THE JOURNAL or lNVESTlGATlVl-I DERMATOLOGY. 67:672—676. 1976
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`Copyright ©1976 by The Williams & Wilkins Co.
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`Vol. 67. No. 5. Part 2 of? parts
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`Printed in l ".S,A
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`PERMEABILITY OF THE SKIN: A REVIEW OF MAJOR CONCEPTS
`AND SOME NEW DEVELOPMENTS
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`ROBERT J. Scuaupuam. PH.D.
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`Department of Dermatology. Harvard Medical School. Boston. Massachusetts, U. S. A.
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`appeared more compact. Rein [1] had theorized
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`this region was the site of a permanent
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`electrical double layer.
`impermeable to anions.
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`This layer.
`identified by some as the stratum
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`lucidum. became the site of the skin's major
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`diffusional
`the minds of most
`resistance
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`authoritative investigators. This mistaken concep-
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`tion persists to this day in some textbooks.
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`although we now know it is not true.
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`The stratum corneum is now widely acknowl<
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`edged to be essentially uniformly impermeable.
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`The best direct evidence comes from studies that
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`reveal the location of substances within the stra—
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`tum corneum some time after application. These
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`studies show that the outer layers.
`in fact. greatly
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`impede penetration and are not significantly dif-
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`ferent from the inner layers. Careful morphologic
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`studies using less destructive techniques give no
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`reason to doubt
`this conclusion. This change in
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`our conception of the stratum corneum from a M»
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`able. porous tissue to a coherent. compact mem-
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`brane has accompanied the increasing sophistica-
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`tion and fidelity of our techniques of visualization
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`using electron microscopy and scanning electron
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`microscopy (Figs. 1. 2i.
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`BIOPHYSICS 0F TRANSPORT
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`Penetration experiments on hundreds of sub-
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`stances have demonstrated that the stratum cor<
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`neum behaves like a passive diffusion barrier [2].
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`Differences between “live" and “dead" skin have
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`been observed but
`these cannot be ascribed to
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`active transport processes.
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`Data on the penetration of water and loW»
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`molecular—weight nonelectrolytes have given clear
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`evidence that permeability through epidermis
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`(stratum corneum included)
`is proportional
`to
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`concentration [3]. Tissuewehicle partition coeffi-
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`cients were obtained and these correlated well with
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`measured permeabilities and explained the ob-
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`served increase in permeability in ascending hov
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`mologous series of nonelectrolytes
`[4]. Further
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`work led to an expanded form of Fick’s law for
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`steady~state transport through skin:
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`J = (BK/5) AC.
`#2,, AC.
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`:
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`(ll
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`Before any topically applied drug can act either
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`locally or systemically.
`it must penetrate the
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`“barrier layer" of the skin. the stratum corneum.
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`The penetration of the stratum corneum is the
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`necessary first step. not only for the therapeutic
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`action of applied drugs. but also for any injury
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`produced by externally applied chemical agents or
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`antigenic substances. Since literally thousands of
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`different substances produce delayed hypersensi-
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`is
`tivity reactions in apparently normal skin,
`it
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`evident that the protective permeability barrier of
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`the skin is not perfect.
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`What is the nature of the barrier layer? How do
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`molecules get through it? Is the stratum corneum
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`uniformly impermeable or is one part more perme-
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`able than another? How fast does penetration
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`occur: and how is this affected by the chemical
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`nature of the penetrating molecules? Can the
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`permeation rates of substances be modified by
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`using different vehicles or by hydration? What
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`concentration levels are produced in the viable
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`layers of the skin by the topical application of a
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`drug? Is the blood perfusion rate a controlling
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`in percutaneous absorption? Answers to
`factor
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`these and related questions are of obvious impor-
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`tance to dermatologic practice. to the formulating
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`of topical preparations. and to skin physiology in
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`general. These issues have been the major concern
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`of investigators of skin permeability.
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`STRL'CTI‘RE OF THE STRATUM (‘ORNEl'M
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`Through most of
`the
`19505. attention was
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`focused on the question of the precise location of
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`the barrier layer within the stratum corneum. To
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`the skin biologists of that era. the stratum corneum
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`appeared to be a highly porous tissue composed of
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`a coarse network of loosely connected cells: clearly
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`not. so it seemed. a plausible candidate for the
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`major permeability barrier of the skin. A variety of
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`skin conditions involving chapped. dried. or des-
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`quamating horny layers and the appearance of the
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`tissue in histologic cross sections (Fig. 1. topi lent
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`support to this View. The damage inflicted on the
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`stratum corneum by the usual histologic tech-
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`niques was not fully appreciated until relatively
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`recently. Attention was drawn to the junction of
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`the viable epidermis and the stratum corneum.
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`where there exists
`a transitional zone which
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`Reprint requests to: Dr. R. J. Scheuplein. Department
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`of Dermatology. Massachusetts General Hospital. Fruit
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`Street, Boston. Massachusetts 02114.
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`where:
`J
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`D
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`= solute flux;
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`= solute diffusion constant in the stratum
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`corneum:
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`: solute partition coefficient;
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`- thickness of stratum corneum;
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`K
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`6
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`672 L'OREAL USA, INC. EX. 1016
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`L'OREAL USA, INC. EX. 1016
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`

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`Nov. I976
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`PEHMEAEILITY OF THE SKIN
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`673
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`apportioned [5], Dermal resistance was found to be
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`negligible except possibly in the case of extremely
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`lipid-soluble highly diffusable penetrants (Fig. 3i.
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`The diffusion constants for low-molecular»weight
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`nonelectrolytes are approximately 10’“ - cm2 '
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`sec'1 and 6 >< 10"a ' cm2 -
`sec ' for stratum
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`corneum and dermis, respectively.
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`(‘HEMM'AL NATURE OF THE PENETRANT
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`It became clear that hydrated stratum corneum
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`had an affinity for both water-soluble and lipid-
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`soluble nonelectrolytes. As a result. the stratum
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`corneum. while not very permeable to any sub-
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`stance.
`is slightly permeable to both water-soluble
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`and lipid-soluble substances. Both the mechanism
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`of diffusion and the diffusion pathway through the
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`tissue taken by penetrating molecules appears to
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`depend upon whether they are water-soluble or
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`water~insoluble.
`lipid-soluble molecules. Activa—
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`tion energies for
`the permeation of water and
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`water-soluble alkanols were found to be : 15 kcal.
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`male '1 the activation energies for the correspond-
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`ing lipid-soluble alkanols are : 10 kcal rmol' ‘. In-
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`creasing the polar character of the penetrant mole-
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`cule by increasing the number of polar groups re»
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`sulted in higher activation energies and still lower
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`permeabilities (Fig. 4). From these and other data
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`it was determined that
`the major pathway for
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`water—soluble molecules was primarily transcellu-
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`i.e.. through cells and cell walls alike without
`lar.
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`discrimination. The lipid—protein-water keratin
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`structure within the cells l'Fig. 5| was pinpointed
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`2 o
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`1 5 t
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`EPIDERMIS
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`FIG. 1, Top: Stained cross section of human skin.
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`Stratum t'orneum has porous appearance typical of
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`histologic preparations I
`- 57). Bottom: Electron photo-
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`micrograph of uppermost
`layer of epidermis. Stratum
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`comeum appears more compact than above. but spaces
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`are evident between cells;
`these are not present
`in
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`well-prepared specimens l
`> 2.200..
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`AC,
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`:
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`‘2. Scanning electron photomicrograph of upper»
`FIG.
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`most layer of stratum corneum. The overlap and close
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`packing of adjacent cells is evident t); 540).
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`external concentration difference of sol-
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`ute in the vehicle on opposite sides of
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`the tissue.
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`This relation succinctly summarized hundreds of
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`observations and became the fundamental basis of
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`more sophisticated studiea By measuring the
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`permeability constants for the same substances
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`through stratum corneum. epidermis. and dermis
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`separately. the different diffusional resistances (R
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`: l/kp) of these layers of the skin were accurately
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`s '
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`s‘u
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`E
`'7‘
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`E
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`«-
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`u:\u-
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`10 l—
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`.
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`05 —
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`DERMlS
`Oo-v-vrv'yuy-t-
`O
`2
`4
`6
`CARBON NUMBER {W
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`FIG. 3, Relative effectiveness of epidermis [including
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`the stratum corneuml and dermis as barriers to penetra—
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`tion of the alkanols. For percutaneous absorption in vivo
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`only 100—200 ,u of
`the dermis is involved. and the
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`diffusional resistance of this thinner layer is far less than
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`that shown for the entire dermis.
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`8
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`1O
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`

`

`CH,
`
`cu,
`
`
`(£20
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`
`
`PEHMEABlLITV
`comsrnm
`
`(kpcmhr'HlO'H
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`
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`1500
`
`
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`600
`
`
`E”!c=o
`
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`won
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`|
`cuzon
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`450
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`Vol. 67, No.5, Part2 of2parts
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`VEHlCLES [Till
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`Most liquids can damage or alter the stratum
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`corneum; organic solvents and particularly mix
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`tures of organic solvents. e.g.. chloroform:meth
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`anol, ethanolzether. are efficient delipidizing sol
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`vents and rapidly damage the barrier. Vehicle:
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`are normally chosen from mild or innocous liquids
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`and the influence of the vehicle on the release and
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`penetration of the solute is still not completeh
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`understood. Some progress has been made, how»
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`ever, and in contrast to past doctrine it is now clear
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`that vehicles can affect solute permeation even it
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`the stratum corneum per se is not affected A>
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`shown by equation (ll the flux depends on tht
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`product of external concentration iifACc = CH and
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`the partition coefficient K = (Cm/Cu) where C. is
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`the solute concentration in the tissue). As the
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`vehicle is changed so that the solute becomes less
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`soluble in it. C... and K increase and so does
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`permeability. For example.
`the polar alkanols
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`674
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`scuauruzm
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`PROGESTERONE
`
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`CN,
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`04
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`HYOHOXY-
`PROGESTERONE
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`0//
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`CORTEXONE
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`CORTEXOLONE
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`75
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`FIG. 4. Decrease in the permeability constant of ste-
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`roid molecules as more hydroxyl groups are introduced
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`l4 ].
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`as the site of the tissues“ major diffusional resist~
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`ance for water-soluble molecules. A great deal of
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`evidence supports the hypothesis that
`the water
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`within this structure is “bound" in the sense that
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`the diffusion of this water and the solutes dis-
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`solved within it occurs very slowly.
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`The pathway for lipid—soluble molecules is not
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`known; it presumably follows the endogenous lipid
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`within the stratum corneum. Present evidence
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`suggests that the bulk of these lipids are intercel‘
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`lular. But earlier work suggested that lipids were
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`also located between the keratin filaments within
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`the cells [6].
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`SKIN APPENDAGES 1:3",
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`Sweat ducts and hair follicles can act as diffu-
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`sion shunts. i.e., relatively easy pathways through
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`the stratum corneum. For the most part. the effect
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`of these appendageal shunts is minimized owing to
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`their relatively small
`total fractional area~1()'3
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`(on abdominal skin). But for ions, polyfunctional
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`polar compounds, e.g.. cortisol, and extremely
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`large molecules that can penetrate the bulk stra»
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`tum corneum only very slowly. diffusion through
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`shunt pathways can be very significant and must
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`be taken into account. Since the lag times for a
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`shunt pathway can be quite small.
`this route of
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`entry is the likely one when a chemically complex
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`drug is observed to produce a pharmacologic re-
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`sponse within a few minutes after application to
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`the skin. Transport through shunts has been ob-
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`served in vitro for ions and in vivo for charged dyes
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`[5].
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`the filament
`FIG. 5. Top: Schematic drawing of
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`matrix ultrastructure of epidermal keratin. Bartom'
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`Electron photomicrograph of stained epidermal keratin
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`Lipid-rich regions are stained dark and appear betweei
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`the keratin filaments (:- 65.000). I'F‘rom Brody [6])
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`

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`Nou.1976
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`STRATUM
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`CORNEUM
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`l
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`C0
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`C1
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`C5—-—-0
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`EPIDERMIS
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`DERMIS
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`K. szczfx=x2
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`0—S‘__W—,—Sz
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`.fi
`a a“ -
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`dx (DdX/l —O— 01 Steady State
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`J:
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`Cs
`a .2 +1.
`[K
`‘ 2
`k
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`=k C
`"
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`5
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`5
`l
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`1E =§R. ‘Rsc + RExDid + Rpm
`=107
`+ 4 xio3+ 3~3o xtOslsec cm“:
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`FIG. 6. Steady-state concentration levels in the skin.
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`Boxed equation shows the limiting form ol'the permeabil»
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`ity constant to be an additive function of three separate
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`diffusional resistances.
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`I), (stratum corneuml
`: 6 .x 10’9-cm1-sec'
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`D, (viable epidermis) : 5 A
`lt)"‘cm’~sec
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`K = 10
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`)\ = 6 - 10' "cm-sec"
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`PERMEAZBILITY OF THE SKIN
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`675
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`action in the skin. It is not usually appreciated that
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`not only penetration must occur, but adequate
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`penetration must occur to give effective concentra-
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`tion levels at the site or sites desired. At
`the
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`present time it is not feasible to measure experi-
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`mentally the time-dependent concentration levels
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`in the skin after a substance is applied topically.
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`However,
`this kind of
`information is now wail
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`within our capacity to calculate using a realistic
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`model for the skin. The skin can be considered to
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`be a composite diffusion media corresponding to
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`stratum corneum. epidermis. and a thin layer of
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`dermis. each with its corresponding diffusion con-
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`thickness. and partition coefficient. This
`stant.
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`overlays a reservoir (the blood stream] which offers
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`a diffusional resistance inversely proportional to
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`blood flow and which is saturable by the solute.
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`The problem is mathematically complex and
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`has to be solved by approximate methods. Some
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`initial results are given in Figures 6 and 7 which are
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`steady-state and time-dependent concentration
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`levels. respectively. The expression for the flux in
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`Figure 6 shows that the rate of blood perfusion can
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`be treated as an additive resistance after steady
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`state is achieved. The numerical values suggest
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`that it
`is negligible even under basal conditions.
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`Because the diffusivity of the viable epidermis and
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`dermis is so much greater than the stratum cor-
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`the concentration levels in the epidermis
`neum.
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`for all practical purposes. always flat. Both
`are.
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`Figures illustrate the role of the partition coeffi‘
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`in markedly lowering the concentration of
`cient
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`lipid—soluble nonelectrolytes in the viable tissue as
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`compared to their concentrations in the stratum
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`corneum.
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`,-),7, EPmERms
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`éTRAiUM‘CORMEUM _,
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`x =5x ID‘“ sec"
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`D. = E- : 10's sz set:-1 m]
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`‘
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`.‘
`
`\_
`"
`i
`6 ,t e.
`t
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`i
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`i
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`'.
`i
`i
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`.
`tr
`l\
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`\
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`‘t
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`\s
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`‘
`x
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`.
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`B ‘3
`Q
`11
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`04
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`02
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`_
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`penetrate better from organic vehicles than they do
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`from water.
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`It has been suggested that for saturated solu-
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`tions. C... should. ideally. be constant and that the
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`penetration of a solute from its saturated solution
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`should be maximal and independent of the vehicle
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`used. Behavior of this type has been observed in
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`isolated instances but it
`is by no means generally
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`true [8]. Apparently, most vehicles are absorbed to
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`some extent by the stratum corneum and produce
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`direct effects on it. These lead to changes in the
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`solubility and diffusivity of substances in the
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`tissue and. accordingly. in their permeation rates.
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`Water and aprotic solvents like dimethylsulfoxide
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`are capable of increasing permeation rates mark-
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`edly. Neither vehicle acts as a “carrier" nor is the
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`increased permeation due simply to a more favora-
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`ble partition coefficient for the particular solute or
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`to irreversible tissue damage [9].
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`CONCENTRATION LEVELS IN THE SKTX
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`It was emphasized that drugs must penetrate the
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`stratum corneum in order to have a pharmacologic
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`Ho
`x
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`'i‘
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`\
`
`z
`
`82
`8‘
`92: — + — =7‘36mm
`«0—,
`to:
`
`“1\
`
`' we
`‘ mm
`
`‘~J:—i
`«R
`‘3’
`
`‘n
`
`t
`\T=to"
`\
`I“
`
`\
`
`\q
`
`‘R
`
`
`
`L.
`v—————
`t
`Nan”,
`~\\T=IO’2
`1:5
`
`,
`1mg,”
`ozaeaiom'mists
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`
`DISTANCE x r0"
`
`
`Fm. T. Time—dependent concentration levels in the
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`skin. Time in minutes 2 g’ T. At approximately 40 min
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`the concentration in the viable epidermis (solid line
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`beyond 10 u) is approximately 0.09 C...
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`

`

`
`676
`
`SCHEUPLEIN
`
`
`
`Vol. 67. N0. 5, Part 2 0f2parrs
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`6. BI:0dy If J Ultrastruct Res 4:267, 1960
`REFERENCES
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`
`
`V
`T. H1guchl T: J Soc Cosmet Chem 11:85“196.0
`l. Rein H: Z Biol 812125, 1924
`
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`2‘ Tregear RT: In Monographs in Theoretical and Exper— 8. Fouls-en B]: In advances 1n Blology 01 Skin. v01 XII
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`
`imental Biology. vol 5. New York. Academic. 1966
`Edited by W Mantegna‘ R Stoughton. EJ .va'
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`3. Scheuplein RJ. Blank IH: J Invest Dermatol 60:17:86,
`3%)“ New ‘Ork' Appleton—Century—Cr0fts. 19'2"
`
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`
`
`1973
`,
`‘
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`4. Scheuplein RJ, Blank 1H: Physiol Rev 51:702. 1971
`9‘ Elgfiagm SG‘ Laden 1‘: J 5“ Cosmet Chem 1928‘”
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`5. Scheuplein RJ: J Invest Dermatol 48:79. 1967
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