.[. Soc.

CosmeticChemists20 487-499 (1969) _ 1969Societyo[' Cosmetic

Chemists
of GreatBritaht

Skin penetration
C.

W.

BARRETT*

Presentedat the symposiumon "Skin", organised

bytheSocietyof Cosmetic
Chemistsof GreatBritain,
at Eastbourne, Sussex, on 20th November 1968.

Synopsis--The types of adverse reaction, both local and systemic due to penetration of the
skin are summarised, and more recent views on pathways and mechanics of absorption
discussed.Those factors influencing penetration are reviewed with particular reference to the
physico-chemicalproperties of the penerrant, the vehicle, and the penerrant vehicle relationship. The usefulnessof excisedskin in diffusion cells as a method of determining penetration
is described.

INTRODUCTION

Naturally occurringsubstanceshave been applied to the skin since

the beginning of time, for belligerent and religiouspurposesas well as
cosmeticand medicinal. That these substancesmight penetrate through
the skin to produceserioustoxic effectswas not considereduntil the work
of Schwenkenbecher
in 1904 (1). He concludedfrom his experiments that
the skin waspermeableto lipid-solublesubstances
and gases,but practically
impermeableto electrolytesand water.
The rapid developmentof sensitiveanalytical techniquesin the last 50
years has enabledresearchworkersto monitor the passageof substances
into, and through, the skin and learn something of the factors which
either hinder or enhancetheir progress.

Chemicalsare being synthesisedtoday in ever increasingnumbers,for

the dermatologist to treat skin conditions, for the cosmetic chemist to
prepare a wider range of commerciallyavailable preparationsand for an
* The I,ondon Hospital, lx)ndon, E.1.
487

488

JOURNALOF THE SOCIETYOF COSMETICCHEMISTS

enormousvariety of other purposes.In all casesthough they have to be

handled,and there is then a possibilitythat they will comein contactwith
the skin. It is impoitant therefore not just to the dermatologistand cosmetic chemist but to all those handling chemicalsthat the ability of a
chemicalto passinto, or through, the skin and producetoxic symptoms
can be quickly and accuratelyassessed.
ADVERSE

REACTIONS

DUE TO PENETRATION

OF THE SKIN

The toxicity of substancesentering the skin has been reviewed by

Malkinsonand Rothman (2), Suskind(3), and Idson (4). Somesubstances
will passthrough the skin without eliciting an untoward reactionwhilst
otherswill produceskin reactionsby penetratingonly the upper layers of
the stratum

corneum.

Primary irritant reactions are causedby substanceswhich directly

damage or kill epidermal cells. Relatively strong acids and alkalis, and
substanceswhich are readily oxidised or reduced may act as primary
irritants. The severity of the reaction may dependon the concentration
applied, the frequency of reapplication, contact time, and the type of
vehiclein which the substanceis incorporated.Occasionallythe skin may
recover from the effects of a primary irritant and become resistant to
further irritation (5).
Substancesproducing sensitivity reactions must penetrate the skin

sufficientlyto stimulatethe formationof antibodies.This almostcertainly

means that they penetrate through the stratum corneum and into the
Malpighianlayer. Many substances
have beenshownto producesensitivity
reactions;of those which have been used in cosmeticpreparationsthe
p-phenylenediamine
oxidationtype hair dyes,eosintype lipstickcolorants,
the easilyoxidisableaidehydeand ketonecontainingperfumesand lanolin

may be mentionedand of the topically applied drugs, sulphonamides,

penicillins,
theantihistamines,
localanaesthetics,
andthehydroxybenzoic
acid esters.

Many substances,however, produce serious systemic effects after

penetratingthroughthe skin and into the bloodstream.Piquet and Hemmeler (6) reportedthe occurrence
of fatal poisoningfrom the percutaneous
absorptionof tetraethyl lead containedin petrol. Abrams, Hamblin and
Marchand (7) reported 198 casesof poisoningdue to organophosphorus
insecticides
absorbedpartly throughthe skin during the first five yearsof
their usein the U.S.A. The compoundsare relativelyvolatile, possess
good

SKIN PENETRATION

489

lipid solubility and slight water solubility which enablesthem to pass

rapidly through the skin to producecholinergicside effects.
Fitzpatrick, Griswoldand Hicks (8) reportedfive instancesof increased
weight and ankle oedemain patients applying 0.2% fluorohydrocortisone
acetate

lotion

for the treatment

of eczematous

dermatosis.

The

fluoro-

hydrocortisonehad penetrated the skin sufficientlyto produce systemic

mineralocorticoid

effects.

Boric acid, althoughnow deletedfrom officialpharmacopoeial

preparations, has been widely used as a topical antisepticfor many years yet
Meyler (9) describesseveralcasesof fatal poisoningdue to its penetration
throughthe skin. This is a substancewhichdoesnot penetratenormalskin
in significant amounts but will penetrate inflamed or abraded skin to
produceserioussystemictoxic effects.
Occlusion
with plasticfilm is nowwidelyusedto promotethe absorption
into the skin of topicallyappliedanti-inflammatorycorticosteroids.
Plastic
film dressings,however,must be used with care where the drug applied
may producetoxic systemiceffects.Vickersand Fritsch (10) reportedsix
casesof toxic reactionsafter the application of naphazolineto the skin
under polyethylenefilm.
PATHWAYS AND MECHANISMS OF PENETRATION

A substancemay penetratethe skin either transepidermallyor transappendageally.Palmar skinhasbeenshownto be lesspermeablethan other

skin sitesin man, even thoughit containsthree times as many sweatglands
per unit area. It seeInsunlikely, therefore,that the sweatglandsrepresent
a significantpathway of penetration.
In rodents, the number of hair follicles and therefore the relative area

of invaginated epithelium within hair folliclesper unit area of skin is

greater than in man. Yet it has been shown for many substancesthat
penetrationof rodentskin is not correspondingly
higher.Autoradiographic
techniqueshave shownthat substancesdo penetratedown the hair follicles
{11). This suggeststhat penetration of the epithelium within the hair
folliclesis similar to that surroundingthem. Tregear (12) showedthat
tri-n-butyl phosphatepenetratedpig skinequallywell,whetherit contained
hair folliclesor not. As the stratified system constitutesthe major area of
the epidermisin man this is undoubtedlythe major route of penetration.
With the exceptionof sodiumions and water which may be actively
pulled into the skin(13)most substances
are thought to penetratethe skin

4,6)0

JOURNALOF THE SOCIETYOF COSMETICCHEMISTS

by passive diffusion. This conclusionhas been reached becausemost

penerrantsobey Fick's law, excisedskin retains its impermeability for
many days after it has beenremoved(14) and the stratum corneum,which
is composedof metabolically inactive cells, is consideredto be the major
barrier to penetration.
A substancemay crossthe stratum corneumby passingeither through
or betweenthe cells.Although much work has beencarried out to discover
which path is followed (13, 15-17) the questionstill remainsunresolved.
FACTORS INFLUENCING

PENETRATION

The factors influencingpercutaneousabsorptionhave been reviewed

by Shelmire(18), Higuchi (19), Wagner (20), Barr (21) and Tregear (13).
The followingvariablesmay be considered:1. Speciesdifferences.
2. Skin age and site.
3. Skin temperatureand peripheralcirculation.
4. The state of the skin (normal,abraded,or diseased).

5. The areaof application,contacttime andfrequencyof re-application.

t3. The degreeof hydration of the skin.
7.

Pretreatment

of the skin.

8. The physicalcharacteristicsof the penetrant.

9.

The vehicle.

10. The penerrant vehiclerelationship.

It has beenshownthat skin permeabilityvariesbetweenspecies.Thus
rabbit skin is more permeablethan that of the guinea-pig,while human
skin is lesspermeablethan both. This is a factor whichmust be considered
when laboratory animals are used to evaluate the performance of new
compounds.
Cronin and Stoughton(22) and Marzulli (2:3)have shown that sub-

stancespenetratedifferentskin sitesat differentrates. Tregear (13)has

shownthat the permeabilityof rat skin to 5% aqueoustriethyl phosphate
solutiondecreasesquite sharply during the sevendays before birth, and
more slowly after birth, even after the epidermisappearshistologically
mature.

Human skin, which is sparselycoveredwith hair, is subjectto quite

rapid variationsin surfacetemperaturedependingon the environment.It
hasbeenshownthat the penetrationrate of somesubstances
is significantly
altered by this changein temperature.The state of the peripheralcircula-

SKIN PENETRATION

491

tion has little effect on penetration rates but would influencethe length of
time a substancewould act. Thus, the local vasoconstrictionproducedby
corticosteroidswould be expectedto delay their removal from the skin.
Penetration has been shown to be greatly enhanced when skin is
abraded, broken or inflamed. Loefflerand Thomas (24) found that 50%
of Sr89 labelled strontium chloridewas absorbedthrough abradedrat skin
in contrast to 10% absorptionin intact skin sites. Livingood (25) has
shownthat hydrocortisone-4-C14
penetratesseveraltimes faster through
patchesof irritative or atopicdermatitisthan through normal skin.
The area of application, contact time and frequency of reapplication
would be expectedto have a direct effect on the extent of penetration.
McKenzieand Stoughton(26) have shownexperimentallythat penetration of corticosteroids
may be increased100-foldby occludingthe site of

application,and thus hydrating the stratum corneum.Vickers (27) has

demonstrated that occlusionnot only enhancespenetration of corticosteroidsbut createsa depot effect in the stratum corneum. Although
the penetrationof many substances
has beenshownto be enhancedwhen
the stratum corneumishydrated, Brown (28) found that
percutaneous
LD so of parathionwas greaterwhen the skin was occludedthan when it
was left uncovered.

Pretreatment
of theskinwithorganic
solvents
hasvariableeffects
on
permeability.Treatment with ether did not alter the penetrationrate of
salicylates (29) or surfactants (30) whilst the polar solvents,acetone,
alcoholand hexane greatly increasedthe penetrationof water into the
skin (31).
It is generallyconsideredthat the physico-chemical
characteristicsof
a penetrantare the mostimportant factorscontributingto its penetration.
Solubility, molecularsize, particle size, crystalline form, volatility and
polarity may all influencepenetrationrates. Stoughton,Clendenningand
Kruze (32) usinga seriesof nicotinicacidesters,Clendenningand Stoughton
(33) using a seriesof phenylboronicacid compounds,and Treherne (34)
usinga seriesof non-electrolytes
showedthat those compoundsthat penetrated best had a lipid/water partition coefficientclosestto one. However,
someionsin aqueoussolutionhave beenshownto penetrateskin as rapidly
as other aqueoussolutes(34).
There appearsto be somecorrelationbetweenmolecularsizeand penetration rate, small moleculespenetrating faster than large ones,within a
large rangeof molecularsizes.However, Iunin (35) has reportedthe transferenceof colloidalsulphur acrossrabbit skin, and Lizgunova (36) has

49

JOURNAl.

OF THE SOCIETY OF COSMETIC CHEMISTS

found bacteria below the skin after dipping rodents' tails in concentrated
bacterial

culture.

A reduction of the particle size of fluocinolone acetonide has been

shownto enhanceits penetration (37). Where a drug exists in more than
onecrystallineform the onewith the highestthermodynamicactivity would
be expectedto penetratemost rapidly, provided it is stable.
Cronin and Stoughton (38) usingexcisedhuman skin showedthat ethyl
nicotinate penetrates 37,000 times better than nicotinic acid. This was
attributed either to the differencein ether/water partition coefficient
(ethyl nicotinate 0.136, nicotinic acid 9.25) or to the fact that ethyl nicotinate is 10,000 times as volatile as nicotinic acid. Certainly volatility
would be expectedto contribute to penetration provided the substance
penetrates the skin in the vapour state. If a substancepenetrates in
solutionthen volatility vouldonly contributeto the initial build up at the
skin surface.

Schlagel(39) reviewing topical anti-inflammatorysteroidshas shown

that, with the exceptionof hydrocortisoneacetate,the more polar and less
mobile compoundshave the lessertopical potencies.Thus triamcinolone
acetonidehas a topical activity one thousandfoldgreater (40) than the
more polar triamcinolone.
The vehicle may enhancethe penetration of a substanceby making
closecontact with the skin surface,by being misciblewith the skin lipid
film and by providing an occlusiveeffect which would tend to hydrate the
stratum corneum. Hovever, it is the physico-chemicalrelationship of
penetrant to vehicle which is probably more important. The literature on
the influenceof vehicleson skin penetration is confusingand sometimes
contradictory, firstly becausea variety of experimental animals have been
used,secondlybecausemany different methods of estimating skin penetration have been used, and thirdly becauseof a lack of awarenessof

possibledrug vehicleinteractionsand of the functionsof differentvehicles.

The following factors may be consideredin the penetrant vehicle
relationship:1. The solubility of penetrant in the vehicles or a constituent of the
vehicle.

2. The rate of diffusionof penetrantwithin the vehicle.

3. The rate of releaseof penetrant from the vehicle.
4. The possiblereleaseof penetrant in solubilisedform togetherwith a
constituent

of the vehicle.

The directionof flow in a systemis from higherthermodynamicpotential

Figure 1
()cclusive technique for topical corticosteroid preparations.

[acing page 492

Figure 2

Comparisonof the vasoconstrictorresponseto:

Facing page 493

A.

T.H.F.A.

B.
C.
D.
E.

Hydrocortisone0.1 /oin T.H.F.A. cream vehicle.

Betamethasone- 17 - valerate 0.1 o in aqueouscream B.P.
Hydrocortisone 1 o in T.H.F.A. cream vehicle.
Betamethasone- 17 - valerate 0.05 % in aqueouscream B.P.

cream vehicle, unmedicated.

SKIN PENETRATION

493

to lower thermodynamicpotential. It is thus important that the thermodynamic activity of a penetrant in the vehicle is high. Thermodynamic
activity is a product of the concentrationand activity coefficientof the
penetrantin the vehicle.Thusa weaklyacidcompoundbufferedto a weakly
acid pH will have a higheractivity than if it were bufferedat an alkaline
pH, and consequentlyits releasewill be dramatically improved in the
former case.The converseis true of weakly basiccompounds.
Similarly solutesheld firmly by the vehicle, such as the complexing

of phenolicsand polyethyleneglycols(41), are released

slowly.Solutesheld
looselyby the vehicle exhibit high activities and are releasedquickly.
Thus an oil-solubledrug would be releasedrapidly by a polyethyleneglycol
vehicle.Blank (41) has demonstratedthis well in the study of a seriesof
simplealcohols.Thus the water-solubleethanol penetratesbetter from an

oily than from an aqueousvehicle, whereas the oil-solublepentanol

penetratesbetter from an aqueousthan from an oily vehicle.
Using a modification of the occlusivetechnique of McKenzie and
Stoughton(26), Barrett et al (43) investigatedthe effectof formulationon
the penetration of hydrocortisonefree alcohol. Standard test discs of
ointment(37) werepreparedon 16mm squaresof polyethylenefilm which
were then arranged, ointment uppermost,on a strip of cellulosetape
leavinga borderof approx.25 mm of tape aroundeachsquareof film (Fig.
1). The completedressingwasthen appliedto the flexoraspectof the forearm and left in placefor 16 h. The resultantvasoconstriction
was scored
subjectivelyas follows:0 - no vasoconstriction

1 - slight vasoconstriction
2 - obvious vasoconstriction

13- pronouncedvasoconstriction
Whereas no vasoconstrictorresponsecould be demonstrated from
hydrocortisone1% ointmentBP or creamBPC, a significantvasoconstriction was obtained from o/w creamscontaining25% tetrahydrofurfuryl
alcohol(T.H.F.A.) or 25% dimethylacetamide,
and ointmentscontaining

15% T.H.F.A., or 10% dimethylacetamide

(44). (TablesI and II). Both
T.H.F.A. and dimethylacetamideare water-miscibleand solubilisehydrocortisone,and werepresentin the o/w creamsin sufficientamountsto keep
the hydrocortisonein solution.
Fig. showsthe vasoconstrictor
responseto 0.1% and 1% hydrocortisone in T.H.F.A. cream vehicle as compared vith the responseto

0.1% and0.05% betamethasone-17-valerate

in aqueous
creamB.P.

494'

JOURNALOF THE SOCIETYOF COSMETICCHEMISTS

Table

The percutaneous penetration of hydrocortisone from vehicles containing T.H.F.A.

Degree of vasoconstriction
Preparation
Mean

(Ten subjects, two tests)

T.H.F.A. ointment vehicle containing:
1 o hydrocortisone
0.5 o hydrocortisone
0.25 o hydrocortisone
0.1 o hydrocortisone
0.05 o hydrocortisone
Unmedicated

1.8

1.5
1.3
1.0

0.5

1-3
1-2
1-2
0-2
0-1

0
0

vehicle

Hydrocortisone 1 o ointment B.P.

T.H.F.A. cream vehicle containing:
1 o hydrocortisone
0.5 o hydrocortisone
0.25 o hydrocortisone
0.1 o hydrocortisone
0.05 o hydrocortisone
Unmedicated

Range

1.9
1.8
1.4
1.2
0.7
0
0

vehicle

Hydrocortisone 1 cream B.P.

Table

1-3
1-3
1-2
0-2
0-2
_

II

The percutaneous penetration of hydrocortisone from vehicles

containing dimethylacetamide
Degree of vasoconstriction
Preparation

Mean

(Ten subjects, two tests)

Range

Dimethylacetamide ointment
vehicle containing:

1 o hydrocortisone
0.5 o hydrocortisone
0.25 hydrocortisone
0.1 o hydrocortisone
0.05 o hydrocortisone
Unmedicated

vehicle

Dimethylacetamide cream
vehicle containing:
1 o hydrocortisone
0.5 o hydrocortisone
0.25 o hydrocortisone
0.1 o hydrocortisone
0.05 o hydrocortisone
Unmedicated

vehicle

1.6
1.3
0.8
0.4
0

1-2
0-2
0-2
0-1
--

1.9

1.5
1.3
0.7
0.3
0

1-3
0-3
O-3
0-2
0-1
--

SKIN PENETRATION

495

The in vitro penetration of hydrocortisonefrom T.H.F.A. cream vehicle

acrossa cuprophanefilm and into purified water was measured(Fig. 3).
In fact both hydrocortisoneand T.H.F.A. penetratedacrossthe film. The
looo
2 5% IH.EA

E 8OO
,-' 600o

.o2_

20% T,HF.A.

15%

o 400-

10% T,H.EA,

T.H.EA.

-u

5% T.H.F.A.

'T-

0% T.H.F..A.
200-

20

4'0

40

'oo

Tim (hr')
Figure $

The in vitro release of hydrocortisonefrom 1% hydrocortisonecreams containing 0-25 %

T.H.F.A. (Each point is the mean of three readings.)

influenceof T.H.F.A. on the ether/water partition coefficientof hydrocortisonewas also measured (Fig. t). T.H.F.A. lowers the ether water
partition coefficientof hydrocortisone
primarily by increasingthe solubility
of ether in water.

Although it has often been stated that a vehicle cannot 'carry' a

penerrantinto the skin, theseexperimentstend to suggestthat if a vehicle
containsa solventwhich is in itself a penetrant, and which will solubilise
the true penetrant, then it might diffuse from the vehicle and into the
stratum corneumcarryingthe penetrantin solution.Although the existence
of the solubilisedsystemas suchin the skin may be shortlived, the major
barrierto penetrationmight quite possiblyhave beenovercomewithin this
period.

496

JOURNALOF THE SOCIETYOF COSMETICCHEMISTS

1.2

c
o

.o, 0.8
.4.-,, b

i::::)..u

o4

10

15

20

25

"[H.F.A.(':'/o)
Figure 4

The influence of T.H.F.A. on the ether/water partition coefficientof hydrocortisone.

METHODS OF DETERMINING

PENETRATION

Many methodsfor determiningpercutaneouspenetrationhave been

adoptedand thesehave beenreviewedby Blank (45). The disadvantageof
most of them is that they do not give comparablequantitative data.
The useof excisedskin in diffusioncells(14) has now enabledquantitative data to be collected.When usingexcisedskin it is necessaryto assume
that no living processaffects the skin's impermeability, that the dermis
doesnot affect penetration, and that the skin surfaceconditionsaresimilar
to those in life.

Burch and Winsor (4t3) measuring the permeability of water, and

Dirnhuber and Tregear (47) measuriugthe permeability of tri-n-butyl

SKIN PENETRATION

497

phosphatehave shownthe similarity of resultsusing excisedand intact

skin. Bettley and Donoghue(48) have used excisedskin for several days
without noticeablechangein the results.
Where full thicknessskin is usedthe penetrant has to crossthe dermis,
whereasin intact skin it would probably be picked up by the capillary
network at the dermo-epidermaljunction. For aqueoussolutesthe difference would probably be small, whereasfor sparingly water solublepenetrants it may be significant.The useof epidermisalonehasthe disadvantage
that it is fragile and holesappear at the hair follicles.
In practice, however, this technique is relatively simple, will give
rapid and reproducibleresultsand allowsdirect measurementof the amount
of penetrant diffusing,the rate of diffusionand the amount retained by
the skin.
CONCLUSIONS

With the ever increasingproductionof new synthetic chemicalsand

their widespreaduse in our daily lives, the need to ensurethat they are
not harmful to the skin, or by penetrating the skin, is becomingmore
necessary.

Although a considerablevolume of work has been carried out to elucidate skin structure,physiology,barrier propertiesand the mechanismsby
which substancesenter and crossthe skin, there is clearly still much to
learn.

It is necessaryto elucidate, eventually at the molecularlevel, how the

skin keepsmany invading chemicalsat bay. For thosesubstancesthat do
penetrate the skin, those physico-chemicalproperties,or combination of
properties,which enablethem to breachthe skin barrier must be worked
out. With this information it might then be possibleto spot a potential
skin penetrant at an early stage.In particular, informationon the influence
of vehicleson skin penetrationis still sparseand often contradictory.There
is much scopefor developingvehicleswhich will enablethe drug to reach
the site of action rapidly and which will maintain a sufficientconcentration
at the site for the requiredlength of time.

(Received:9th September
168)
REFERENCES

(1) Schwenkenbecher,A. Arch. Anat. _Physiol.121-165. (1904).

(2) Mallkinson, F. D. and Rothman, S. Handbuch der Haut und Geschlechtshranhheiten.
in
J. Jadassohn. (1963). (Springer, Berlin).

498

JOURNALOF THE SOCIETYOF COSMETICCHEMISTS

(3) Suskind, R. R. The evaluationof therapetuicagentsand cosmetics.

in Sternberg.
T. H. and Newcomer, V. D., in (1964). (McGraw-Hill Book Co. N.Y.) 171
(4) Idson, B. J. Pharm. Sci., ?, 1 (1968).
(5) McOsker, D. E. and Beck, L. W. J. Invest. Dermatol., 48, 372 (1967).
(6) Piquet, J. C. and Hemmeier, G. Aertxl. Monatsh. 4, 181. (1948).
(7) Abrams, K. H., Hamblin, D. O. andMarchand,J.F.J. Am. Me&Assoc.,144,107 (1950).
(8) Fitzpatrick, T. B., Griswold, H. C. and Hicks, J. H. J. Am. Med. Assoc.,18, 1149 (1955).
(9) Meyler, L. Side effectsof drugs. Excerpta Medica Foundation. (1966).
(10) Vickers, C. F. H. and Fritsch, W. C. Arch. Dermatol., 87, 633 (1963).
(11) Choman,B. R. J. Soc. CosmeticChemists,11, 127 (1960).
(12) Tregear, R. T. J. Physiol. 10, 303 (1961).

(13) Tregear, R. T. Physicalfunctionsof theskin. (1966). (AcademicPress,Londonand New

York).
Ainsworth, M. J. Soc. CosmeticChemists,11, 69 (1960).
Scheuplin,R. J. J. Invest. Dermatol.,4, 334 (1965).
Scheuplin, R. J. J. Invest. Dermatol., 48, 79 (1967).
Blank, I. H. and Scheuplein,R. J. J. Invest Dermatol.,40, 582 (1967).
Shelmire, A. Arch. Dermatol., 8,, 24 (1960).
Higuchi, I. J. Soc. CosmeticChemists,11, 85 (1960).
Wagner, J. G. J. Pharm. Sci., 0, 359 (1961).
Barr, M. J. Pharm. Sci. 1, 395 (1962).
Cronin, E. and Stoughton, R. B. Brit. J. Dermatol., ?4, 265 (1962).
Marzulli, F. N.J. Invest. Dermatol., 87, 387 (1962).
Loeffier, R. K. and Thomas, V. U.S. Atomic Energy Comm. Rept. AD-225. B. Nucl.
Sci. Abstr. , No. 323 (1951).
(25) Livingood, S.C. Discussionof F. D. Malkinson (1958).
(26) McKenzie, A. W. and Stoughton, R. B. Arch. Dermatol., 80, 608 (1962).
(27) Vickers, C. F. H. Arch. Dermatol.,88, 20 (1963).
(28) Brown, V. K. Structure and Function of Epidermal Barriers. International Symposium,
Brno. (1964).
(29) Wurster, D. E. and Kramer, S. F. J. Pha'm. Sci., 0, 288 (1961).
(30) Blank, I. H. and Gould, E. J. Invest. Dermatol.,87, 311 (1962).
(31) Onken, H. D. and Moyer, C .A. Arch. Dermatol., 87, 584 (1963).
(32) Stoughton, R. B., Clendenning, W. E. and Kruse, D. J. Invest. Dermatol., $5, 337
(1960).
(33) Clendenning,W. E. and Stoughton,R. B. J. Invest. Dermatol.,89, 47 (1962).
(34) Treherne, J.E.J. Physiol., 188, 171 (1956).
(35) Iunin, A. N. Intern. Abstr. Me& Sci., 14, 2331 (1958).
(36) Lizgunova, A. V. Bull. Exp. Biol. Med. U.S.S.R. l{nglish Transl., 47, 28 (1959).
(37) Barrett, C. W., Hadgraft, J. W. and Sarkany, I. Brit. J. Dermatol., 76, 479 (1964).
(38) Cronin, E. and Stoughton, R. B. Arch. Dermatol., 87, 445 (1963).
(39) Schlagel, C. A. J. Pharm. Sci., 54, 335 (1965).
(40) McKenzie, A. W. Arch. Dermatol., 86, 611 (1962).
(41) Guttman, D. and Higuchi, T. J. Pharm. Sci., 45, 659 (1956).
(42) Blank, I. H. j'. Invest. Dermatol., 48, 415 (1964).
(43) Barrett, C. 5V., Hadgraft, J. W., Caron, G. A. and Sarkany, I. Brit. J. Dermatol., 77,
576 (1965).
(44) Sarkany, I., Hadgraft, J. r., Caron, G. A. and Barrett, C. W. Brit. J. Dermatol., 77,
569 (1965).
(45) Blank, I. H. J. Soc. CosmeticChemists,11, 59 (1960).
(46) Burch, G. E. and Winsor, T. Arch. Intern. Med. 74, 437 (1946).
(47) Dirnhuber, P. and Tregear, R. T. J. Physiol., 152, 58 (1960).
(48) Bettley, F. R. a.ndDonoghueNature, 185, 17 (1960).

(14)
(15)
(16)
(17)
(18)
(19)
(20)
(21)
(22)
(23)
(24)

SKIN PENETRATION

499

DISCUSSION

MR. M. J. BUSSE:I think if you plot the resultsin TablesI and JI on the effectof
hydrocortisonein vehiclescontainingT.H.F.A. and dimethylacetamide on the vasoconstriction responseyou will show a very approximate linear relationship between
log concentrationof hydrocortisoneand the vasoconstrictorresponse,and I suspect
that if you had slightly extendedthe concentrationsin the upper and lower range of
hydrocortisone,you would have obtained a Sigmoid-shapedcurve. In _Fig. the
responsesare shown to 0.5% and 0.1% betamethasone-17-valeratein a cream base.
In my laboratory work I have shownthat if you plot log concentrationof tetramethasone valerate in a cream base against the vasoconstrictor response, one gets
the classicalbiologicalresponseSigmoid-shapedcurve and the linear portion of this

Sigmoid-shapedcurve lies between concentrationsof 0.0001% and 0.001% of betamethasone-17-valerate, and the 0.5% and 0.01% concentrations shown in _Fig.
would appear to be supramaximal for vasoconstriction.When I calculated the doses
of betamethasone-17-valerate in cream base required to cause vasoconstriction in

50% of subjects,the actualdosagein ggcorrelatevery closelywith thosefoundoriginally in the work of McKenzie and Atkinson (49).
THE LECTURER: We have tried unsuccessfully to produce a vasoconstriction

using concentrationsof betamethasone-17-valeratelower than 0.05%. I think it is

important to remember the technique that we were using, i.e. applying approx.
7.Smgof medicaments(viz. vehiclewith betamethasone
valerate, not betamethasone17-valerate) to a small area of skin and, therefore, one cannot necessarilycompare
results unlessone has a similar experimental scheme. This is quite a small amount
of vehicle to apply to the skin, but we thought that the thickness applied was fairly
closeto that which would be apphed in a normal condition, and we did not produce
vasoconstrictionat concentrationslower than 0.05%, possiblybecauseof our technique.

MR. M. J. 13USSE:
Usingyour techniquehave you tried concentrationsof betamethasone-17-valeratelower than 0.05% in a cream base?
It would have been very interesting to have seen an attempt to produce vasoconstriction with hydrocortisone in a vehicle without the penerrant solvents in an

attempt to producea similar doseresponsecurve as is shownin TablesI and II,

and thereby attempting to calculate a potency ratio for hydrocortisonein a vehicle
with, and without, solvents.

THE LECTURER:We tried 1% hydrocortisonein the pharmocopaealcream and

ointment bases,and got no responseat all; we were therefore unable to tackle this
problem.

A MEMBEROF TH AUDieNCE: In page 488 you state that some substanceswill

passthroughthe skinwithoutelicitingan untowardreactionwhilstotherswill produce

skin reactionsby penetrating only the upper layers of the stratum corneum. Would

you like to expanda little on this statement;couldyou say what typesof materials
you have in mind?
THE LECTURER:I was concernedhere with the various groupsof irritant response
i.e. those materials that only damage cells in the stratum corneum, not necessarily

producingdamageany further downin the skin, e.g. dilute acidsand alkalis.

{49)McKenzie,A.W. andAtkinson,R. M. Arch.Dermatol.,
89 741(1964).