J. Cosmet.

Sci., 54, 143-159 (March/April 2003)

Penetrationof mixedmiceliesinto the epidermis:Effectof

mixingsodiumdodecylsulfatewith dodecyl
hexa(ethyleneoxide)

PETER N. MOORE, ANAT SHILOACH,

SUDHAKAR PUVVADA, and DANIEL BLANKSCHTEIN,
Department
of Chemical
Enginering,Massachusetts
Instituteof
Technology,
Cambridge,
MA 02139 (P.N.M., D.B.) and Unilever
Homeand PersonalCare NA, Trumbull, CT 06611 (A.S., S.P.).

Accepted
for publication
November
15, 2002.

Synopsis
The penetrationof the anionicsurfactantsodiumdodecylsulfate(SDS)into the epidermisfrom contacting
solutionsof SDSand the nonionicsurfactantdodecylhexa(ethylene oxide)(C12E6)wasmeasured for three
SDS concentrations (25 raM, 50 raM, and 100 raM) and three SDS solutioncompositions (1, 0.83, and
0.50). The additionofC•2E6 to the SDSsolutions wasfoundto decrease the amountof SDSpenetratinginto
the epidermis.The observed decreaseoccurredvia two plausiblemechanisms: (i) the additionof C12E6
decreased the SDSmonomerconcentration, thusreducingthe drivingforcefor the penetrationofmonomeric
SDSinto the epidermis,and(ii) the additionof C12E6 reduced,or prevented,the penetrationof micellarSDS
into the epidermis.Using dynamiclight scattering,the hydrodynamicradii of the SDS/%2E6micelieswere
determined
tobe20•, fortheOtn•
= 1 micelies,
24 • fortheOtn•
= 0.83micelies,
and27 • fortheOtn•
=
0.50 micelles(whereO•n•
denotesthe SDSmicellecomposition).
A comparison
with typicalstratumcomeurn
aqueous
poreradiireported
in theliterature
(10-28•) suggests
thattheO•n•
= 1 (pureSDS)micelles
are
ableto penetrateinto the epidermis,while the o%•= 0.83 and the o•m = 0.50 SDS/C12E 6 mixedmicelles
aresterically hinderedfromdoingsodueto theirlargersizes.The observed reduced penetration of SDSinto
the epidermisuponthe additionof Ct2E6 couldleadto a reductionin the skin irritation potentialof SDS,
providedthat there is a relationshipbetweenthe concentration of SDS in the epidermisand the skin
irritation inducedby SDS.

INTRODUCTION

The studyof why andhowsurfactants induceskin irritationandskin damagehasbroad

implications,from the designof mild personalcareproductsto assistingthe transport
of therapeuticdrugs acrossthe stratum corneum(SC) (1-12). Previousstudieshave
comparedthe irritation potential of different surfactants(3,8,10,11,13-16), and have
alsodeterminedhow differentsurfactants canleadto changes in the permeabilityof the

Addressall correspondence
to Daniel Blankschtein.

143
144 JOURNAL OF COSMETIC SCIENCE

skin (1,2,9,17-20). Althoughvariousmechanisms havebeeninvokedto explainsurfac-

tant-inducedskin irritation, in the majority of thesemechanisms the surfactantmust
penetrateinto the skin in orderto induceirritation (1,3,7,9,10,19-23). Accordingly,a
simple way to reducethe skin irritation potential of a surfactantsolution involves
reducingthe amountof surfactantthat penetratesinto the skin.
A widely accepted view regardingsurfactant-inducedskinirritationis that, at surfactant
concentrationsexceedingthe critical micelie concentration(CMC), where surfactant
miceliesfirst form,onlysurfactant
monomers canpenetrateinto the skin,eitherbecause
surfactantmicellesare not surface-active
or becausethey are too largeto penetrateinto
the SC (3,6,14,16,18,24,25).This descriptionof surfactantmonomerpenetrationinto
the skin will be referredto hereafteras the monomerpenetration model.The monomer
penetrationmodel is basedprimarily on experimentalobservations usingmixturesof
surfactants,where surfactant-inducedskin irritation was correlatedwith the CMC of the
surfactantmixturesexamined(6,24,26). The surfactantmonomerconcentrationis ap-
proximatelyequal to the CMC (27), and therefore,accordingto the premiseof the
monomerpenetrationmodel, only the surfactantmonomersshouldcontributeto the
observed surfactant-induced skin irritation.

We haverecentlychallengedthe monomerpenetrationmodelby unambiguously dem-

onstratingthat micellesof the anionicsurfactantsodiumdodecylsulfate(SDS)contrib-
ute significantlyto SDSpenetrationinto the epidermisat SDS concentrations exceeding
the CMC (28). The factthat SDSmicelieswerefoundto contributeto SDSpenetration
into the epidermisclearlycontradictsthe monomerpenetrationmodel, which predicts
that the micellarsurfactantshouldhaveno effecton surfactantpenetrationinto the
epidermis.In addition, we demonstratedthat the SDS micelle contributionto skin
penetrationcanbe eliminatedby mixing SDSwith poly(ethylene oxide)(PEO), a non-
ionicpolymerknownto bind to SDSmicelies,to form PEO-boundSDS micelies(28).
To explainboth findings,we proposed a new modelof surfactantpenetrationinto the
skin, in which the freeSDSmiceliesaresufficientlysmallto access the aqueous poresof
the SC,while the PEO-boundSDSmicellesarestericallyhinderedfrom doingsodue to
their largersize.In contrastto the monomerpenetrationmodel,the new surfactantskin
penetrationmodel highlightsthe potentialimportanceof the micellesin determining
surfactantpenetrationinto the skin. If the miceIlarsurfactantis ableto penetrateinto
the skin, then one predictsthe commonlyreporteddose-dependent skin irritation re-
sponseto surfactants(2,3,8,13,16,18), as well as providing an explanationfor the
increasedpenetrationof surfactantsinto the skin beyondthe CMC (25,28,29). The
monomerpenetrationmodelfails to predictthis observeddosedependence because at
surfactantconcentrations exceedingthe CMC, where the concentrationof surfactant
monomersis constant,there shouldbe no effect of increasingthe total surfactant
concentration on the surfactant-induced skin irritation.

An importantquestionthat arosefromourpreviousinvestigation(28) is whethermixing

surfactants will havean effecton the ability of the micellarsurfactantto penetrateinto
the skin. It is well known that mixing surfactantscan lower the surfactantmonomer
concentration (24,30,31). In fact,the relationshipobservedbetweenthe reductionin the
surfactantmonomerconcentrationdue to mixing surfactantsand the resulting skin
irritationreductionwasusedasthe basisfor the monomerpenetrationmodel(6,24,26).
However,havingdemonstrated that the micellarsurfactantcancontributeto surfactant
penetrationinto the skin (28), it becameimportant to determinewhether mixing
 PENETRATION OF MIXED MICELLES INTO THE EPIDERMIS 145

surfactants
couldalsoreducethe penetrationof the miceIlarsurfactantinto the skin in
additionto reducingthesurfactantmonomer penetration.In thisrespect,
it alsobecame
importantto determinethe relativecontributions of the monomeric and the miceliar
surfactant
fractionsto surfactant
penetrationinto the skin,includingquantifyingwhich
oneis reducedthe mostby mixing surfactants.
With this in mind, we measuredthe amountof SDS that penetratesinto the epidermis
fromaqueous
mixturesof SDSandthe nonionicsurfactant
dodecylhexa(ethylene
oxide)
(C12E6) afterfivehoursof exposure.
We foundthat SDSin SDS/C12E 6 mixedmicelies
is lessableto penetrate
intotheepidermis
thanSDSin pureSDSmicelies.We alsofound
that the majorityof SDSpenetratinginto the skin from SDS/C•2E
6 mixturesresults
from the monomericfraction.Dynamiclight scattering(DLS) measurements indicated
that mixingSDSwith C•2E6 leadsto an increase in the miceliesize.We propose that
it is the increasedmicelie sizethat reduces,or prevents,the penetrationof the SDS/
C•2E6 mixedmiceliesinto the epidermis.
Furthermore,
we propose
that, in general,
surfactantmixturesthat obeythe monomerpenetrationmodelcontainmixed micelies
that are too large to be able to penetrateinto the epidermis.

EXPERIMENTAL

MATERIALS

Sodiumdodecylsulfate(SDS)andsodiumchloride(NaCI) werepurchased
from Sigma
Chemicals(St. Louis, MO) and were used as received.Dodecyl hexa(ethyleneoxide)
(C12E6)
waspurchased
fromNikko Chemicals
(Tokyo,Japan)andwasusedasreceived.
Waterwasproduced
using
aMillipore
Academic
water
filter.•4C-radiolabeled
SDSwas
purchased from AmericanRadiolabeled
Chemicals(St. Louis,MO) and was usedas
received.
Phosphate-buffered
saline(PBS)waspreparedusingPBStabletsfrom Sigma
Chemicalsand Millipore filtered water.

PREPARATION OF SKIN SAMPLES

FemaleYorkshirepigs(40-45 kg) werepurchased fromlocalfarms.Skinfromthe back

of thepig washarvested
withinonehourof sacrificingtheanimal.The subcutaneousfat
wastrimmedoff usinga razorblade,andthe full-thickness
pig skinwascut into 2-cm
x 2-cmpiecesandstoredin a -80 øCfreezeruntil used.

EXPERIMENTAL PROTOCOL

After allowingthe skinto thawfor a halfhourat roomtemperature,

the pig skinwas
mountedin a verticalFranzdiffusioncell (PermegearInc., Riegelsville,PA), with the
SC facingthe donorcompartment.
The donorand the receivercompartments
of the
diffusioncell werefilled with phosphate-buffered
saline(PBS;phosphateconcentration
of 10 mM; NaCI concentration of 137 mM; SigmaChemicalCompany),and the skin
wasleft to hydratefor onehour.The PBSin the donorcompartment wasremoved,and
1.5 ml of surfactantsolutionwasaddedto the donorcompartment.The solutionin the
donorcompartment,
referredto hereafter
asthecontacting
solution,
contained
mixturesof
146 JOURNAL OF COSMETIC SCIENCE

SDSandC12E6,
each
withabout
0.5iaCi/ml
of•4C-radiolabeled
SDSand100mMNaC1.
We verifiedthat the concentration of radiolabeledSDS in the contactingsolutiondid
not changeappreciably duringthe five-hourexposure to the skin.A five-hourexposure
waschosenbecause this time wassufficientto enablesignificantpenetrationof SDSinto
the skin, but shortenoughto preventthe saturationof the skin with SDS. The tem-
peratureof the diffusioncell was ambient, that is, 20ø + 1 øC.
After five hoursof exposure,the contactingsolutionwas removed,and the donor
compartmentwasrinsedfour timeswith 2 ml of PBSto removeany SDS that wasnot
boundto the skin. The skin wassubsequentlyheat-strippedby soakingit in a bath of
water at 60 øC for two minutes, and the epidermis(SC and viable epidermis)was
separatedfrom the dermis.The exposedepidermiswasthen dried in a fume hoodfor two
daysandweighed.The dried epidermiswasdissolvedin 1.5 ml of Soluene-350(Packard,
Meriden, CT). Ten milliliters of Hionic Fluor scintillation cocktail (Packard) was added
to the Soluene-350after the epidermiswas dissolved,and the concentrationof radiola-
beledSDSwasdeterminedusinga PackardTri-Carb 4350 scintillationcounter.Know-
ing the concentration
of SDSin the contactingsolution,Csos,the radioactivityof the
contactingsolution,
Crad,do
.... thedryweightof theepidermis,
m,andtheradioactivity
of theepidermis,
Crad,
Jkinit waspossibleto determine
theconcentration
of SDSin the
driedepidermis,CsoS,skinusingthe followingequation:
Crad,
skin
' CSDS
Csz>s,
,kin
= C•,•on•'
m (1)
DYNAMIC LIGHT SCATTERING

The SDS and the SDS/C•2E

6 solutionswerepreparedin Millipore filteredwaterwith
100 mM NaC1. The 100 mM NaC1 was added to the surfactant solution to screen
electrostaticintermicellar interactionsin the DLS measurements(32-35). To prevent
dust from interferingwith the light-scatteringmeasurements, the surfactantsolutions
were filtered through a 0.02-lam Anotop 10 syringefilter (Whatman International,
Maidstone,England)directlyinto a cylindrical-scattering
cell, andsealeduntil use.DLS
wasperformedat 25 øC and a 90 ø scatteringangleon a BrookhavenBI-200SM system
(Brookhaven, Holtsville,NY) usinga 2017 Stabiliteargon-ionlaser(SpectraPhysics) at
488 nm. The autocorrelation
functionwasanalyzedusingthe CONTIN programpro-
vided by the BIC dynamiclight scatteringsoftware(Brookhaven,Holtsville,NY),
which determinedthe effectivehydrodynamicradius,Rh, using the Stokes-Einstein
relation (36):
--

kBT
Rh
- 6•r•l• (2)
wherek•3is the Boltzma__nn
constant,
T is theabsolute
temperature,
xI is theviscosity
of
the salt solution,and D is the mean diffusioncoefficientof the scatteringspecies.In
order to eliminate the effectsof intermicellarinteractionswhen measuringthe hydro-
dynamicradii of the micelies,the effectivehydrodynamicradii were determinedat
severaldifferenttotal surfactantconcentrationshavinga fixed solutioncomposition,and
the averageeffectivehydrodynamicradii wereextrapolatedto a zeromicelieconcentra-
tion (32-35,37).
 PENETRATION OF MIXED MICELLES INTO THE EPIDERMIS 147

MICELLIZATION BEHAVIOR OF THE SDS/Ct2E6 SURFACTANT MIXTURES

In this paper,o•x denotesthe fractionof the total surfactantthat is SDS, referredto as

the SDS composition,and is definedas follows:

Otx
=ismSix
q_
[C12E6]x (3)
where[SDS] denotesthe concentration of SDS, [C•2E6] denotesthe concentration of
C12E6,and the subscriptx refersto the monomericfraction(x = 1), to the miceliar
fraction(x = m), or to the overallsolution(x = s). Accordingly,% -- 0.83 impliesthat
83% of the surfactant in the contactingsolutionis SDS,andthat the remaining17% (1
- % = 0.17) is C12E6. Recentlydevelopedmolecular-thermodynamic theoriesof mi-
cellization(30,31) were usedto predict the micellizationbehaviorof the SDS/C12E6
surfactant mixtures.Specifically,
the concentrationandthe composition of the surfactant
monomers and of the mixedmicelleswerepredictedasa functionof the total surfactant
concentration and solutioncomposition. The resultingpredictedvaluesof oq, O•m,and
the total surfactantmonomerconcentration, C•, for the contactingsolutionsexamined
are reportedin TablesI and II.

RESULTS AND DISCUSSION

EFFECT OF ADDING Ci2E6AT A FIXED SDS CONCENTRATION ON THE PENETRATION OF SDS INTO
THE EPIDERMIS

It is well knownthat whentwo surfactants

that interactsynergistically
are mixed,the
surfactant mixture often exhibits lower skin irritation than either of the individual
surfactants
(6,24,26). It is alsoknownthat SDSand C12E6 interactsynergistically
to
reduce the CMC of the surfactant mixture (30,31). SDS is a model skin irritant
(10,13,15,16,26,38),while Cx2E6 is thoughtto be a mild surfactant, althoughit may
lead to skin dryness(3,39). The systemof SDS and C12E6 was chosenas a model
surfactantmixture becauseof the synergythat it exhibits,as well as becausethe skin
irritationpotentialof this surfactantmixture is expectedto resultprimarily from the
actionof the irritating surfactant,
SDS.This, in turn, allowsusto relatethe penetration
of SDSinto the epidermisto skinirritation,while neglectingthe irritationpotentialof
C•2E6.
Evidencefor the relationshipbetweenthe concentration
of SDSin the epidermisandthe
skin irritation inducedby SDSwaspresentedin our recentpaper(28), in which the
concentration of SDSin the epidermiswasobserved to be dose-dependentfor % = 1,

Table I
PredictedValuesof oq and o•m for Mixturesof SDSand C12E6 in 0.1 M NaC1at the VariousSDS
Concentrations
and SolutionCompositions (O•s)Used for the SDS Skin PenetrationExperiments(30,31)
25 mM SDS 50 mM SDS 100 mM SDS
O•s 0•1• O•m 0•1, O•m 0•1• O•rn

1 1,1 1,1 1,1

0.83 0.96, 0.83 0.96, 0.83 0.96, 0.83
0.50 0.925, 0.50 0.925, 0.50 0.925, 0.50
148 JOURNAL OF COSMETIC SCIENCE

Table II
PredictedTotal SurfactantMonomerConcentration,
C• (mM), for the Mixturesof SDSand C12E6in 0.1
M NaC! at the VariousSDSConcentrations
and SolutionCompositions (%) Usedfor the SDSSkin
PenetrationExperiments(30,31)

% 25 mM SDS 50 mM SDS 100 mM SDS

1 0.850 0.864 0.877
0.83 0.683 0.695 0.707
0.50 0.266 0.270 0.276

corresponding to the dose-dependent SDS skin irritation potentialobservedby other

researchers(2,3,8,13,16,18). However,it shouldbe notedthat, in this paper,we have
not measured the amountof C12E6 that penetratesinto the epidermis.Therefore,we did
not ascertainwhetherthe interactionbetweenCliE 6 and the SC is indeedmild. In this
respect,experiments by de la Mazaetal. haveshownthat nonionicsurfactants canhave
a strongeffecton reducingthe barrierpropertiesof SC lipid bilayers(19,40). However,
other researchers have observed that nonionic surfactants tend to have a smaller effect on
the skin thanSDS(3,39,41).Therefore,althoughthe assumption that C12E6 is benign
irritation-wisemay not be entirely accurate,it is expectedthat the skin irritation
potentialof SDSshouldoverwhelmthat of C12E6. An investigation of the skinirritation
potentialof C•2E6 is underway,and the resultsof this investigationwill be reported
elsewhere.

Basedon the premisethat the skin irritation inducedby SDS is relatedto the concen-
tration of SDS in the epidermis,we measuredwhetheraddingC12E6to a fixed SDS
concentration(50 mM) in the contactingsolution would reducethe concentrationof
SDS in the epidermisafterfive hoursof exposure,C•ki,, and consequently, reducethe
skin irritation potential of the surfactantsolution.The purposeof conductingthe
experiments at a fixedSDSconcentration is to ensurethat anyobserved decreasein Cski,
uponthe additionof C•2E6 wouldnot resultfrom the decrease in the total SDS con-
centrationin the contactingsolution,but insteadwould be related to changesin the
solutionbehaviorof SDS.Figure1 showsthat aso•s is decreased by addingmoreC12E6
to the contactingsolution,C•i, decreases.The observed decreasein C,•, aso•sdecreases
is consistentwith reportedobservations of the reducedskin irritation potential of
surfactantmixtures, provided that Cs•, is related to the observedskin irritation
(6,24,26).

EFFECT OF INCREASING % ON THE ABILITY OF MICELLAR SDS TO PENETRATE INTO

THE EPIDERMIS

There are two plausiblemechanisms responsible for the decrease

in C,•i, observedin
Figure 1: (i) the additionof C12E6reducesthe SDSmonomerconcentration, aspredicted
by the monomerpenetration model,and(ii) the additionof C12E6reduces theability of
the miceliarSDS to penetrateinto the epidermis,aspredictedby our recentlyproposed
micelie penetrationmodel (28). It is entirely possiblefor both mechanisms to act
simultaneously. In view of that, we conductedthe following experimentsto clarify
whethermechanism (ii) wasinvolvedin the reductionof C•k•,observed in Figure 1.
We testedwhethermixedmicellespresentin the SDS/C•2E
6 surfactant
mixturescould
 PENETRATION OF MIXED MICELLES INTO THE EPIDERMIS 149

•5

1.00 0.83 0.50

Solution Composition of SDS, as

Figure 1. The effectof decreasing the compositionof SDS, %, in the contactingsolutionon the concen-
tration of SDS in the epidermisaftera five-hourexposure(Cj/•,,,)to solutionscontaining50 mM SDS and
increasingconcentrations of C12E6. The error barsreflect a 95% confidenceinterval basedon six samples
of eachcomposition.

penetrateinto the epidermisby maintaininga constanto•svalueand increasingthe total

surfactantconcentrationin the contactingsolution.In general,the ability of miceliesto
penetrateinto the skin can be determined by measuringhow increasingthe total
surfactantconcentrationbeyondthe CMC, at a fixed (xs value, affectsthe amount of
surfactantpenetratinginto the epidermis(28). If the surfactantconcentration in the
epidermisis foundto increase,then surfactantin miceliarform contributesto surfactant
penetrationinto the epidermis.Conversely,if the surfactantconcentrationin the epi-
dermis is found to remain constant,then surfactant in miceliar form doesnot contribute
to surfactantpenetrationinto the epidermis,in which casethe surfactantpenetration
shouldobeythe monomerpenetrationmodel.
The SDS/C•2E 6 surfactant
mixturesthat wereinvestigated hadsolutioncompositions of
% = 1, 0.83, and 0.50. Figure2 showsthe effectof increasing the total SDS concen-
trationin the contactingsolution(from25 mM to 100 mM) on C,,•i, at thesethreefixed
% values.As shownin TablesI and II (30,31), for eachvalueof % overthe rangeof
surfactantconcentrations examined,%n = O•s,O• is constantand C• is approximately
constant.Therefore,any observedincreasein C.,3.i,as the total SDS concentrationin-
creasesfor each% valueexaminedcanonly be attributedto the penetrationof miceIlar
SDSinto the epidermis,because only the micelleconcentrationis increasing.(Recallthat
the SDS monomerconcentrationis equal to oqC•, which remainsconstant,while the
concentration of SDS in miceIlarform is equal to %n(Ct - C•), where C• is the total
surfactant concentration, which increasesin this case.)
150 JOURNAL OF COSMETIC SCIENCE

.._,6

1 I 'I-
0
1.00 0.83 0.50

Solution Composition of SDS, =s

Figure 2. The effectof increasing the SDSconcentration in the contactingsolutionon the concentration
of SDSin the epidermis aftera five-hourexposure(C.,,•i,).For eachcomposition(% = 1, 0.83, and0.50),
the concentrations
of SDSin thecontacting solutionare25 mM (emptybats),50 mM (solidbars),and 100
mM (stripedbars).The errorbarsreflecta 95% confidence intervalbasedon six samplesat eachSDS
concentration.

The increase
in Cski,
, with increasing
totalSDSconcentration
observed
in Figure2 for tx•
-- 1, 0.83, and 0.50 clearly indicatesthat the miceliespresentin thesesolutionsdo
contributeto SDSpenetration into the epidermis,with their contribution
decreasing
as
txs decreases.
Specifically,
by comparingthe observed increase in Cski,
, asthe SDScon-
centrationin the contactingsolutionis increased
from25 mM to 100 mM (AC,•i,,) for
eachtxsvalueexamined,it is clearthat the pureSDSmicelies(ixs = 1) contributemore
to C•i,, (AC•i,, • 0.08)thanthemixedmicelies corresponding
to txs = 0.83 (AC•in=
0.03)andtotxs= 0.50(Ac,kin = 0.02).Thisisclearevidence
thatchanging tXs,
andhence
tXm,canaffectthe ability of the miceliarSDSto penetrateinto the epidermis,because
for eachtxsvalueexamined, the SDSconcentration in the contactingsolutionincreases
by thesameamount(from25 to 100 raM), but theeffecton AC•i,, is foundto decrease
as txs is decreased. Although this simpleanalysis,basedon the experimentalresults
presentedin Figure 2, clearlydemonstrates that addingC]2E6 to the SDS solution
reduces the abilityof the miceliarSDSto penetrateinto the epidermis,asproposed in
mechanism (ii), a morequantitativeanalysis,presentedbelow,is requiredto determine
the contributions of mechanisms (i) and(ii) to SDSskinpenetration. It shouldbe kept
in mind that the abilityto reducethe penetration of the miceliarSDSinto the skinby
mechanisms (i), (ii), or both shouldhavea pronounced effecton reducingthe skin
irritation inducedby SDS.
We haverecentlydemonstrated
that the contributionof the miceliarSDS to C•i,, is
comparableto the contributionof the monomericSDS at low SDS concentrations
(28).
However, becausethe concentration of SDS micelies increasesas the total SDS concen-
tration increases
beyondthe CMC, while the concentrationof SDS monomersremains
constant,we concluded(28) that it is the penetrationof the miceliarSDS that leadsto
 PENETRATION OF MIXED MICELLES INTO THE EPIDERMIS 151

the dose-dependent skin irritation response observed by many researchers

(2,3,8,13,16,18). Indeed, we found that the SDS miceliar contributionoverwhelmsthe
SDS monomericcontributionat the higher SDS concentrations (28). Accordingly,re-
ducing,or preventing,the contributionof the miceliarsurfactantto C,/•i, by mixing
surfactants
shouldlead to a reductionin the skin irritation potentialof the surfactant
mixture, in addition to any beneficialeffectdue to a reductionin the surfactantmono-
met concentration.

REGRESSION ANALYSIS OF THE CONTRIBUTIONS OF MICELLAR AND MONOMERIC SDSTO Cs•,n

FROM SOLUTIONS OF SDS/C•2E6

Figure2 showsthat aso•s decreases, the contributionof the SDS/C•2E

6 mixedmicelies
to Cs•i,
, decreases.To quantifythe relativecontributionsof SDSin mixedmicelleform
(o•m = 1, 0.83, and 0.50) and in monomericform to Cs•i,,,we carriedout a multiple
linear regressionanalysisusing all the experimentaldata, prior to averaging,that was
usedto generateFigure 2. The simplestrelationshipbetweenthe SDS concentrations in
miceliarandmonomeric
formto C•,•i,,isa linearone.The basisforthislinearrelationship
is that in Fickiandiffusionfrom an infinite reservoirwith a large concentrationdiffer-
ence, the net permeant flux at a given time is directly proportionalto the initial
permeantconcentration
(42). With this assumption
in mind, we fitted C•,•i,,to the
following expression:

C,•i, = o•ßC•,sos + b' C(o•

m = 1) + c' C(o•
m = 0.83)+ d' C(o•
m = 0.50) (4)
where a, b, c, and d are the regressioncoefficientsthat were determinedfrom the
regression
analysis,
Cj,sos is the SDSmonomerconcentration,
C(O•m)
is the SDScon-
centrationin miceliesof compositionO•m,and C,/•, is the SDS concentrationin the
epidermis(in units of mmols of SDS per gram of dry epidermis).For the regression
analysis,
Cj,sos = oqC•andC(o•,•)= oq•(C
t - Cj)usingtheappropriate
values
ofo•, o•m,
and Cj reportedin TablesI and II (30,31). In this manner,we wereable to isolatethe
contributionsto C.,•i, due to the miceliarSDS for the three micelie compositions
ex-
amined (reflected in b, c, and d), as well as due to the monomeric SDS (reflected in a).
The followingvaluesof a, b, c, and d were obtainedfrom the regression
analysis:

4.1 +_
1.0C,/•i,/Cl,so
s
0.032 +0.014Cskin/C(O•
m'- 1)
0.003 +0.012C•/•i,/C(o•
m= 0.83)
0.0009+_0.0092C,/•i,/C(o•
m= 0.50)
Accordingto theseregression results,the O•m = 0.50 miceliesdo not contributeto C,/•,
at all, because
d is essentially
equalto zero.The o•m = 0.83 miceliescontributeverylittle
or not at all to C,/•i,, becausealthoughthe averagevalue of c is not zero, the 95%
confidenceinterval includeszero.On a per SDS moleculebasis,the contributionof the
SDS monomersis quite large, with one SDS moleculein monomericform being 130
times more skin penetratingthan one SDS moleculein a pure SDS micelie (o•m = 1).
However, at the higher SDS concentrations,there is significantlymore miceliar SDS
than monomericSDS,and asa result,the net contributionto C•/•i, due to the miceliar
SDS may overwhelm that due to the SDS monomers.
152 JOURNAL OF COSMETIC SCIENCE

To more clearly describethe relative contributionsof the monomericSDS and the

miceliar SDS to skin penetration,Figure 3(a-c) showsthe total contributionsof the
monomericand the miceliar fractionsof SDS to Cs•i, for o•s = 1, 0.83, and 0.50
respectively,
basedon the regression datagivenabove.Specifically,the SDSmonomeric
contribution
to Cs•i,is a'C•,sos, and the threemiceliarcontributions
to Cs•i,are
b ßC(o•m = 1), c' C(o•m = 0.83), andd' C(o•m = 0.50). Figure3(a-c) clearlyshowsthat
the SDSmonomers makea contributionto Cs•i,that is largerthanthat of the miceliar
SDS for the three o•svaluesexamined,as seenby the empty bars (representingthe
monomericcontribution)alwaysbeing larger than the solid bars (representingthe
miceliarcontribution).It is only for o• = 1, the pure SDS case,that the miceliesmake
a large contributionto Cs•;,, particularlyat the highestsurfactantconcentrations ex-
amined(seeFigure 3a). In Figures3b and 3c, which correspond to the o• -- 0.83 and
0.50 surfactantmixtures,respectively,the miceliarcontributionis almostnon-existent.
Indeed,considering the confidence intervalfor the coefficients
c andd, it is apparentthat
the miceliarcontributionsincludethe possibilityof a zerocontributionto Cs•;,.There-
fore,the monomerpenetrationmodelrepresents a reasonableapproximationfor the two
SDS/C•2E 6 surfactantmixturesexamined,wherethe miceliarSDS doesnot penetrate
appreciablyinto the epidermisfor the SDS concentrations examined(25, 50, and 100
raM). However,the reductionin Cs•i,observed with decreasing o•s, shownin Figures1
and 2, results from both the reduction in the SDS monomer concentrationand the
reductionin the ability of the miceliar SDS to penetrateinto the epidermis.
Generalizingthe observations madein the caseof the SDS/C•2E 6 surfactantmixturesto
other surfactantmixtures,it is plausiblethat the observedreductionin skin irritation
uponmixing surfactants reportedby severalresearchers occursbecause boththetoohomeric
and themiceliars•rfactant penetrationsintotheskinare diminished(6,24,26). At the high
total surfactantconcentrations commonlyutilized in commercialsurfactantproducts,
the micellar contributioncan be quite large, as demonstratedby the dose-dependent
surfactant-induced skin irritation resultsreportedin the literature(2,3,8,13,16,18).
Consequently, anyreductionin the ability of the micellarsurfactantto penetrateinto the
skin,asreflectedby lowervaluesof the regression coefficients
(suchasb, c, andd), should
havea significantimpacton C_,•n at high total surfactantconcentrations. In otherwords,
reducingthe miceliar contributionto Cs•i, shouldlead to a reductionin the skin
irritation potential of the surfactantsystemcontactingthe skin.

DYNAMIC LIGHT SCATTERING DETERMINATION OF SDS/C•2E6 MIXED MICELLE SIZES

In Figure4, the hydrodynamic radii of the SDS/C•2E

6 mixedmicellesare determined
usingDLS by extrapolatingthe effectivehydrodynamic radii of thesemiceliesto a zero
micelieconcentration. At thesurfactant concentrations
corresponding to Figure4, O•mis
predictedto be approximatelyequalto o•, and therefore,one cantreat the miceliesas
havinga constantO•m valueoverthe entiresurfactantconcentration rangeexamined(see
Table I). This is important,becausea changein o•m could lead to a changein the
hydrodynamic radii of the micelies.(The hydrodynamic radii of the miceliesdetermined
usingthis methodare reportedin Table III.) Accordingto the surfactant penetration
modeladvancedin our recentpaper(28), the sizeof the miceliedeterminesits ability
to penetrateinto the SC. (Note that the discussionin the followingsectionintroduces
the caveatthat electrostaticinteractionsmay alsoplay a role.) The micelie penetration
 PENETRATION OF MIXED MICELLES INTO THE EPIDERMIS 153

25 mMSDS 50 mMSDS 100 mMSDS

3.5

3.0

2.5

2.0
1.5

1.0

0.5

0.0 ! i

b 25 mM SDS 50 mM SDS 100 mM SDS

1.4

1.2

0.4

0.2

0.0 I I

c 25 mM SDS 50 mM SDS 100 mM SDS

Figure3. The contribution of monomeric SDS(openbars)andmiceliarSDS(solidbars)to Cj,•i,,calculated
usingthe resultsof the multiplelinearregression
analysis
for: (a) ots= 1, (b) ot•= 0.83, and (c) ors= 0.50.
Adding up the contributionsfrom the two barsyieldsthe combinedcontributionof the SDSmonomersand
the miceliarSDS to Cs,•i
,. Note that the verticalaxesin a-c are scaleddifferently.
154 JOURNAL OF COSMETIC SCIENCE

29

• 27
.• 25

n, 23
E
= 2'1

o '19

ß'v 17

5 I I I I I I I I I I I I I I I I I I I I I I I I
0 10 20 30 40 50

Concentrationof MiceliarSDS (mM)

Figure4. Measured effectivehydrodynamic radiiof SDS/C•2E6 mixedmicelies
for o•m = 1 (0), o•m = 0.83
([•), ando•,• = 0.50 (l•) asa functionof the concentration
of miceliarSDS(thatis, the SDSconcentration
minusthe predictedSDStoohomerconcentration oqC•; seeTablesI and II) (30,31) usingDLS at 25øCin
0.1 M NaC1. The miceliarradii weredeterminedusinga CONTIN analysis.The errorbarsreflecta 95%
confidenceinterval basedon eight samplesat eachSDS concentration.The actualhydrodynamicradiusis
equal to the intercept.

Table III
The Micelie HydrodynamicRadii DeterminedUsing a CONTIN Analysisof the CorrelationFunction

O•
s RH
1 20+1
0.83 24 + 1
0.50 27 + 3

The actualhydrodynamic radiusof the micelieis determinedby extrapolatingthe effectivehydrodynamic

radii in Figure 3 to a zeromicelieconcentration. The errorvaluesreflecta 95% confidenceinterval.

model is basedon the premisethat only micellesthat are small enoughto accessthe
aqueousporesin the SC can contributeto surfactantpenetrationinto the epidermis.
Other researchershavedeterminedthe averageaqueouspore radiusin the skin using
permeability and/or conductivitymeasurements in the context of hindered-transport
theories,
andhavereported
radiivalues
between
10• and28 • (9,12,43-45).
Basedon the miceliehydrodynamicradii reportedin Table III and a purely stericmodel
of micelie penetrationinto the skin that ignoreselectrostaticinteractions(discussed
below),
andconsidering
askinaqueous
poreradius
ofatmost28•, theOQn
= 1micelles
shouldbe ableto penetrateinto the SCmoreeasilythan the OQn= 0.83 andthe o•n•= 0.50
micelies.This conclusionis consistent
with the resultsof the multiple linearregression
 PENETRATION OF MIXED MICELLES INTO THE EPIDERMIS 155

analysispresented above,andlendsgreatervalidity tOthe ideaput forwardby usrecently

(28) that stericfactorscanplay a key rolein determiningwhetherthe miceliarsurfactant
canpenetrateinto the skin. Concernsthat the penetrationof SDSinto the SC may alter
the characteristicporesizein the SC aremitigatedby the work of PecketaL (9). These
authorsfoundthat the averageporesizeof the SC measuredby hinderedtransportwas
unaffectedby exposingthe epidermisto SDS solutionsfor 18 hours.Instead, they
concludedthat the increasedpermeabilityof the skin resultedfrom an increasein the
effectiveporosity/tortuosityof the SC. Nevertheless,
we believethat additionalresearch
shouldbe conductedto better understandthe effectof surfactantpenetrationinto the
skin on the aqueouspathwaysof the SC.

POSSIBLE ELECTROSTATIC EFFECTS ON SDS SKIN PENETRATION

Interestingly,the oL
m = i micelieshavean equal,or slightly lower value,of the regres-
sioncoefficient,b (0.032 + 0.014), thanthe onereportedin our recentpaper(0.043 +
0.006) (28), while the SDSmonomers penetrateinto the epidermismuchmorereadily
according to the resultsreportedin thispaper(a = 4.1 + 1.0 hereversus
a = 0.14 + 0.04
in reference(28)). The main differencein the conditionscorresponding to the two sets
of experimentsis the presenceof 0.1 M NaC1 in the systemsexaminedin this paper,
comparedto the no-added-salt caseconsidered in the previouspaper(28). It is known
that the skin carriesa net negativecharge(9), and that the addition of salt screensthis
negativecharge.Screeningthe negativechargewould make it easierfor negatively
chargedSDSmonomers to approachthe skin surface,whichcouldexplainthe observed
increasein the value of a. However,the sameargumentshouldapply to the O•m = 1
micelies,which arealsonegativelycharged.Nevertheless,the SDSmiceliesdo not show
a significantchangein their contributionto SDSpenetrationuponthe additionof salt.
In fact,the pureSDSmiceliesappearto be somewhatlessableto contributeto Cs•i,in
the presence of salt(b = 0.0032) than in the absence of salt(b -- 0.0043 in reference
(28)).
It is importantto keep in mind, however,that the additionof salt may lead to some
miceliegrowth (32,46). As a result,applyingour modelof miceliepenetration,the
largermiceliesin the presenceof salt may be lessable to penetrateinto the skin, thus
counteracting the effectof any decrease in the electrostatic repulsionsbetweenthe skin
and the SDS micelies.

The discussion aboveaboutpotentialelectrostatic effectsaffectingsurfactantpenetration

into the skin indicatesthat steric hindrancemay not be the only factor determining
whether a micelie can penetrateinto the aqueousporesof the skin. Iontophoresis
experimentswith chargedpermeantshave shownthat the aqueousporesin the SC are
charged,and that positivelychargedpermeantstraversethe skin more easily than
negativelychargedpermeants(9,44). However,it is alsoknown that the size of the
permeantrelativeto that of the aqueousporeaffectsthe penetrationof the permeantinto
the skin (9,43). If the permeantis largerthan the aqueous poresize,then electrostatic
effectsshouldbe irrelevant,sincethe sterichindrancewouldpreventanyaccess into the
pore.However,whenthe permeantis physicallysmallenoughto access the skin aqueous
pores,then the electrostaticinteractionsbetweenthe permeantand the pores,aswell as
the stericinteractions betweenthe permeantand the porewall, will play a role in the
transportof the permeantacross the skin (9,12,43,45,47).
In our experiments,
all the miceliesare negativelychargeddue to the presence
of SDS,
156 JOURNAL OF COSMETIC SCIENCE

but the surfacechargedensityof the SDS/C•2E 6 mixed miceliesdecreases as o•m de-

creases.This reductionin surfacecharge density should make it easierfor the less
negativelychargedmixedmiceliesto access the negativelychargedskin pores.However,
the additionof C12E6alsocauses the miceliesto growandstericallyhinderstheir access
to the skinpores,therebycounteractingthissurfacechargereductioneffect.Futurework
aimedat studyingthe effectof electrostatics
on permeantpenetrationinto the epidermis
shouldexaminethe penetrationof fixed-sizechargedspeciesat differentionic strengths.

CONCLUSIONS

It is well known that mixing surfactantscan lead to a reductionin the skin irritation
potential of a surfactantsystem(6,24,26). Basedon the premisethat the irritating
surfactantmust penetrateinto the skin to induceskin irritation, we testedwhether
mixingthe irritatingsurfactant SDSwith C12E6affectedthe amountof SDSpenetrating
into the epidermis(Cski•).We foundthat increasingthe concentration of C12E6in the
contactingsolution,while maintaininga fixed concentration of SDS,led to a decrease in
Cski•
,. Providedthat the skinirritationinducedby SDSis relatedto C,.•i,, thesefindings
are consistentwith the expectationof reducingskin irritation by mixing surfactants.
In our recentpaper(28), we foundthat both monomericand miceliarSDS are able to
penetrateinto the epidermis.An important considerationin the caseof SDS/C•2E6
surfactantmixtureswaswhetherthe reductionin the amountof SDS penetratinginto
the epidermis was due to the reducedSDS monomer concentrationand/or due to a
reductionin the skinpenetrationability of miceliarSDS.A regression
analysis,
basedon
our experimentalresults,demonstratedthat only pure SDS micelies(O•n•= 1) contrib-
utedto C,/•i,,at a levelcomparable
to the contributionof theSDSmonomers, particularly
at the highestsurfactantconcentrations examined(seeFigure 3a). For the SDS/C•2E6
surfactantmixtures,corresponding
to mixed micelieshavingcompositions of o•m = 0.83
and 0.50, the monomericSDS contributedsignificantlymore to skin penetrationthan
the miceliarSDS,whichessentiallydid not contributeto C,/•i, (seeFigures3b and 3c).
Consequently, mixingSDSwith C•2E6 reducedCs•i,bothby reducingthe concentration
of monomericSDS and by almostentirelypreventingmiceliarSDS from penetrating
into the epidermis.
Using DLS measurements, we demonstratedthat the averagehydrodynamicradii of the
SDS/C•2E6 mixedmiceliesincreasedasthe solutioncomposition of SDSdecreased.This
corresponded to the observeddecreased
ability of the SDS/C•2E 6 mixed miceliesto
penetrateinto the SC. Comparingthe hydrodynamicradii of the SDS/C•2E6 mixed
miceliesexamined
(24• forgm= 0.83and27• forgm= 0.50)withthehydrodynamic
radiiofthePEO-bound
SDSmiceliesin ourprevious
paper
(25•, in reference
(28)),the
sterichindrancemodel for the preventionof micelie penetrationinto the skin remains
consistentwith our experimentalfindingsin this paper,with SDS in the largermixed
miceliesnot contributingto
From our results,onecanunderstandhow the monomerpenetrationmodelwasderived
from mixed-surfactant skin irritation data.Mixing surfactants
oftenleadsto growth in
micelie size (30,31). When the mixed miceliescannotpenetrateinto the skin, then
the surfactantpenetrationmechanismreducesto the monomerpenetrationmodel. In
that case,sincethe CMC is comparableto the surfactantmonomerconcentration,there
 PENETRATION OF MIXED MICELLES INTO THE EPIDERMIS 157

is a direct correlation between the CMC and the observedskin irritation. However,
preventingthe micellarSDS,or for that matteranymiceliarsurfactant, frompenetrating
into the skin hasa pronounced effecton skin irritation, because
it shouldeliminatethe
dose-dependent behavior commonly observed for pure surfactant systems
(2,3,8,13,16,18). Once the miceliesare preventedfrom penetratinginto the skin, the
only other mechanismto reduceC•i, involvesa reductionin the surfactanttoohomer
concentration.

ACKNOWLEDGMENTS

We thank Hua Tang for numeroususefuldiscussions about the preparationof skin

samplesand other experimentaldetails,as well as on hindered-transporttheories.We
alsothankAllisonFielderfor her assistance
in developingthe surfactantskinpenetration
technique.We are grateful to Unilever Home and PersonalCare NA for financial
supportfor this work. PeterMoorethanksthe Natural Sciences and EngineeringRe-
searchCouncilof Canadafor the awardof a PGS-B scholarship.

REFERENCES

(1) W. Abraham,"Surfactant Effectson Skin Barrier,"in Surfactantsin Cosmetk•,M. M. RiegerandL. D.

Rhein, Eds.(MarcelDekker, New York, 1997), pp. 437-487.
(2) K. I. Cumming and A.J. Winfield, In vitroevaluationof a seriesof sodiumcarboxylates as dermal
penetrationenhancers, Int.J. Pharm.,108, 141-148 (1994).
(3) J. A. Faucherand E. D. Goddard,Interactionof keratinoussubstrates with sodiumlauryl sulfateII.
Permeationthrough stratumcorneum,J. Soc.Cosmet. Ch•z., 29, 339-352 (1978).
(4) C.L. Froebe,F.A. Simion,L.D. Rhein, R.H. Cagan,and A. Kligman, Stratumcorneumlipid
removalby surfactants: Relationto in vivoirritation, Dermatologica,181, 277-283 (1990).
(5) S. E. Friberg,L. Goldsmith,H. Suhaimi,and L. D. Rhein, Surfactants and stratumcorneumlipids,
Colloids Surf, 30, 1-12 (1988).
(6) T.J. Hall-Manning, G. H. Holland, G. Rennie,P. Revell,J. Hines, M.D. Barratt, and D. A. Bas-
ketter, Skin irritation potentialof mixed surfactantsystems,Fd. Chem.Toxic.,36, 233-238 (1998).
(7) I. Hama, H. Sasamoto, T. Tamura,T. Nakamura,and K. Miura, Skin compatibilityand ecotoxicity
of ethoxylatedfatty methyl esternonionics, J. Surf Det., 1, 93-97 (1998).
(8) C. H. Lee and H. I. Maibach,Studyof cumulativeirritant contactdermatitisin man utilizing open
applicationon subclinically irritatedskin, ContactDermatitis,30, 271-275 (1994).
(9) K. D. Peck,J. Hsu, S. K. Li, A.-H. Ghanem,and W. I. Higuchi, Flux enhancement effectsof ionic
surfactantsupon passiveand electroosmotic transdermaltransport,J. Pharm.Sci., 87, 1161-1169
(1998).
(lO) L.D. Rhein, C. R. Robbins,K. Fernee,and R. Cantore,Surfactantstructureeffectson swellingof
isolatedhuman stratumcorneum,J. Soc.Cosmet.
Chem.,37, 125-139 (1986).
(11) K.-P. Wilhelm, G. Freitag,andH. H. Wolff, Surfactant-induced
skinirritationandskinrepair,J.Am.
Acad. Dermatol.,30, 944-949 (1994).
(12) H. Tang, S. Mitragotri, D. Blankschtein,and R. Langer,Theoreticaldescriptionof transdermal
transportof hydrophilicpermeants:Applicationto low-frequencysonophoresis,
J. Pharm.Sci., 90,
545-568 (2001).
(13) T. AgnerandJ. Serup,Sodiumlauryl sulphatefor irritant patchtesting•A dose-response
studyusing
bioengineering
methodsfor determination
of skinirritation,J. Invest.Dermatol.,
95, 543-547 (1990).
(14) J. Vilaplana,J. M. Mascaro,C. Trullas,J. Coll, C. Romaguera,C. Zemba, and C. Pelejero,Human
irritant responseto different qualitiesand concentrations
of cocoamidopropylbetaines:A possible
modelof paradoxical
irritant response,
Contact
Dermatitis,26, 289-294 (1992).
(15) K.-P. Wilhelm, M. Samblebe,
andC.-P. Siegers,Quantitativein vitroassessment
of N-alkyl sulphate-
158 JOURNAL OF COSMETIC SCIENCE

inducedcytotoxicityin humankeratinocytes
(HaCaT): Comparisonwith in vivohumanirritation tests,
Br. J. DermatoL,130, 18-23 (1994).
(16) K.-P. Wilhelm, A. B. Cua, H. H. Wolff, and H. I. Maibach, Surfactant-inducedstratum corneum
hydrationin vivo:Predictionof the irritationpotentialof anionicsurfactants,J.Invest.Dermatol.,101,
310-315 (1993).
(17) C. Szolar-Platzer,
S. Patil, and H.I. Maibach,Effectof topicallaurocapram
(Azone
©) on the in vitro
percutaneouspermeation of sodiumlaurylsulfateusinghumanskin,ActaDerre.VenereoL,
76, 182-185
(1996).
(18) M. Loden,The simultaneous penetrationof water and sodiumlauryl sulfatethrough isolatedhuman
skin,J. Soc.Cosmet. Chem.,41, 227-233 (1990).
(19) A.D.1. Maza, L. Coderch,O. Lopez,J. Baucells,and J.L. Parra, Permeabilitychangescausedby
surfactants in liposomes that modelthe stratumcorneumlipid composition,JOACS, 74, 1-8 (1997).
(20) J. L. Zatz andB. Lee,"SkinPenetrationEnhancement by Surfactants,"
in S•rfactants
in Cosmetics,M. M.
Riegerand L. D. Rhein, Eds.(MarcelDekker, New York, 1997), pp. 501-517.
(21) G. Imokawa,K. Sumura,and M. Katsumi, Studyon skin roughness causedby surfactants. II. Cor-
relationbetweenproteindenaturationand skin roughness, JOACS, 52, 484-489 (1975).
(22) P. Thau, "Surfactants for Skin Cleansers,"in Surfactants
in Cosmetics,
M. M. Rieger and L. D. Rhein,
Eds.(MarcelDekker, New York, 1997), pp. 285-306.
(23) A.D.1. Maza,J. Baucells,P. Gonzalez,andJ. L. Parra,Sublyriceffectscausedby C•4-alkylbetaine/
sodiumdodecylsulfatemixtures in liposomesmodeling the stratum cometunlipid composition,
Colloids Surf A, 133, 253-260 (1998).
(24) L. D. Rhein, F. A. Simion,R. L. Hill, R. H. Cagan,J. Mattai, and H. I. Maibach,Human cutaneous
response to a mixed surfactantsystem:Role of solutionphenomenonin controllingsurfactantirrita-
tion, Dermatologica, 180, 18-23 (1990).
(25) K. P. Ananthapadmanabhan, C.L. Meyers,and M.P. Aronson,Binding of surfactants to stratum
corneum,J. Soc.Cosmet. Chem.,47, 185-200 (1996).
(26) L. Rigano,T. Cavalletti,S. Benetti, and S. Traniello,Evaluationof predictableirritativepowerof
surfactantmixturesby humanfibroblastcultureand its correlationto physico-chemical parameters,
Int. J. Cosmet. Sci.,17, 27-43 (1995).
(27) M.J. Rosen,Surfactants and InterfacialPhenomena,2nd ed. (JohnWiley & Sons,New York, 1989).
(28) P. Moore, S. Puvvada,and D. Blankschtein,Challengingthe surfactantmonomerskin penetration
model:Penetrationof sodiumdodecylsulfatemiceliesinto the epidermis, J. Cosmet.Sd., 54, 29-46
(2003).
(29) J. A. Faucherand E. D. Goddard,Interactionof keratinoussubstrates
with sodiumlauryl sulfate.I.
Sorption,J. Soc.Cosmet.
Chem.,29, 323-337 (1978).
(30) A. Shiloach
andD. Blankschtein,
Predictingmiceliarsolutionpropertiesof binarysurfactant
mixtures,
Langmuir,14, 1618-1636 (1998).
(31) A. Shiloachand D. Blankschtein,Measurement
and predictionof ionic/nonionicmixed micellefor-
mationand growth,Langmuir,14, 7166-7182 (1998).
(32) A. Rohdeand E. Sackman,Quasieleaticlight-scatteringstudiesof miceIlar sodiumdodecylsulfate
solutionsat the low concentration
limit, J. Colloid.Interface
Sci.,70, 494-505 (1979).
(33) P.J. Missel,N. A. Mazer, G. B. Benedek,and M. C. Carey,Influenceof chainlength of the sphere-
to-rodtransitionin alkyl sulfatemicelles,
J. Phys.Chem.,87, 1264-1277 (1983).
(34) P. L. Dubin, J. H. Grubher,J. Xia, and H. Zhang, The effectof cationson the interactionbetween
dodecylsulfate
micellesandpoly(ethyleneoxide),J.
Colloid.Interface
Sci.,148, 35-41 (1992).
(_35) L. Magid, "Light Scatteringin MiceIlar Systems,"
in DynamicLight Scattering:
TheMethodand Some
Appli•tionJ,W. Brown,Ed. (Oxford UniversityPress,Oxford, 1993), pp. 554-593.
(36) A. Einstein,InveJtigation
ontheTheoryof Brownian
Movement
(Dover,New York, 1956), p. 58.
(37) W. Brown,J. Fundin, and M. G. Miguel, Poly(ethylene
oxide)-sodiumdodecylsulfateinteractions
studiedusingstaticand dynamiclight scattering,MacromolecMes,
25, 7192-7198 (1992).
(38) A.d. Nardo,K. Sugino,P. Wertz, J. Ademola,andH. I. Maibach,Sodiumlaurylsulfate(SLS)induced
irritant contactdermatitis:A correlationstudybetweenceramidesandin vivoparameters of irritation,
ContactDermatitis,35, 86-91 (1996).
(39) H. Korting, T. Herzinger, A. Hartinger, and M. Kerscher,Discriminationof the irritancypotential
of surfactantsin vitroby two cytotoxicityassays
usingnormalhuman keratinocytes,HaCaT cellsand
3T3 mousefibroblast:Correlationwith in vivodata from a soapchamberassay, J. Dermatol.Sci., 7,
119-129 (1994).
 PENETRATION OF MIXED MICELLES INTO THE EPIDERMIS 159

(40) A.d. 1. Maza and J. L. Parra, Subsolubilizing effectsof alkyl sulfateson liposomesmodelingthe
stratum.corneumlipid composition, Langmuir,12, 6218-6223 (1996).
(41) P. v. d. Valk, J. Nater, and E. Bleumink,Skin irritancyof surfactants asassessedby watervaporloss
measurements,J. Invest.Dermato/.,82, 291-293 (1984).
(42) J. R. Welty, C. E. Wicks, andR. E. Wilson, Fundamentals ofMomentum, Heat,andMassTransfer,3rd
ed. (JohnWiley & Sons,New York, 1984).
(43) K. D. Peck,V. Srinivasan, S. K. Li, W. I. HiguchiandA.-H. Ghanem,Quantitativedescription of the
effectof molecularsize upon electroosmotic flux enhancement during iontophoresisfor a synthetic
membraneand human epidermalmembrane,J. Pharm.Sci., 85,781-788 (1996).
(44) P. M. Lai andM. S. Roberts,An analysis of solutestructure-human epidermaltransportrelationships
in epidermaliontophoresis usingthe ionic mobility: Pore model,J. Controlled Release,58, 323-333
(1998).
(45) S. K. Li, W. Suh,H. H. Parikh,A.-H. Ghanem,S.C. Mehta,K. D. Peck,andW. I. Higuchi,Lagtime
datafor characterizing the porepathwayof intactand chemicallypretreatedhumanepidermalmem-
brane,Int. J. Pharm.,170, 93-108 (1998).
(46) D. F. EvansandH. Wennerstrom,TheColloidalDomainWherePhysics, Chemistry, Biology
andTechnology
Meet.Advances in InterfacialEngineeringSeries,E. CohenandE. Gutoff, Eds.(VCH Publishers,New
York, 1994).
(47) W. M. Deen, Hinderedtransportof largemoleculesin liquid-filled pores,AIChEJ., 11, 1306-1314
(1987).