticlespresentmoremoleculesonthesurfaceoftheparticlethusincreasing37thetotalmassthatmaytransfertothesurroundingmedium.Thispropertycanbeusedtoachieveincreaseddrugconcentrationandbioavailability.Studieshavedemonstrated

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Table1

Examplesofdrugsmadeintonanoformulationsasdrypowderinhalers(DPIs).Drug/agentClass

Condition

Routeof

administrationVancomycinAntibioticInfectionDPI67ClarithromycinAntibioticInfection

DPI67SalmoncalcitoninHormone

HypocalcemiaDPI85TacrolimusandImmunosuppressant

AllograftrejectionDPI7,10cyclosporineApreventionin

lungtransplantation

BudesonideGlucocorticoidAsthmaandCOPDDPI74?Tranilast

AntiallergicagentBronchialasthmaDPI73DiatrizoicacidRadiocontrastagentImagingofairwayDPI86?CiprofloxacinAntibioticCysticfibrosisDPI62CyclosporineA

ImmunosuppressantLungtransplant

DPI7,87?rejectionprevention

PaclitaxelMicrotubuleinhibitorLungcancerDPI68TobramycinAntibioticInfectionDPI66AzithromycinAntibioticInfectionDPI66RifampicinAntibioticTuberculosisDPI88OfloxacinAntimicrobialInfectionDPI89MoxifloxacinAntibacterialInfectionDPI89DoxorubicinAnticanceragentLungcancerDPI90InfluenzavirusAntigenInfluenzaNasal27AnthraxrPAAntigenAnthraxNasal28#FluticasoneAnti-inflammatory/Asthmaand

DPI91propionate/β2-agonist

COPDalbuterolsulfate

Salbutamolsulfateβ2-agonist

Asthma

DPI92Abbreviation:COPD–chronicobstructivepulmonarydisease;rPA–recombinantprotective?antigen.

Invivostudyconductedinaratmodel#Invivostudyconductedinarabbitmodel

thatparticles37withdecreasedsizearebetterinternalizedbycells.Nanoparticlescanactasdrugcarriersbydissolving,entrapping,encapsulating,adsorbing,orattachingtothedrug.2Nanoparticlesareusedinbothdrypowderinhalerandnasaldeliveryoftherapeutics.Table1listssomeofthedrugswhichhavebeensuccessfullymadeintoinhalablenanopowdersfortargetedrespiratorydelivery.However,furtherdetailsontheirsuccessfuluseinrodentsorhumanstandstobeexplored.Inparticular,nanoparticlescanbeeffectiveascancertreatmentduetotheirselectiveabilitytoaccumulateinsidetumorsthroughtheenhancedpermeabilityandretention(EPR)effect.38,42AnotherimportantadvantageforusingnanoparticlesinDPIsisthatitisaviableoption42todelivermacromoleculeslikeprotein,peptide,insulin.Somenanocarriersthathavebeenexploredaspotentialdrugdeliverysystemincludebutarenotlimitedtoliposomes,39,43solidlipidnanoparticles,4339,43lipidorpolymericmicelles,39poly-mericnanoparticlesanddendrimers.39Commonlyusedpolymersasnanocarriersaregelatin,chitosan,alginateandsyntheticpolymerslikepoloxamer,poly(lactic-co-glycolic)39acid(PLGA)andpoly(ethyleneglycol)(PEG).Modificationofinhalablenanoparticles

ThemostcommonchallengesinusingnanoparticlesforDPIdeliveryarei)maintainingtheparticleindrystateuntildelivery,ii)

topreventaggregationoftheparticlesintheinhaler,iii)efficient

redispersionofdruginthelungfluid,iii)preservationoftheparticleandthebiologicalactivityofthedrugthroughoutprocessingstages.Particleengineeringisaconvenienttooltoachieveparticlesofdesiredcharacteristicswithlesserexpense.44Varioustechniques44canbeadoptedtomakeparticleswithnarrowsizedistribution,improveddispersibility,44sustainedrelease44withinhalableproperties.Somepopularparticleengineeringtechniquesarei)surfacemodificationtoimprovenanoparticlecharacteristicsasadeliveryvehicleandtoprotectitfromdeterioration,ii)makinglargehollowparticlefordeeplungdeposition,iii)encapsulatingnanoparticleswithinmicroparticlestopreventparticleaggregates,iv)makingeffervescentparticlestoimprovedispersion.Table2listssometechniquesthatcanbeusedtofabricateparticlesforinhalation.

Surfacemodification

Surfacecoatingofnanoparticleswithneutrallychargedmoleculessuchaspoly(ethyleneglycol)(PEG)hasdemonstrat-edmanyadvantageswhichincludesimprovedtransportofparticlesacrossmucuslayer.4Thiswouldenhancethechancesoftheparticlesurvivalthatcouldreachdeeplungsites.ItisalsoshowedbyseveralstudiesthatPEGylationofnanoparticlesevadesphagocytosisbyalveolarmacrophageandimprovedbioavailabilityofthedrug.45-50ThesterichindranceandthenegativezetapotentialcreatedbyPEGmoleculehelpitescapefrombloodprotein.46Oncetheparticlesaremodifiedtoreachthelung,translocationacrossair-bloodbarrieristhenextobstacle.1Smallermoleculesthatmakeittothelungsareclearedquicklywhilelargerparticleslikeproteinaredegradedbyproteaseenzymes.Hence,itisnecessarytoencapsulatethedrugmoleculeintonanoparticletoavoidpulmonary1clearanceordegradationandensuresustainedrelease.Mostpopularencapsulationisdoneinpolymerorliposome.Interestingly,surfacemodificationalsohasaneffectintranslocationofnanoparticles.Neutralandnegativelychargedparticlesweremorerapidlytranslocatedthancationicparticles.1,4Hollownanoparticlesandnanoaggregates

Formulatingnanoparticlesintolargeholloworporousparticlesincreasesthegeometricdiameteranddecreasesaerodynamicdiameterofparticles,therebymakingtheparticlemoresuitabletodepositinthelung.18Geometricdiameterofaparticlecontributeslesstoparticledepositionwhileaerodynamicdiameterdeterminesthedeeplungdepositionofnanoparticles.Largeparticlescanbeimprovedtobehavelikesmallparticles.AstudyconductedbyEdwardetaldemonstratedthatporousparticleswithdrughaveahigheraerosolizationefficiency,sustainedreleaseandincreasedbioavailability.51Nanoparticleaggregatesaredrugcontainingnanoparticlesaccumulatedtogether,whichmaydissociateintoindividualnanoparticleandreleasethedruginthelungsorrespiratorytract.Largehollownanoparticulateaggregateswhichpossessgeometricdiameter~10μmexhibitasmallaerodynamic