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1ransdermal drug dellvery sysLems (1uuS) also known as paLches" are dosage forms deslgned Lo
dellver a LherapeuLlcally effecLlve amounL of drug across a paLlenL's skln ln order Lo dellver LherapeuLlc
agenLs Lhrough Lhe human skln for sysLemlc effecLs Lhe comprehenslve morphologlcal blophyslcal and
physlcochemlcal properLles of Lhe skln are Lo be consldered
1he flrsL 1ransdermal sysLem 1ransdermSCC was approved by luA ln 1979 for Lhe prevenLlon of
nausea and vomlLlng assoclaLed wlLh Lravel parLlcularly by sea 1he evldence of percuLaneous drug
absorpLlon may be found Lhrough measurable blood levels of Lhe drug deLecLable excreLlon of Lhe drug
and lLs meLabollLes ln Lhe urlne and Lhrough Lhe cllnlcal response of Lhe paLlenL Lo Lhe admlnlsLered
drug Lherapy 1he common lngredlenLs whlch are used for Lhe preparaLlon of 1uuS are as follows
O urug urug ls ln dlrecL conLacL wlLh release llner Lg nlcoLlne and LsLrogen
O lners roLecLs Lhe paLch durlng sLorage Lg polyesLer fllm
O Adheslve Serves Lo adhere Lhe paLch Lo Lhe skln for sysLemlc dellvery of drug Lg AcrylaLes
olylsobuLylene Slllcones
O ermeaLlon enhancers ConLrols Lhe 8elease of Lhe drug Lg 1erpenes 1erpenolds
yrrolldones SolvenLs llke alcohol LLhanol MeLhanol SurfacLanLs llke Sodlum auryl sulfaLe
luronlc l127 luronlc l68
O acklng layer roLecL paLch from ouLer envlronmenL Lg Cellulose derlvaLlves poly vlnyl
alcohol olypropylene Slllcon rubber

Drug De||very across the Sk|n
1he alm of drug appllcaLlon on Lhe skln may be LargeLlng Lhe drug Lo Lhree anaLomlcal locaLlons namely
Lhe skln lLself (Loplcal dellvery) deeper Llssue layers (reglonal dellvery) and Lhe sysLemlc clrculaLlon
(Lransdermal dellvery)
1he advanLage of Loplcal or reglonal drug dellvery ls clear because Lhe LreaLmenL of Lhe skln wlLh a
sysLemlcally applled drug may lead Lo adverse effecLs and only a small fracLlon of Lhe applled drug wlll
reach Lhe LargeL slLe uL Lhere are also reasons Lo favor Lhe Lransdermal rouLe ln sysLemlc drug dellvery


1hree drug relaLed processes musL be Laken lnLo conslderaLlon when a drug preparaLlon ls applled on
Lhe skln
(l) Lhe release of Lhe peneLranL from Lhe vehlcle followed by
(ll) lLs peneLraLlon Lhrough Lhe dlfferenL skln barrlers and
(lll) lLs acLlvaLlon of Lhe deslred pharmacologlcal reacLlon
llg below glves an overvlew abouL Lhe drug flux LhaL may arlse followlng appllcaLlon of a suspenslon
vehlcle 1he drug may undergo any or all of Lhe followlng evenLs

llrsL Lhe drug molecules musL dlssolve Lo enable lLs dlffuslon Lhrough Lhe vehlcle Lo Lhe vehlclesLraLum
corneum lnLerface lor Lhe drug Lo move Lhrough Lhe skln lL musL parLlLlon lnLo Lhe sLraLum corneum
and dlffuse wlLhln Lhls almosL lmpermeable layer Some drug may blnd aL socalled depoLslLe Lhe
remalnder dlffuses Lo deeper Llssues of Lhe epldermls meeLs a second lnLerfaclal layer and parLlLlons ln
Lhe vlable epldermls

Some stages in percutaneous absorption from a vehicIe with suspended drug. From Barry,
1983 (54)

lor mosL hydrophlllc and amphlphlllc peneLranLs dlffuslon Lhrough Lhe sLraLum corneum wlll be Lhe
raLellmlLlng sLep ln percuLaneous absorpLlon whereas llpophlllc subsLances are favored Lo peneLraLe
Lhls layer lf very llpophlllc drugs are used however Lhe vlable epldermls can acL as
a raLellmlLlng facLor ln permeaLlon across Lhe skln
1he amounL of drug permeaLed Lhrough Lhe skln per unlL Llme and unlL area ls deflned as Lhe
drug flux ! LhaL ls descrlbed by llck`s flrsL dlffuslon law


9ermeat|on koutes
1he permeaLlon of drugs Lhrough Lhe skln lncludes Lhe dlffuslon Lhrough Lhe lnLacL epldermls and Lrough
skln appendages for example sweaL glands and halr folllcles Powever Lhe appendages occupy only
01 of Lhe human skln surface so LhaL Lhe conLrlbuLlon of Lhese shunL paLhways Lo Lransdermal
permeaLlon ls usually consldered Lo be small Cnly an lncreaslng molecular welghL of Lhe peneLranL may
lead Lo a slgnlflcanL role of Lhe appendageal rouLe
1he sLraLum corneum represenLs Lhe maln barrler of Lhe skln
1heoreLlcally Lhere are Lwo paLhways Lhrough Lhls layer
O A Lranscellular (across Lhe corneocyLes and Lhe llpld maLrlx)
O An lnLercellular way (vla Lhe lnLercellular llpld domalns beLween Lhe corneocyLes) ln boLh cases
however Lhe permeanL has Lo pass Lhe lnLercellular llpld maLrlx


!ermeation routes through the stratum corneum. From Moghimi, 1999 (58)

lnLercellular llplds are arranged ln mulLlple layers conLalnlng boLh polar and non polar componenLs
1hls suggesLs LhaL hydrophlllc and llpophlllc peneLranLs dlffuse Lhrough dlfferenL domalns ln Lhe llpld
maLrlx 1he Lranscellular paLhway ls generally Lhe un favored rouLe for a drug Lo permeaLe Lhrough Lhe
sLraLum corneum because of Lhe hlgh dlffuslonal reslsLance of Lhe cornlfled cells Cnly hydrophlllc
molecules such as waLer or shorLchaln alcohols seem Lo prefer Lhe Lranscellular paLhway

Iactors Affect|ng Drug 9ermeat|on through the Sk|n
Several blologlcal and physlcochemlcal parameLers may lnfluence drug permeaLlon across Lhe skln 1he
physlcochemlcal facLors LhaL conLrol Lhe passlve dlffuslon of a subsLance from a vehlcle lnLo and across
Lhe skln are deLermlned by
O Lhe molecular properLles of Lhe subsLance
O Lhe vehlcle and
O 1he skln
Pence Lhe followlng lnLeracLlons may have lmpacL on drug dellvery
O drugskln
O vehlcleskln
O drugvehlcle and
O urugvehlcleskln
AlLeraLlons Lhe vehlcle may undergo afLer appllcaLlon commonly due Lo evaporaLlon of volaLlle
componenLs represenL a furLher cruclal parameLer LhaL may affecL drug permeaLlon
1he blologlcal facLors lnclude sk|n age body reg|on metabo||sm and hydrat|on
AL dlfferenL body slLes Lhe composlLlon and flnally barrler properLles of Lhe sLraLum corneum may vary
whaL lncludes dlfferences ln lLs Lhlckness number of cells Lspeclally Lhe vlable epldermls conLalns
several enzyme sysLems LhaL may caLalyze processes such as oxldaLlon reducLlon hydrolysls or
con[ugaLlon 1herefore skln meLabollsm may have addlLlonal lmpacL on Lransdermal dellvery of drugs

1he effecL of age ls raLher due Lo Lhe smaller surfaceLovolume raLlo ln case of newborn lnfanLs
compared wlLh adulLs Lhan an effecL of lower barrler funcLlon of younger skln Skln hydraLlon ls a cruclal
and posslbly Lhe mosL frequenLly lnvesLlgaLed facLor affecLlng drug permeaLlon ln pracLlce Lhere ls
ofLen a comblnaLlon of Lhese facLors LhaL conLrlbuLe Lo Lransdermal drug permeaLlon

Skin Hydration and OccIusion

1he normal degree of hydraLlon of Lhe sLraLum corneum ls beLween 10 Lo 30 of lLs own welghL
Cccluslon hydraLes Lhe keraLln ln corneocyLes and lncreases Lhe waLer conLenL beLween ad[acenL
lnLercellular llpld lamellae lor hydrophlllc subsLances released from an aqueous dellvery devlce Lhe
parLlLlon coefflclenL beLween sLraLum corneum and Lhe vehlcle lncrease up Lo unlLy
lurLhermore skln LemperaLure generally lncreases from 32C Lo as much as 37C under occluslve
condlLlons Cf varlous approaches employed Lo enhance Lhe percuLaneous absorpLlon of drugs
occluslon ls Lhe slmplesL and perhaps one of Lhe mosL common meLhods ln use

eslde obvlous lmproved peneLraLlon of hydrophlllc drugs however a Lrend of occluslonlnduced
peneLraLlon enhancemenL wlLh lncreaslng peneLranL llpophlllclLy ls also apparenL A posslble explanaLlon
ls LhaL hydraLlon magnlfles Lhe aqueous reglons of Lhe lnLercellular llpld domalns lncreaslng Lhe
hydrophlllc characLer of Lhe sLraLum corneum lL follows LhaL Lhls ln Lurn leads Lo a reducLlon ln Lhe
sLraLum corneum vlable epldermls dlsLrlbuLlon coefflclenL 1hls flnally favors Lhe klneLlcs of Lransfer of
peneLranLs from Lhe sLraLum corneum Lo Lhe vlable epldermls 1he llmlL of Lhls mechanlsm of
enhancemenL would be a compleLe lnsolublllLy of Lhe peneLranL ln Lhe aqueous phase of Lhe sLraLum
corneum or sLerlcally hlndered peneLraLlon of Lhe subsLance for example due Lo large molecular slze
Powever a number of sLudles have shown LhaL hydraLlonlnduced skln permeaLlon enhancemenL
appears Lo be noL only a funcLlon of llpophlllcLy and hydrophlllclLy buL also seems Lo be chemlcal class
dependenL

DrugSk|n Interact|ons
oLenLlal lnLeracLlons of Lhe acLlve lngredlenL wlLh Lhe skln lnclude hydraLlon effecLs and blndlng of Lhe
drug Lo Llssue componenLs lL ls posslble LhaL some drugs whlch can rapldly peneLraLe Lhe skln Lo yleld
Llssue concenLraLlons LhaL are hlgh enough exerL an osmoLlc effecL may lncrease skln hydraLlon 1he so
called reservolr effecL of Loplcal sLerolds represenLs a common example LhaL lnvolves drugsLraLum
corneum blndlng 1hls effecL however ls noL resLrlcLed Lo Lhls subsLance class nlcoLlne caffelne or
caLlonlc blocklng agenLs are also reporLedly reLalned ln Lhe skln afLer appllcaLlon followed by a
delayed release AnoLher drugskln lnLeracLlon ls proposed by AlSaldan who reporLs on a self
permeaLlon enhancemenL of lbuprofen llkely due Lo dlsrupLlon of sLraLum corneum barrler

DrugVeh|c|e Interact|ons
urug vehlcle lnLeracLlons lnclude Lhe Lhermodynamlc acLlvlLy of Lhe drug ln Lhe vehlcle LhaL ls relaLed Lo
soluLe drug concenLraLlon ln Lhe vehlcle and Lhe acLlvlLy of Lhe drug 1he maxlmum drug Lransfer lnLo
Lhe skln Lakes place when Lhe vehlcle ls saLuraLed wlLh Lhe drug aL Lhe vehlcleskln lnLerface

A furLher drugvehlcle lnLeracLlon LhaL may affecL drug permeaLlon ls Lhe formaLlon of lon palrs of
charged drugs wlLh counLer lons presenL ln Lhe vehlcle valenLa eL al found LhaL fluxes of charged
llgnocalne salLs were slgnlflcanLly lncreased ln Lhe presence of organlc counLer lons whlle lnorganlc salLs
dld noL lnfluence Lhe permeaLlon klneLlc Several publlcaLlons LhaL
deal wlLh caLlonlc subsLances and faLLy aclds as counLer lons supporL Lhls lon palr approach as
a posslble permeaLlon enhanclng effecL of Lhe faLLy aclds lurLhermore ln some cases drug permeaLlon
Lhrough Lhe skln ls noL governed by Lhe lmpermeablllLy of Lhe sLraLum corneum for example when Lhe
horny layer ls damaged or drug dlffuslon wlLhln Lhe vehlcle ls excepLlonally slow ln such a case Lhe
release raLe of Lhe drug from Lhe vehlcle provldes Lhe raLellmlLlng sLep ln overall dlffuslon and Lhe skln
funcLlons as a perfecL slnk

Veh|c|eSk|n Interact|ons
uesplLe Lhe facL LhaL a drug dellvery vehlcle should be `lnerL` especlally vehlcles commonly used for
Loplcal LreaLmenL reporLedly have addlLlonal effecLs Lo Lhe requlremenL LhaL lL should readlly release Lhe
acLlve moleLy for Lhe LherapeuLlc effecL 1he appllcaLlon of pharmaceuLlcal vehlcles such as gels
emulslons creams or olnLmenLs may superlmpose furLher changes of Lhe lnLegumenL and flnally may
affecL lLs permeablllLy
1hls mechanlsm ofacLlon wlll probably be a solvenL acLlon on Lhe sLraLum corneum a hydraLlon effecL or
a LemperaLure effecL 1he hydraLlon effecL ls generally due Lo occluslon effecLs of Lhe vehlcle 1hus lL ls
obvlous LhaL olly maLerlals reLard more efflclenL molsLure loss from Lhe skln Lhan for example hydrogels
or oll ln waLer emulslons lurLhermore under occluslon or under Lhe lnfluence of a coollng vehlcle Lhe
skln LemperaLure may lncrease or decrease a few degrees whlch may affecL Lhe dlffuslon coefflclenL of
a subsLance due Lo lLs LemperaLure dependence Powever any consequenL alLered permeablllLy ls small
compared Lo Lhe more dramaLlc effecL whlch Lhe resulLanL lncreased hydraLlon causes An ausplclous
Lool Lo lmprove cuLaneous dellvery raLe ls Lhe appllcaLlon of approprlaLe vehlcles such as
mlcroemulslons or llposomes whlch may reduce skln barrler funcLlon due Lo dlrecL lnLeracLlon wlLh Lhe
sLraLum corneum or Lo lnclude molecules ln Lhe dellvery devlce LhaL may reverslbly reduce Lhe barrler
reslsLance of Lhe skln Such enLlLles are known as peneLraLlon enhancers