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Skin penetration
C.
W.
BARRETT*
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
488
REACTIONS
DUE TO PENETRATION
OF THE SKIN
corneum.
penicillins,
theantihistamines,
localanaesthetics,
andthehydroxybenzoic
acid esters.
SKIN PENETRATION
489
lotion
of eczematous
dermatosis.
The
fluoro-
effects.
4,6)0
PENETRATION
Pretreatment
of the skin.
The vehicle.
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
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.
found bacteria below the skin after dipping rodents' tails in concentrated
bacterial
culture.
of the vehicle.
Figure 1
()cclusive technique for topical corticosteroid preparations.
Figure 2
A.
T.H.F.A.
B.
C.
D.
E.
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
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
494'
1.8
1.5
1.3
1.0
0.5
1-3
1-2
1-2
0-2
0-1
0
0
vehicle
Range
1.9
1.8
1.4
1.2
0.7
0
0
vehicle
Table
1-3
1-3
1-2
0-2
0-2
_
II
Mean
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
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 $
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.
496
1.2
c
o
.o, 0.8
.4.-,, b
i::::)..u
o4
10
15
20
25
"[H.F.A.(':'/o)
Figure 4
METHODS OF DETERMINING
PENETRATION
SKIN PENETRATION
497
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.
(Received:9th September
168)
REFERENCES
498
(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
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
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