NASAL DRUG DELIVERY SYSTEM

This Slide is prepared by SIDHARTHA JYOTI BORA

1. NASAL DRUG DELIVERY SYSTEM
SIDHARTHA JYOTI BORA
M.PHARM 2
ND
SEMESTER
Roll no-180520011011
ReGnn0-201805218

2. CONTENTS
INTRODUCTION
ADVANTAGES
LIMITATIONS
BARRIERS TO NASAL ABSORPTION
FACTORS INFLUENCING NASAL DRUG ABSORPTION
STRATEGIES TO IMPROVE NASAL ABSORPTION
NASAL DRUG DELIVERY SYSTEM DOSAGE FORMS
APPLICATIONS
CONCLUSION
REFERENCES

3. INTRODUCTION
Nasalmucosahasbeenconsideredasapotentialadministrationroutetoachieve
fasterandhigherlevelofdrugabsorptionbecauseitispermeabletomore
compoundsthanthegastrointestinaltractduetolackofpancreaticandgastric
enzymaticactivity,neutralpHofthenasalmucusandlessdilutionby
gastrointestinalcontents.
Inrecentyearsmanydrugshavebeenshowntoachievebettersystemic
bioavailabilitythroughnasalroutethanbyoraladministration.
Formanyyearsdrugshavebeenadministerednasallyforbothtopicaland
systemicaction.Topicaladministrationincludesthetreatmentofcongestion,
rhinitis,sinusitisandrelatedallergicorchronicconditions,andhasresultedina
varietyofdifferentmedicationsincludingcorticoids,antihistamines,anti-
cholinergicandvasoconstrictors.
Onlyafewnasaldeliverysystemsusedinexperimentalstudiesarecurrentlyon
themarkettodelivertherapeuticsintothenasalcavities,i.e.nasaldropsas
multipleorsingle-doseformulation,aqueousnasalsprays,anasalgelpump,
pressurizedMDIsanddrypowderinhalers.

4. ADVANTAGES
Drugdegradationthatisobservedinthegastrointestinaltractis
absent.
Hepaticfirstpassmetabolismisavoided.
Rapiddrugabsorptionandquickonsetofactioncanbe
achieved.
Thebioavailabilityoflargerdrugmoleculescanbeimprovedby
meansofabsorptionenhancerorotherapproach.
Thenasalbioavailabilityforsmallerdrugmoleculesisgood.
Drugsthatareorallynotabsorbedcanbedeliveredtothe
systemiccirculationbynasaldrugdelivery.
Studiessofarcarriedoutindicatethatthenasalrouteisan
alternatetoparenteralroute,especially,forproteinandpeptide
drugs.

5. LIMITATIONS
Thehistologicaltoxicityofabsorptionenhancersusedin
nasaldrugdeliverysystemisnotyetclearlyestablished.
Relativelyinconvenienttopatientswhencomparedtooral
deliverysystemssincethereisapossibilityofnasalirritation.
Nasalcavityprovidessmallerabsorptionsurfaceareawhen
comparedtoGIT.
Thereisariskoflocalsideeffectsandirreversibledamageof
theciliaonthenasalmucosa,bothfromthesubstanceand
fromconstituentsaddedtothedosageform.

6. MECHANISM OF NASAL ABSORPTION
Manyabsorptionmechanismswereestablishedearlierbutonlytwo
mechanismshavebeenpredominantlyused,suchas:
1.Firstmechanism-Itinvolvesanaqueousrouteoftransport,which
isalsoknownastheparacellularroutebutslowandpassive.
Thereisaninverselog-logcorrelationbetweenintranasal
absorptionandthemolecularweightofwater-soluble
compounds.Themolecularweightgreaterthan1000Daltons
havingdrugsshowspoorbioavailability.
2.Secondmechanism-Itinvolvestransportthroughalipoidalroute
anditisalsoknownasthetranscellularprocess.Itisresponsible
forthetransportoflipophilicdrugsthatshowaratedependency
ontheirlipophilicity.Drugalsocrosscellmembranesbyan
activetransportrouteviacarrier-mediatedmeansortransport
throughtheopeningoftightjunctions

7. BARRIERS TO NASAL ABSORPTION
Followingfactorsarethebarrierstotheabsorptionofdrugsthroughnasal
cavity:
Lowbioavailability:
Lipophilicdrugsaregenerallywellabsorbedfromthenasalcavity
comparedtopolardrugs.Themostimportantfactorlimitingthenasal
absorptionofpolardrugsandespeciallylargemolecularweightpolar
drugssuchaspeptidesandproteinsisthelowmembranepermeability.
Drugscancrosstheepithelialcellmembraneeitherbythetranscellular
routeexploitingsimpleconcentrationgradients,byreceptormediatedor
vesiculartransportmechanisms,orbytheparacellularroutethroughthe
tightjunctionsbetweenthecells.Polardrugswithmolecularweights
below1000Dawillgenerallypassthemembraneusingthelatterroute.
Largerpeptidesandproteinshavebeenshowntobeabletopassthenasal
membraneusinganendocytotictransportprocessbutonlyinlowamounts
.

8. Lowmembranetransport:
Anotherimportancefactorislowmembranetransportisthegeneralrapid
clearanceoftheadministeredformulationfromthenasalcavityduetothe
mucociliaryclearancemechanism.Thisisespeciallythecasefordrugsthatare
noteasilyabsorbedacrossthenasalmembrane.Ithasfurtherbeensuggestedthat
thedepositionofaformulationintheanteriorpartofthenasalcavitycandecrease
clearanceandpromoteabsorption.Mostnasalspraysofvariousmakeshavebeen
showntodelivertheformulationtoalimitedareaintheanteriorpartofthenasal
cavityasopposedtonasaldropswhichwillbedeliveredtoalargerareafurther
backinthenasalcavity.Theclearancemayalsobereducedbydepositingthe
formulationintheanterior,lessciliatedpartofthenasalcavitythusleadingto
improvedabsorption.
Enzymatic Degradation:
Anothercontributingfactortothelowtransportofespeciallypeptidesandproteins
acrossthenasalmembraneisthepossibilityofanenzymaticdegradationofthe
moleculeeitherwithinthelumenofthenasalcavityorduringpassageacrossthe
epithelialbarrier..Theuseofenzymeinhibitorsand/orsaturationofenzymesmay
beapproachestoovercomethisbarrier

9. FACTORS INFLUENCING NASAL DRUG
ABSORPTION
The factors influencing nasal drug absorption are described as follows.
Physiochemical properties of drug.
1.Molecular size.
2.Lipophilic-hydrophilic balance.
3.Enzymatic degradation in nasal cavity.
Nasal Effect
1.Membrane permeability.
2.Environmental pH
3.Mucociliaryclearance
4.Cold, rhinitis.
Delivery Effect
1.Formulation (Concentration, pH, osmolarity)
2.Delivery effects
3.Drugs distribution and deposition.
4.Viscosity

10. Physiochemicalpropertiesofdrug
Molecular size
Themolecularsizeofthedruginfluenceabsorptionofthe
drugthroughthenasalroute.Thelipophilicdrugshavedirect
relationshipbetweentheMWanddrugpermeationwhereas
water-solublecompoundsdepictaninverserelationship.The
rateofpermeationishighlysensitivetomolecularsizefor
compoundswithMW≥300Daltons.
Lipophilic-hydrophilic balance
Thehydrophilicandlipophilicnatureofthedrugalsoaffects
theprocessofabsorption.Byincreasinglipophilicity,the
permeationofthecompoundnormallyincreasesthrough
nasalmucosa.Althoughthenasalmucosawasfoundtohave
somehydrophiliccharacter,itappearsthatthesemucosaeare
primarilylipophilicinnatureandthelipiddomainplaysan
importantroleinthebarrierfunctionofthesemembranes.

11. Enzymatic degradation in nasal cavity
Incaseofpeptidesandproteinsarehavinglowbioavailability
acrossthenasalcavity,sothesedrugsmayhavepossibilityto
undergoenzymaticdegradationofthedrugmoleculeinthelumen
ofthenasalcavityorduringpassagethroughtheepithelialbarrier.
Thesebothsitesarehavingexo-peptidasesandendopeptidases,
exo-peptidasesaremono-aminopeptidasesanddi-aminopeptidases.
ThesearehavingcapabilitytocleavepeptidesattheirNandC
terminiandendopeptidasessuchasserineandcysteine,whichcan
attackinternalpeptidebonds.

12. Nasal effect factors
Membranepermeability
Nasalmembranepermeabilityisthemostimportantfactor,whichaffectthe
absorptionofthedrugthroughthenasalroute.Thewatersolubledrugsand
particularlylargemolecularweightdrugslikepeptidesandproteinsarehavingthe
lowmembranepermeability.Sothecompoundslikepeptidesandproteinsare
mainlyabsorbedthroughtheendocytotictransportprocessinlowamounts.
Water-solublehighmolecularweightdrugscrossthenasalmucosamainlyby
passivediffusionthroughtheaqueouspores(i.e.tightjunctions).
EnvironmentalpH
TheenvironmentalpHplaysanimportantroleintheefficiencyofnasaldrug
absorption.Smallwater-solublecompoundssuchshowthattheirnasalabsorption
inratoccurredtothegreatestextentatthosepHvalueswherethesecompounds
areinthenonionisedform.However,atpHvalueswherethesecompoundsare
partiallyionized,substantialabsorptionwasfound.Thismeansthatthe
nonionisedlipophilicformcrossesthenasalepithelialbarrierviatranscellular
route,whereasthemorelipophilicionizedformpassesthroughtheaqueous
paracellularroute

13. Mucociliaryclearance
Mucociliaryclearanceisaoneofthefunctionsoftheupperrespiratorytractisto
preventnoxioussubstances(allergens,bacteria,viruses,toxinsetc.)fromreaching
thelungs.Whensuchmaterialsadhereto,ordissolvein,themucusliningofthe
nasalcavity,theyaretransportedtowardsthenasopharynxforeventualdischarge
intothegastrointestinaltract.Clearanceofthismucusandtheadsorbed/dissolved
substancesintotheGITiscalledtheMCC.Thisclearancemechanisminfluence
theabsorptionprocessduetothedissolveddrugsinthenasalcavityaredischarge
bytheboththemucusandthecilia,whichisthemotoroftheMCCandthemucus
transportrateis6mm/min.ItisofutmostimportancethattheMCCisnot
impairedinordertopreventlowerrespiratorytractinfections.
Cold, rhinitis
Rhinitisisamostfrequentlyassociatedcommondisease,itinfluencethe
bioavailabilityofthedrug.Itismainlyclassifiedintoallergicrhinitisand
common,thesymptomsarehypersecretion,itchingandsneezingmainlycaused
bytheviruses,bacteriaorirritants.Allergicrhinitisistheallergicairwaydisease,
whichaffects10%ofpopulation.Itiscausedbychronicoracuteinflammationof
themucousmembraneofthenose.Theseconditionsaffecttheabsorptionofdrug
throughthemucusmembraneduetheinflammation.

14. Delivery effect factors
Factorsthataffectthedeliveryofdrugacrossnasalmucosasuchassurfactants,
dose,pH,osmolarity,viscosity,particlesizeandnasalclearance,drugstructure
canbeusedtoadvantagetoimproveabsorption.
Formulation (Concentration, pH, Osmolarity)
ThepHoftheformulationandnasalsurface,canaffectadrug’spermeation.To
avoidnasalirritation,thepHofthenasalformulationshouldbeadjustedto4.5–
6.5becauselysozymeisfoundinnasalsecretions,whichisresponsiblefor
destroyingcertainbacteriaatacidicpH.Underalkalineconditions,lysozymeis
inactivatedandthetissueissusceptibletomicrobialinfection.Inadditionto
avoidingirritation,itresultsinobtainingefficientdrugpermeationandprevents
thegrowthofbacteria.Concentrationgradientplaysveryimportantroleinthe
absorption/permeationprocessofdrugthroughthenasalmembraneduetonasal
mucosaldamage.ExamplesforthisarenasalabsorptionofL-Tyrosinewasshown
toincreasewithdrugconcentrationinnasalperfusionexperiments.Anotheris
absorptionofsalicylicacidwasfoundtodeclinewithconcentration.Thisdecline
islikelyduetonasalmucosadamagebythepermanentTheosmolarityofthe
dosageformaffectsthenasalabsorptionofthedrug;itwasstudiedintheratsby
usingmodeldrug.Thesodiumchlorideconcentrationoftheformulationaffects
thenasalabsorption.

15. Drugs distribution and deposition
Thedrugdistributioninthenasalcavityisoneoftheimportant
factors,whichaffecttheefficiencyofnasalabsorption.Themode
ofdrugadministrationcouldeffectthedistributionofdruginnasal
cavity,whichinturnwilldeterminetheabsorptionefficiencyofa
drug.Theabsorptionandbioavailabilityofthenasaldosageforms
mainlydependsonthesiteofdisposition.Theanteriorportionof
thenoseprovidesaprolongednasalresidentialtimefordisposition
offormulation,itenhancestheabsorptionofthedrug.Andthe
posteriorchamberofnasalcavitywilluseforthedepositionof
dosageform;itiseliminatedbythemucociliaryclearanceprocess
andhenceshowslowbioavailability.Thesiteofdispositionand
distributionofthedosageformsaremainlydependsondelivery
device,modeofadministration,physicochemicalpropertiesof
drugmolecule.

16. Viscosity
Ahigherviscosityoftheformulationincreasescontacttime
betweenthedrugandthenasalmucosatherebyincreasingthetime
forpermeation.Atthesametime,highlyviscousformulations
interferewiththenormalfunctionslikeciliarybeatingor
mucociliaryclearanceandthusalterthepermeabilityofdrugs.

17. STRATEGIES TO IMPROVE NASAL ABSORPTION
Variousstrategiesusedtoimprovethebioavailabilityofthedruginthenasal
mucosawhichincludes
1.Toimprovethenasalresidencetime
2.Toenhancenasalabsorption
3.Tomodifydrugstructuretochangephysicochemicalproperties.
Several methods have been used to facilitate the nasal absorption of drugs
includes
Nasalenzymeinhibitors:Nasalmetabolismofdrugscanbeeliminatedbyusing
theenzymeinhibitors.Mainlyfortheformulationofproteinsandpeptide
moleculedevelopmentenzymeinhibitorslikepeptidasesandproteasesareused.
Theabsorptionenhancerslikesaltsandfusidicacidderivativesalsoshows
enzymeinhibitionactivitytoincreasetheabsorptionandbioavailabilityofthe
drug.Theotherenzymeinhibitorscommonlyusedfortheenzymaticactivityare
tripsin,aprotinin,borovaline,amastatin,bestatinandboroleucininhibitors.

18. Permeation enhancers
Thepermeationenhancersaremainlyusedfortheenhancementof
absorptionoftheactivemedicament.Generally,theabsorption
enhancersactviaoneofthefollowingmechanisms:
1.Inhibitenzymeactivity;
2.Reducemucusviscosityorelasticity;
3.Decreasemucociliaryclearance;
4.Opentightjunctions;and
5.Solubilizeorstabilizethedrug

19. Prodrugapproach
Prodrugapproachismainlymeantforoptimizingfavorable
physicochemicalpropertiessuchassolubility,taste,odor,
stability,etc.Prodrugisusuallyreferredaspromoiety,itisto
covertheundesiredfunctionalgroupswithanotherfunctional
groups.Thisprodrugapproachismainlyforimprovingthe
nasalbioavailabilityespeciallyfortheproteinsandpeptidesto
enhancethemembranepermeabilityalongwithincreased
enzymaticstability.Theprodrugundergoesenzymatic
transformationtoreleasetheactivemedicament,whenit
crossestheenzymaticandmembranebarrier.Theabsorptionof
peptideslikeangiotensinII,bradykinin,caulein,carnosine,
enkephalin,vasopressinandcalcitoninareimprovedby
preparedintoenaminederivatives,theseagentsshowed
absorptionenhancementwithprodrugapproach.

20. Structural modification
Modificationofdrugstructurewithoutalteringpharmacological
activityisoneofthelucrativewaystoimprovethenasal
absorption.Thechemicalmodificationofdrugmoleculehasbeen
commonlyusedtomodifythephysicochemicalpropertiesofa
drugsuchasmolecularsize,molecularweight,Pkaandsolubility
arefavorabletoimprovethenasalabsorptionofdrug.Example,
chemicalmodificationofsalmoncalcitonintoecatonin(C-Nbond
replacestheS-Sbond)showedbetterbioavailabilitythansalmon
calcitonin.

21. NASAL DRUG DELIVERY SYSTEM DOSAGE
FORMS
Theselectionofdosageformdependsuponthedrugbeingused,
proposedindication,patientpopulationandlastbutnotleast,
marketingpreferences.Fourbasicformulationsmustbeconsidered,
i.e.solution,suspension,emulsionanddrypowdersystems.
LIQUID NASAL FORMULATIONS
Liquidpreparationsarethemostwidelyuseddosageformsfornasal
administrationofdrugs.Theyaremainlybasedonaqueousstate
formulations.Theseveraltypesdosageformsavailableinliquid
formaredescribedbelow.

22. 1. Instillation and rhinylecatheter
Cathetersareusedtodeliverthedropstoaspecifiedregionofnasal
cavityeasily.Placetheformulationinthetubeandkepttubeone
endwaspositionedinthenose,andthesolutionwasdeliveredinto
thenasalcavitybyblowingthroughtheotherendbymouth.Dosing
ofcathetersisdeterminedbythefillingpriortoadministrationand
accuracyofthesystemandthisismainlyusedforexperimental
studiesonly.
2. Compressed air nebulizers
Nebulizerisadeviceusedtoadministermedicationintheformofa
mistinhaledintothelungs.Thecompressedairisfilledintothe
device,soitiscalledcompressedairnebulizers.Thecommon
technicalprincipalforallnebulizers,istoeitheruseoxygen,
compressedairorultrasonicpower,asmeanstobreakupmedical
solutions/suspensionsintosmallaerosoldroplets,fordirect
inhalationfromthemouthpieceofthedevice

23. 3. Squeezed bottle
Squeezednasalbottlesaremainlyusedasdeliverydevicefor
decongestants.Theyincludeasmoothplasticbottlewithasimplejet
outlet.Whilepressingtheplasticbottletheairinsidethecontaineris
pressedoutofthesmallnozzle,therebyatomizingacertainvolume.By
releasingthepressureagainairisdrawninsidethebottle.Thisprocedure
oftenresultsincontaminationoftheliquidbymicroorganismsandnasal
secretionsuckedinside.
4.Metered-dosepumpsprays
Mostofthepharmaceuticalnasalpreparationsonthemarketcontaining
solutions,emulsionsorsuspensionsaredeliveredbymetered-dosepump
sprays.Nasalsprays,ornasalmists,areusedforthenasaldeliveryofa
drugordrugs,eitherlocallytogenerallyalleviatecoldorallergy
symptomssuchasnasalcongestionorsystemically,seenasal
administration.Althoughdeliverymethodsvary,mostnasalsprays
functionbyinstillingafinemistintothenostrilbyactionofahand-
operatedpumpmechanism.Thethreemaintypesavailableforlocaleffect
are:antihistamines,corticosteroids,andtopicaldecongestants.Thedose
accuracyofmetered-dosepumpspraysisdependentonthesurfacetension
andviscosityoftheformulation.Forsolutionswithhigherviscosity,
specialpumpandvalvecombinationsareonthemarket.

24. POWDER DOSAGE FORMS
Drypowdersarelessfrequentlyusedinnasaldrugdelivery.Major
advantagesofthisdosageformarethelackofpreservativesandthe
improvedstabilityoftheformulation.Comparedtosolutions,the
administrationofpowderscouldresultinapro-longedcontactwith
thenasalmucosa.Thetypesofpowderdosageformsaredescribed
below:
1.Insufflators
Insufflatorsarethedevicestodeliverthedrugsubstancefor
inhalation;itcanbeconstructedbyusingastrawortubewhich
containsthedrugsubstanceandsometimesitcontainssyringealso.
Theachievedparticlesizeofthesesystemsisoftenincreased
comparedtotheparticlesizeofthepowderparticlesdueto
insufficientdeaggregationoftheparticlesandresultsinahigh
coefficientofvariationforinitialdepositionareas.Manyinsufflator
systemsworkwithpre-dosedpowderdosesincapsules.

25. 2. Dry powder inhaler
Drypowderinhalers(DPIs)aredevicesthroughwhichadry
powderformulationofanactivedrugisdeliveredforlocalor
systemiceffectviathepulmonaryroute.Drypowderinhalersare
bolusdrugdeliverydevicesthatcontainsoliddrug,suspendedor
dissolvedinanonpolarvolatilepropellantorindrypowderinhaler
thatisfluidizedwhenthepatientinhales.Thesearecommonlyused
totreatrespiratorydiseasessuchasasthma,bronchitis,emphysema
andCOPDandhavealsobeenusedinthetreatmentofdiabetes
mellitus.Themedicationiscommonlyheldeitherinacapsulefor
manualloadingoraproprietaryformfrominsidetheinhaler.Once
loadedoractuated,theoperatorputsthemouthpieceoftheinhaler
intotheirmouthandtakesadeepinhalation,holdingtheirbreathfor
5-10seconds.

26. 3.PRESSURIZED MDIs
Ametered-doseinhaler(MDI)isadevicethatdeliversaspecificamountof
medicationtothelungs,intheformofashortburstofaerosolizedmedicinethat
isinhaledbythepatient.Itisthemostcommonlyuseddeliverysystemfor
treatingasthma,chronicobstructivepulmonarydisease(COPD)andother
respiratorydiseases.Themedicationinametereddoseinhalerismostcommonly
abronchodilator,corticosteroidoracombinationofbothforthetreatmentof
asthmaandCOPD.Othermedicationslesscommonlyusedbutalsoadministered
byMDIaremastcellstabilizers,suchas(cromoglicateornedocromil).Touse
theinhalerthepatientpressesdownonthetopofthecanister,withtheirthumb
supportingthelowerportionoftheactuator.Thepropellantprovidestheforceto
generatetheaerosolcloudandisalsothemediuminwhichtheactivecomponent
mustbesuspendedordissolved.Actuationofthedevicereleasesasinglemetered
doseoftheformulationwhichcontainsthemedicationeitherdissolvedor
suspendedinthepropellant.Breakupofthevolatilepropellantinto
droplets,followedbyrapidevaporationofthesedroplets,resultsinthegeneration
ofanaerosolconsistingofmicrometer-sizedmedicationparticlesthatarethen
inhaled.

27. NASAL GELS
Nasalgelsarehigh-viscositythickenedsolutionsor
suspensions.Untiltherecentdevelopmentofprecisedosing
devices,therewasnotmuchinterestinthissystem.Thead-
vantagesofanasalgelincludethereductionofpost-nasaldrip
duetohighviscosity,reductionoftasteimpactduetoreduced
swallowing,reductionofanteriorleakageoftheformulation,
reductionofirritationbyusingsoothing/emollientexcipients
andtargetdeliverytomucosaforbetterabsorption.The
depositionofthegelinthenasalcavitydependsonthemode
ofadministration,becauseduetoitsviscositytheformulation
haspoorspreadingabilities.Withoutspecialapplication
techniquesitonlyoccupiesanarrowdistributionareainthe
nasalcavity,whereitisplaceddirectly.Recently,thefirstnasal
gelcontainingVitaminB12forsystemicmedicationhas
enteredthemarket.

28. APPLICATIONS
1.Delivery of non-peptide pharmaceutical
2.Delivery of peptide-based pharmaceuticals
3.Delivery of Drugs to Brain through Nasal Cavity
4.Delivery of Vaccines through Nasal Route
5.Delivery of diagnostic drugs

29. CONCLUSION
Nasaldrugdeliverysystemisapromisingalternativerouteofadministration
fortheseveralsystemicallyactingdrugswithpoorbioavailabilityandithas
advantagesintermsofimprovedpatientacceptabilityandcompliancecompared
toparenteraladministrationofdrugs.Thisdeliverysystemisbeneficialin
conditionslikeParkinson’sdisease,Alzheimer’sdiseaseorpainbecauseit
requiresrapidand/orspecifictargetingofdrugstothebrainanditisasuitable
routetoproduceimmuneresponseagainstvariousdiseaseslikeanthrax,influenza
etc.,bydeliveringthevaccinesthroughthenasalmucosa.Innearfuture,wehope
thatintranasalproductsmostprobablycompriseforcrisistreatments,suchas
erectiledysfunction,sleepinduction,acutepain(migraine),panicattacks,nausea,
heartattacksandParkinson’sdiseaseandnovelnasalproductsfortreatmentof
long-termillnesses,suchasdiabetes,growthdeficiency,osteoporosis,fertility
treatmentandendometriosis,willalsobemarketed.

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