THE JOURNAL OF INVESTIGATIVE DERMATOLOGY, 67:672-676, 1976
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`Copyright © 1976 by The Williams & Wilkins Co.
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`Vol. 67, No. 4, Part 2 of 2 parts
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`Printed in U.S.A
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`PERMEABILITY OF THE SKIN: A REVIEW OF MAJOR CONCEPTS
`AND SOME NEW DEVELOPMENTS
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`Department of Dermatology, Harvard Medical School, Boston, Massachusetts, U. S. A.
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`ROBERT J.
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`SCHEUPLEIN, PH.D.
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`J = (DK/5) AC,
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`= k, AC,
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`qd)
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`Before anytopically applied drug can act either
`appeared more compact. Rein [1] had theorized
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`locally or systemically,
`it must penetrate the
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`this region was the site of a permanent
`that
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`“barrier layer’ of the skin, the stratum corneum.
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`electrical double layer,
`impermeable to anions.
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`The penetration of the stratum corneum is the
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`This layer,
`identified by some as the stratum
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`necessary first step, not only for the therapeutic
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`lucidum, became the site of the skin’s major
`diffusional
`resistance
`the minds of most
`in
`action of applied drugs, but also for anyinjury
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`produced byexternally applied chemical agents or
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`authoritative investigators. This mistaken concep-
`antigenic substances. Since literally thousands of
`tion persists to this day in some_textbooks,
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`different substances produce delayed hypersensi-
`although we nowknowit is not true.
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`is
`tivity reactions in apparently normal skin, it
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`The stratum corneum is now widely acknowl-
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`evident that the protective permeability barrier of
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`edged to be essentially uniformly impermeable.
`The best direct evidence comes from studies that
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`the skin is not perfect.
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`reveal the location of substances within the stra-
`Whatis the nature of the barrier layer? How do
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`molecules get through it? Is the stratum corneum
`tum corneum some time after application. These
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`uniformly impermeable or is one part more perme-
`studies show that the outer layers,
`in fact, greatly
`able than another? Howfast does penetration
`impede penetration and are not significantly dif-
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`occur; and howis this affected by the chemical
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`ferent from the inner layers. Careful morphologic
`nature of the penetrating molecules? Can the
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`studies using less destructive techniques give no
`permeation rates of substances be modified by
`reason to doubt
`this conclusion. This change in
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`our conception of the stratum corneum fromafri-
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`using different vehicles or by hydration? What
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`concentration levels are produced in the viable
`able, porous tissue to a coherent, compact mem-
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`layers of the skin by the topical application of a
`brane has accompanied the increasing sophistica-
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`tion and fidelity of our techniques of visualization
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`drug? Is the blood perfusion rate a controlling
`using electron microscopy and scanning electron
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`in percutaneous absorption? Answers to
`factor
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`microscopy(Figs. 1, 2).
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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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`BIOPHYSICS OF TRANSPORT
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`of topical preparations, and to skin physiologyin
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`Penetration experiments on hundreds of sub-
`general. These issues have been the major concern
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`stances have demonstrated that the stratum cor-
`of investigators of skin permeability.
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`neum behaves like a passive diffusion barrier [2].
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`STRUCTURE OF THE STRATUM CORNEUM
`Differences between “live” and ‘‘dead” skin have
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`been observed but
`these cannot be ascribed to
`Through most of
`the 1950s, attention was
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`focused on the question of the precise location of
`active transport processes.
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`the barrier layer within the stratum corneum. To
`Data on the penetration of water and low-
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`the skin biologists of that era, the stratum corneum
`molecular-weight nonelectrolytes have given clear
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`appeared to be a highly porous tissue composed of
`evidence that permeability through epidermis
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`a coarse network of loosely connected cells; clearly
`(stratum corneum included)
`is proportional
`to
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`not, so it seemed, a plausible candidate for the
`concentration (3]. Tissue:vehicle partition coeffi-
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`cients were obtained and these correlated well with
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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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`measured permeabilities and explained the ob-
`quamating horny layers and the appearance of the
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`served increase in permeability in ascending ho-
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`tissue in histologic cross sections (Fig. 1, top) lent
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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
`support to this view. The damageinflicted on the
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`steady-state transport through skin:
`stratum corneum by the usual histologic tech-
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`niques was not fully appreciated until relatively
`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
`of Dermatology, Massachusetts General Hospital, Fruit
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`Street, Boston, Massachusetts 02114.
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`*72
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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;
`K
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`= thickness of stratum corneum;
`6
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`L'OREALUSA,INC. EX. 1016
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`L'OREAL USA, INC. EX. 1016
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`PERMEABILITY 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. 3).
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`The diffusion constants for low-molecular-weight
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`nonelectrolytes are approximately 10°° - cm? -
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`sec? and 6 x 10°® - cm? -
`sec”! for stratum
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`corneum and dermis, respectively.
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`CHEMICAL 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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`mole '; the activation energies for the correspond-
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`ing lipid-soluble alkanols are = 10 kcal-mol~*. In-
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`creasing the polar character of the penetrant mole-
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`cule by increasing the numberof 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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`2.0
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`4a
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`EPIDERMIS
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`40F
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`> ®Q =
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`" °~&~
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`structure within the cells (Fig. 5) was pinpointed
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`Osh
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`DERMIS
`(Gere =e =O
`0
`2
`4
`6
`CARBON NUMBER (n/
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`Fic. 3. Relative effectiveness of epidermis (including
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`the stratum corneum) 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 » of
`the dermis is involved, and the
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`diffusional resistance of this thinner layeris far less than
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`that shown for the entire dermis.
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`8
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`410
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`Nov. 1976
`well-prepared specimens (x 2,200).
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`Stratum corneum has porous appearance typical of
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`histologic preparations (= 47). Bottom: Electron photo-
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`micrograph of uppermost
`layer of epidermis, Stratum
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`corneum appears more compact than above, but spaces
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`are evident between cells;
`these are not present
`in
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`Fic. 2. Scanning electron photomicrograph of upper-
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`most layer of stratum corneum. The overlap and close
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`packing of adjacent cells is evident (x 540).
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`AC,
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`=
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`external concentration difference ofsol-
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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 fundamentalbasis of
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`more sophisticated studies. 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 (FR
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`= 1/k,) of these layers of the skin were accurately
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`

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`674—scHEUPLEIN
`Vol. 67, No. 5, Part 2 of 2 parts
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`PERMEABILITY
`CONSTANT
`CHs
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`_ (kp cmhr-' x 10-8)
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`1500
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`PROGESTERONE
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`CHs
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`CHs
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`VEHICLES [7,8]
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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, ethanol:ether, 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 innocousliquids
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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 completely
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`understood. Some progress has been made, how-
`ever, and in contrast to past doctrine it is now clear
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`that vehicles can affect solute permeation evenit
`the stratum corneum per se is not affected. As
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`shown by equation (1) the flux depends on the
`product of external concentration (if AC, = C, and
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`the partition coefficient K = (C,,/C,) where Cm is
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`the solute concentration in the tissue). As the
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`vehicle is changed so that the solute becomesless
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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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`07
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`HYDROXY -
`PROGESTERONE
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`ue
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`CORTEXONE
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`CORTEXOLONE
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`inc=0
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`<:*OH
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`|
`CH2OH
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`450
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`600
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`Fic. 4. Decrease in the permeability constant ofste-
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`roid molecules as more hydroxyl groups are introduced
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`[4].
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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
`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 veryslowly.
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`The pathwayfor lipid-soluble molecules is not
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`known; it presumably follows the endogenouslipid
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`within the stratum corneum. Present evidence
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`suggests that the bulk ofthese lipids are intercel-
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`lular. But earlier work suggested that lipids were
`also located between the keratin filaments within
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`the cells [6].
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`SKIN APPENDAGES[5]
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`Sweat ducts and hairfollicles 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 smal] total fractional area~10~*
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`(on abdominal skin). But for ions, polyfunctional
`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 onlyveryslowly, diffusion through
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`shunt pathways can be verysignificant 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
`entryis the likely one when a chemically complex
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`drug is observed to produce a pharmacologic re-
`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-
`Fic. 5. Top: Schematic drawing of
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`matrix ultrastructure of epidermal keratin. Battam:
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`Electron photomicrograph of stained epidermal keratin
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`Lipid-rich regions are stained dark and appear betwee
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`the keratin filaments {x 65,000). (From Brody [6])
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`|
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`

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`Nov. 1976
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`PERMEABILITY OF THE SKIN
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`675
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`N\
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`Cs———
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`action in the skin. It is not usually appreciated that
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`STRATUM
`not only penetration must occur, but adequate
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`CORNEUM~—EPIDERMIS DERMIS
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`penetration must occurto give effective concentra-
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`tion levels at the site or sites desired. At
`the
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`pO
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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 well
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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 whichis 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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`STRATUMCORNEUM EPIDERMIS
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`rn|K=Xg
`Pa ecm Sp
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`9 [p9) 29298
`se (os) =Q= Ot Steady State
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`J=
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`Cs
`S81,
`D,K
`De
`»
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`=kyC
`PF
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`3
`\
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`kp ER =Reo + Re xpid + Reert
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`+ 4x10°+ 3-30 x 10°(sec cm")
`=107
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`Fic. 6. Steady-state concentration levels in the skin.
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`Boxed equation showsthelimiting form of 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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`D, (stratum corneum) = 6 = 10°°-cm?-sec~!
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`D, (viable epidermis) = 5 x 10 *-cm*-sec™!
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`K = 10
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`N= 6 x 10°-*-em-sec"?
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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 independentof 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 SKIN
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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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`ce
`te
`
`xe
`g— x
`‘
`O6-S NT
`y
`i
`%,
`\
`w
`“SS
`
`‘Dy
`
`‘\Te 10!
`*.
`
`04
`
`02
`
`L
`L
`o
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`,
`\
`\
`
`ok
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`\
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`®
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`4
`\
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`\
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`2
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`d=6x107* sec!
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`D,= 6109 om? sec" :
`
`gx (Sh 28 = 796 min
`D, De
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`Sa,
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`~o8min
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`a\
`\ Oe
`\1107?
`ica ch
`T=5
`
`1 Bg
`12 14
`4
`6&6
`8
`10
`16
`18
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`DISTANCE x 10-7
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`Fic. 7. Time-dependent concentration levels in the
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`skin. Time in minutes = g? T. At approximately 40 min
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`the concentration in the viable epidermis (solid line
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`beyond 10 y) is approximately 0.09 Co.
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`

`

`
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`676—SCHEUPLEIN Vol. 67, No. 5, Part 2 of 2 parts
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`REFERENCES
`1. Rein H: Z Biol 81:12, 1924
`
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`2. Tregear RT: In Monographsin Theoretical and Exper-
`i
`}
`,
`5
`,
`7
`j
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`
`
`Sesaie Sey, Wel &Dow Yor, Satur, 1
`
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`3. Scheuplein RJ, Blank IH: J Invest Dermatol 60:286,
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`
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`1973.
`
`4. Scheuplein RJ, Blank IH: Physiol Rev 51:702, 1971
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`5. Scheuplein RJ: J Invest Dermatol 48:79, 1967
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`foesor)
`
`. Brody I: J Ultrastruct Res 4:267, 1960
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`.
`. Higuchi T: J Soe Cosmet Chem 11:85, 1960
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`°- iiFgWMentone euaoe _ a
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`*
`‘J
`t
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`Scott. New York, Appleton-Century-Crofts, 1979, ;
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`495
`z
`5
`9. Ten SG, Laden K: J Soc Cosmet Chem 19:841,
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