‘,I
`
`mr.ltwmmsw_,
`
`an
`
`hm
`
`Jacques Wepierre and Jean—Faul Marty f
`
`Laboraroire de Pharmacotlymzmie, Centre d’Emdes Phar/rzacetltiques, rue Jean-Baptiste Clément,
`92290 C/u?tem1y~MaIab_ry, France .
`
`bases. The cell also contains structural
`in Hvgaqrnmga/&§1t~aet/t. 5'5/7‘-!rMa“e?<~f; 347/ /’
`Wrflipids and water soluble substances which
`steottsa t
`l W finite:
`allow hydration of the stratum corneum.
`Finally, the intercellular spaces are filled
`by lipids of larnellar structure released
`during the keratinization process.’ by‘
`granules called ‘membrane coating gran-
`ules’. The diffusion of aqueous solutes is
`controlled by these lipid layers.
`Hence the stratum corneum is a very
`densely packed structure which effectively
`prevents the penetration’ of chemical sub-
`stances. It can almost be described as a
`mosaic of elements with hydrophilic
`properties which are able slowly to trap
`water, These elements are embedded in
`
`The structure of the stratum carneum
`explains this barrier effect (Fig. 1).. The
`stratum corneum consists of 10—2O layers
`formed and continuously replaced, of
`
`Percutaneous absorption is the passage of
`drugs through the cutaneous structures
`and the extracellular medium from the
`
`outside to the blood.strearn, This pheno—
`menon consists of two steps: (12 A. pene~
`tratio
`i.e. the passa e of mo ecu es
`
`t u in structures :
`corneum andthe e idermis ‘v
`Stmcttm
`2
`e
`'ce1lula.r medium. (2) A resorp—.
`tign phase during: which a re a we y rapid
`diffusion occurs -from extracellular‘ fluid
`
`-
`
`to the blood by way: 0 cL_t_t_a_neous micro-a
`circulrationrr
`if.-v.
`..
`-
`.x::.
`If the resorption phase is analogous to
`that observed» during. any absorption
`process, the skin penetration phasevis very
`special. In fact, skinexhibits a superficial
`‘rateslimiting barrier’, which only enables?
`drugs penetration: at a very slow, ,rate,_
`Through, increased; knowledge: of , the
`properties of this barrier, itis now possible
`to understand and explain thevarious,
`aspects of percutaneous absorption of_
`drugs.-.
`7
`-
`e
`-
`*
`
`__
`{
`9 _
`The rate-limiting barrier
`The principal ‘barrier’ function of the-
`skin resides almost entirely in the stratum
`corneum (thin coherent membranes of-
`keratinized dead cells) which prevents the
`penetration of chemical substances. This
`has been proved by various experiments:
`theskin deprived of the stratum corneum;
`is very permeable (Table-ml);
`thegisolated;-.
`stratum corneum» is, almost as impermeable
`as",the.entire*sl<in. Finally, dead skin used’
`in in vitro experiments exhibits almost the
`sanie~-permeability‘; as living skin,
`thusa
`showing that livingcells of epidermis do;
`not-contribute greatly-jto skin imperme«-
`ahility3..‘v.;
`~
`e
`—-
`—
`~
`»
`
`'
`
`‘.
`
`V
`TSTRATUM '
`LUCIDUM ’
`
`STRATUM —*
`_ii‘QFiANULO_SUM V
`
`.
`
`V‘
`
`‘
`
`=..:'.‘i'\ *
`b
`
`(‘ ,.f.srnATuM
`SPWOSUM A’
`
`it
`
`
`
`
`
`
`
`H':‘i/CV’?i\l‘\7'il-l’:3ld'l\7lY_\lH3}\\i"|ANHOH
`
`Fig.1 31’. ‘Schematic represenratiort cfthé~'evolu'tio}t of
`e,Uidermalce1ls.i .»~ "
`‘
`‘
`
`flattened keratinized cells from the under-_g
`lying living epidermis5..Adhesion between
`cells occurs at the level of the altered
`desmosomes which aretight juinctional
`zones between living cells of _epiderrnis.,,
`Each cell (Fig. 2) has a thick membrane,
`which is the most ‘efficient component of
`the protective system.__It
`is resistant to
`keratolytic agents, must of the proteases,
`diluted, strong acids and._bases.,Th_e inner
`part of the cells contains a_—keratin-V fila~
`merits, 648 nm in diameter, representing
`50°7o“o_f the cellular content. The fibrous.
`proteinis embedded in a proteic amor-_V
`phousirnatrix rich in disulphide bonds..1_'
`This structure exhibits a high resistance to!
`chemical agents but is destroyed by kerato-if
`lytic reducing agents, strong acids and
`
`Ratio
`20tolO0
`20
`._
`
`,
`
`.'.
`. 3 »
`Personal results
`
`6600
`2 to 5
`
`‘
`
`the lipids which fill the intercellular space
`and form. a continuous structure with a
`very low permeability to water-asoluble
`ll‘
`-‘:'s.»
`villi.--..-t
`7
`substances. _
`
`Absorption theorycg-::.,,
`
`,
`
`,
`
`From the literature’, ‘it: is clear that
`absorption ‘ofdrugs occurs by passive?
`diffusion’. The living cells ofthe epidermis’
`are relatively moreepcrmeabler than the‘
`‘stratum eornctmr and do not appeartc»-*
`intervene except in? certain cascs.~ The
`horny ilayer
`remains '1 ‘the 7 rate-limiting:
`factor of absorption. For solutions of low
`molecular weight drugs; at least sliglttly
`water soluble, an expanded law derived’
`from Fields‘ law at steady-state transport‘
`canbe‘'applied;» ‘
`_
`"3
`5 “
`
`Dxk
`I'AC' gin
`‘J=_I<n.-Ave t
`:
`~
`t
`A
`-
`,
`'
`.
`-
`—
`wherer.
`J = the flux of the penetrating drugs
`'
`(quantity of drug absorbed per unit
`A
`‘ of area and unit of time),
`- ,
`.
`g
`.
`K, = permeability constant,
`V
`AC = differcnce~ between concentration-
`
`_
`
`’
`
`iabove (C,) and below (C2) the n1eru+-
`bra-ne
`(C1 is generally negligible
`compared. to C‘),
`A
`A
`i
`.
`D = diffusion constantof the drug inthee
`stratum corneuyng
`1
`""3"
`k, = str-atum corrzeum/vehicle - partition
`coefficientof the drug;
`A
`fe ="=thic-kness of the stratum corneumts
`' Equation (1) summarizes the elementary:
`physics of‘ the penetration process through.-'
`the sl<in..Even though it is an oversimpii-1
`fication,i.it includes the main importantt‘
`factors explaining percutaneous absorption"
`ofdrugs.
`'
`The absorption intensity is thus proper-.»
`tional to the concentration of the--dissolved
`drug in the vehicleand to the application».
`area. Using the same quantity of drug, the '
`systemic effects will be greater in proper;
`tion with the area of skin coveredztw ‘“‘:'.'i*;“
`© Elsevier/North-Holland Biomedical Press [979
`
`TABLE 1. Importance of straturri comeum on "the permeability of skin as shown by the ratio K, across skin:
`'
`'
`-
`-
`—
`’
`-
`withoutstrarum comeum/K,. across whole skin.
`‘
`—
`'
`V
`. Reference
`Substance»
`V Species r"
`-
`‘
`' 3-7
`Personalresults
`
`-
`
`A
`“
`
`Water .'
`Ethanol"
`Estradiol‘
`" g Amphetaminevesx
`Trichlorocarbanilide 7
`
`_
`
`/
`
`'
`
`‘Human _
`Mouse“
`" Human '
`':...l-Iumanv
`.Human _
`
`'
`
`1
`
`ALL 2019
`MYLAN PHARMACEUTICALS V. ALLERGAN
`IPR2016-01128
`
`

`

`‘ALAMELL/M3‘
`
`'
`
`-ALTERED
`
`cat" ’
`MEMBRANE
`
`'fl,1O,pHO
`li(ERATlN
`A .M§TmXUs
`FiLAl\fENTS
`t
`l
`—
`'
`1,
`__rouoni.AMsNrs‘igiéruxroitvnttne ‘
`»
`or
`_:[S - POOR] —. v—nicwl F -RIGHT
`SH .
`'
`_ ‘jsi; 5': _ S
`Scliematiciillustratiori of the structure and
`/"c-laemlcal components of-horny cell and lntercellular
`‘substance in the stratum corneum.
`'
`‘
`'~
`
`.. Inrportance of the diffusion coefficieiit
`The diffusion constant representsthe
`rate of migration of a drug through the
`~ horny layer. It is inversely proportional to.
`both size of the molecules and viscosity of _
`. the medium. The stratum corneum exhibits
`. a very high apparent-viscosity so the diffu-
`sion constant of the molecules is very low,
`as being between 10”’ fern? s" foraicohols
`and 10"” to 10”‘? cm2 s"‘ for-steroids”.
`These values are much higher in the living
`a layers of t the skin; ,10'."_ cr_ri2 5"‘. This
`V explains why ‘thewratum corneum is the
`«rate-limiting
`‘factor
`of
`percutaneous
`' absorption."
`T
`‘=- {As the stratum: corneum has non-neglig-
`ible thickness (20-40 um), there is a period
`* of transient diffusion (lag time) after
`-: applying a drug to the skin, during which
`a the rate of transfer through the skin rises
`-1 to reach a steady rate (Fig. 3). The steady
`s state is maintained thereafter indefinitely,
`= provided the system is constant. On the
`‘ skin, the lag time isoften prolonged and
`reaches several hours”.
`
`, Partition coefflcient.-Tstratum ;corneum/
`vehicle
`H
`,
`_.
`_
`.
`
`The partition coefficient k, of the drug
`' between stratum corneum in Fick’s law,
`‘shows the importance of the solubility
`‘charactefistics for a substance to penetrate
`the skin.
`:
`’
`i
`‘
`a
`- Because of the presence of intercellular
`lipids, the stratum corneum exhibits the
`characteristics of a lipophilic structure.
`Many experiments have shown a direct
`~ relation between lipophilic solvent (repre-
`senting stratum corneum) and water parti-
`tion coefficient of an aqueous solute and
`its permeability constant”. Better results
`are often obtained by measuring this par-
`tition between sheets or powder of isolated
`
`'
`
`’
`
`.......;,--...HoRNy
`LAYER“
`
`A SEBACEOUS
`‘
`GLAND
`
`A‘
`
`’
`
`‘
`
`lemoenmls
`
`_
`
`D“ERMlS
`cures ROOT
`
`_ .sHi=.ArH__
`4’ INNER Root
`SHEATH
`
`HAIR
`
`stratum corneum and water, or another
`vehicle containing the drug in solutionl-‘Z.
`, MALP_|GHlAN*
`When k,‘-is high, the drug accumulates
`* ~~tAvsn ,,
`in the stratum corneum and a significant "
`«
`concentration of drug appears at the point
`of contact with the living cells. At this
`level, penetration is rapid by migration in
`the interccllular spaces (which are large in
`the living epidermis) assuming-that their:
`substance‘ is at
`least slightly soluble in
`water. However, with purely lipophilic
`substances,-the penetration does not go ..
`further than the stratum corneum. For
`instan'c_e,'V triglycerides ‘vand’ "perhyd_ro- ‘
`squaleneare very poorly absorbed by the
`sl<in”.:' For water-soluble drugs, absorption-
`is "very "low," the limiting” barrier being
`located in the stratum corneum. However,
`the skin‘, is fairly permeable to water,-which
`seems’-capable ,of ?diffusion by. osmosis
`from the outside or from the inner medium ,
`(insensible water
`loss)»-to the stratum
`comcum.
`‘_
`‘
`” ~
`
`l..
`
`BULB
`V9’
`Fig. 4. Schematic structure ofhairfollicle. The outer
`root sheath is cornifled like epidermis from the
`surface of skin to the opefiing of the excretory duct
`of sebaceous gland. In rheirmer part of the hair
`follicle, cell junctions of the -outer and»im1er’root
`sheaths are light. In these conditions thesebaceous
`gland is the;-cc1sie.rt routefor diffusion.
`
`is much more permeable than normal skin.
`Finally Tcutaneous "irritation and stratum
`corneum stripping considerably increase
`the permeability of the skin. Systemic toxic
`effects have been reported after the appli-
`cation of various drugs on damaged skin
`(hexachlorophane). ‘
`.
`7
`-”=Hydration ofthe stratum corneum. In
`vivo,
`the stratum corneum is partially
`hydrated’. vWater ‘coming from insensibile
`water loss penetrates the cells where it is '
`trapped by water soluble substances inclu-
`ded in cornified cells. Hydration may vary
`to a considerable extent, producing a
`rearrangement of the cellular constituents
`and decreasing their “resistance to diffu-
`sion. Occlusive dressings are used in der-
`matology to increase absorption of cortico-
`steroids which are-normally poorly
`absorbed.‘
`"
`‘
`"
`“
`"
`
`léarallel diffusion pathways} role osfuskin
`appendages ‘
`-
`9
`~
`‘ 'As the stratum corncum is only slightly
`permeable, it is possible to consider parallel
`paths for absorption, e.g. sweat glands
`and pilo-sebaceous apparatus.
`If the sweat glands seem to have a neg-
`ligible role, the pilo-sebaceous system has
`-for a long time been considered as the
`main route for drug absorption. Easier
`diffusion pathways are located, as shown
`in Fig. 4, at the level of the sebaceous
`gland since the sebum is only found between
`the outer medium and the glandular acini.
`The work of Tregearl‘ and of Schcuplein
`land Blankl has shown that epidermis and
`' appendageal diffusion are involved to a
`variable extent in the absorption of drugs.
`Skin appendages act as diffusion shunts
`alongside the slower route directly through ’
`the stratum corneum. In man, there are
`‘relatively few hair follicles and the frac-
`
`H
`
`,
`.
`T
`Otherfactors :
`Local variations of the’ stratum corncum.
`As shown in equation (1), the imperme-
`abillty of the skin is an inverse function of
`the thickness of the stratum "corneum. It
`depends also on variations in structure
`and chemistry of the horiiy--layer from
`one region of the bodylto anotherlrm.
`Plantar and palmar callus are more per-
`meable than the stratum corncum of other
`parts of the body. Permeability, as will be
`seen below, increases with number of hair
`follicles present in the skin.‘ These factors
`explain» variations in the permeability of
`the skin ‘of different parts of the body,
`which can be classified by order of increasé’
`ing diffusional resistance, as follows, palm
`skin, ’-scrotum, ‘posterior part of ear,
`axillaryregions, scalp, arms,‘
`legs’ and
`chest;‘There are large individual variations
`in skin permeability in which age and
`racial factors seem to play an important
`role. Pathological skin (eczema, psogiasis)
`
`‘
`
`
`
`
`
`TOTALAMOUNTABSORBED 4-
`
`STEADY STATE
`DIFFUSION
`
`AG TIME
`TL
`
`' Fig. 3. Time course ofpenetrationfor drug diffusing
`through intact human skin with: TL: lag time,
`or thickness of the membrane, D: diffusion cortslant
`of the drug in the membrane.
`'
`
`2
`
`

`

`tional area of the skin covered by append-
`ages over most of the body is quite small.
`The absorption surface of hair follicles is
`100 to 10,000 times less than that of the
`stratum corneum. The permeability of
`these shunts can be high, since the diffu-
`sion constant of the chemical substances
`through the stratum corneum is 100 to
`10,000 times less than that through the
`sebaceous structures. For a given drug
`therefore,
`the penetration routes will
`mostly be a function of the value of the
`diffusion constants (Fig. 5). For the small,
`diffusible,
`nomelectrolyte
`‘ molecules
`(alcohols),
`the lag time is reduced for
`absorption across epidermis and hair
`follicles; it does not exceed more than a
`few minutes. The flux rapidly becomes
`constant by the two routes, which both
`participate in the absorption. The propor-
`tion of each one depends on the pilosity of
`the skin. For less diffusible molecules, such
`as various steroids,’ the lag times last several
`hours. Absorption occurs at first by the p
`transfollicular. route," then progessively
`also takes place at the epidermis level.
`Finally, for drugs with a very small diffu-
`sion constant through the stratum corneum
`(polar steroids), the lag time reaches several
`days and absorption occurs only via hair
`follicles.
`
`Superficial amldeep retention ofldrugs
`applied to the skin
`A
`_
`A
`Vicl<ers'° was the first to demonstrate
`the existence of a depot in the skin for
`topically applied agents (corticosteroids,
`griseofulvin, estradiol). This phenomenon ~
`called the ‘reservoir effect’ is a property)
`
`
`
`
`
`TOTALAMOUNTABSORBED
`
`HAIRIFOLLICLES AND
`SEBACEOUS GLANDS
`
`‘
`_
`
`.
`
`-I
`
`D1 = D2 >4 100
`__ 0.5% SURFACE
`
`I 5. 4,
`-
`J‘
`
`.
`5TlME:MlNUT-F.
`HOUR
`HOUR x 10
`
`Fig. 5. Total amount of drug absorbed by the entire
`skin (A), by the epidermis (B) and by hair follicles
`(C). From this figure it can be seen that absorption
`by entire skin is the sum of absorption by the epi-
`dermis and hair follicle. II is supposed that the area
`of hair follicle represents 0.5% of the area of the
`epidermis. The diffusion constant through epidermis
`is 100 times /0 wer than the diffusion constant through
`the hairfollicles. At the steady state theflux by hair
`follicles is one-half theflux by the epidermis. The log
`times depend on the constant of diffusion. They can
`vary from some minutes to several hours for
`epidermis.
`'
`V
`"
`
`
`
`
`
`frcqncenrmnoninTlSSUE(ng.g““:
`
`:
`
`P M 3 st:
`ESTRADIOL
`DEXAMETHASONE
`T Q HTHYROXINE
`Fig. 6. Subcutaneous tissue retention of various drugs in the rat after application on the skin; P: plasma,
`M: muscle of the leg, Ma: muscle under surface of application of the drug, SC: tissue immediately wider
`surface of application ofthe drug.
`
`of the cornified cells. The molecules stored
`are partly slowly absorbed, over a period
`of i,>«‘7 days; and partly removed by re-
`peated washing and skin contact. The
`reservoireffect can explain some charac-=
`teristics of percutaneous therapy. A single
`application often leads
`to prolonged
`effects, and this is of significance not only
`for drugs designed forsuperficial effects
`(antiseptics, antibacterial
`agents,
`sun-
`screens), but also for those required for
`deep action. For the latter, retention is
`adequate only for drugs with high bio»
`logical activity,” since the storage capacity
`of the stratum corneum, whose volume is
`reduced, is small.
`’
`‘
`'
`-
`A transient concentration gradient”
`has also been shown in the deep parts of
`the skin and even in thesubcutaneous con»
`nective tissue with, e.g. estradiol, thyroxin,
`corticosteroids, 8-methoxypsoralen (Fig. 6).
`This accumulation may be a consequence
`of the horny-layer
`reservoir effect.
`‘It
`appears when the bloodstream resorption
`rate is insufficient or when. a binding of
`«drug occurs on soluble macromolecules or
`cellular fractions of skin (corticosteroids).
`These phenomena tend to provethat the
`percutaneous route is available to obtain
`local effects in the depth of the skin with-
`out systemic action.
`"
`'
`-
`
`Excipient effect
`The vehicles used in dermatology are
`able to modify percutaneous absorption
`
`of drugs in two ways’: reversible physio-}
`logical change in the properties of the
`stratum corneum (hydration) or change in
`the rate of -release of the drug from the
`vehicle
`by modification of
`stratum
`eorneum/vehicle partition coefficient; T
`.
`
`' if
`Stratum corneurn hydration A
`increased
`Percutaneous absorption is
`by vehicles such as petroleum jelly and
`oils, which form agwaterproof film at the
`surface of the skin and prevent perspira«-
`tion. Like water, aprotic solvents (climethyl.-._t
`sulphoxide) increase the penetration. ra.te-.
`significantly and almost reversibly, but
`they are toxic and their use is limitedl.
`«
`
`Modificationof thepartition coeffI_'t‘.'.ien.t:: I
`stratum corneum/vehicle
`3
`_
`c
`W The permeability constant
`is propose
`tional
`to therstraturn corncum/vehicle -
`partition coefficient. — This
`coefficient
`represents the relative affinity of the dis: j
`solved drug for the vehicle and for the
`stratum cornéum‘-” ., When the coefficient A‘
`is high, the drug easily leaves the vehicle r
`for which it has a low affinity. This happens
`when it is slightly soluble. Conversely a '
`small coefficient means a greater inter- 3
`action between the solute andthe vehicle.
`Based on these.data,_.Blanl<' was able to
`show in a seriesof alcohols the importance.
`of the affinity for the vehicle on the per-.
`cutaneous bioavailahillty. Water—solu'o1e'-«
`ethanol has a higher permeability constant
`
`3
`
`

`

`TIPS - inaugural isszie, I979
`
`«powerful drugs.‘ In‘ addition this ‘route
`lacks precision regarding the real dose
`absorbed. Finally it
`is necessary that
`delivery systems are non-irritant and non-
`sensitizing substances.
`In spite of these
`disadvantages. the search for
`systemic
`effects can be justified: (1) for drugs which
`may be destroyed by enzymes in the diges-
`tive tract or trapped by the liver before
`they reach the systemic bloodstream ‘(first
`pass effect);
`(2) to obtain long lasting
`‘effects;
`‘:.;.:.- e.
`-=
`:..;t
`
`-. Progress in our knowledge regarding
`the effect of vehicles and various absorp-
`tion promoterson the percutaneous absorp-
`tion of drugs should enable a wider use of
`this route,-which is still often neglected. or
`
`absorption in two opposite manners‘~".
`(1) The irritant action increases perine-
`ability of the stratum corneum and absorp-
`tion of drugs. This is the main effect
`observed with anionic and cationic surfac—
`-tants.
`(2) Tensioactive agents ‘increase
`solubility of drugs in the vehicle andin
`this way decrease stratum corneum/vehicle
`partition coefficient , and permeability
`constant of the drug. This is the major
`actionof non-io11ic surfactants which have
`
`no irritant effect. The addition of surfac-
`tant seems to be the greatest when the drug
`is initially poorly soluble in the vehicle
`(Fig. 8).
`_
`V
`1
`1
`.
`I
`.
`:5:
`._
`The role of emulsions," particularly with
`regard to oil in water'(O/W) and water in
`-
`“ oil (W/O) bases is the most difficult_ to
`predict. It seems, however, that the per-
`meability constant, depends, . at
`least
`initially, on the partition coefficientbetween
`the stratum corneum and the continuous
`
`(C01
`
`=cm.h“.1G“3)
`
`-88
`
`V
`
`ETHANOL.
`BUTANOL
`OCTANOL
`
`
`
`
`
` 3PERMEA“BlLlTYCGNSTANT(Kg1Ni3'‘
`
`ATER
`
`1 ISOPPYL
`if
`.. ‘l\/lYRlSTATE
`1
`Fig. 7. Permeability constant of ethanol, bufanol
`and ocranol dissolved in water or isopropyl myrlslute.
`
`when it is dissolved in anbily excipient A
`(olive-oil, parafi“1n»oil)., for which it has
`little affinity, than when it is in an aqueous
`solution in which it is very soluble, and
`where it has a tendency to remain. On the
`' other‘haridfpentanoliarrcl ioctanol give a
`higher permeability constant when they"
`‘are applied to the skin in an aqueous solu-
`tion, where they havelow solubility, than
`in an oily solution (Fig. 7). When the par-
`tition” coefficient stratum r:ornezmz/vehicle
`is high, the drug is poorly soluble in the
`excipient. Under these" conditions, in spite
`of a high permeability constant, the quan-
`tities actually absorbed, which are equal
`to the product of the perineability constant
`by concentration, remain small. Thus two
`factors act in oppositedirections. Poulsen"
`has shown the optimal condition of libera-
`tion in the stratum corneum for cortico-
`steroids 'incorporated iniia water/propylene
`glycol mixture. The liberation is maximized
`by addition of a quantity of propylene
`glycol, just sufficient to dissolve the corticoi
`
`A
`
`‘=
`
`*
`
`1
`
`‘ phase of the emulsion. Investigations of
`this ‘aspect have been made with alcohols,
`estradiol and progcsterone"." M
`
`_
`
`Conclusions
`
`1
`
`The application of drugs to the skin has
`been used for a long time to obtain surface
`effects or to develop a deep localized action.
`The interest in the latter is justified since
`we now know that many drugs areretained
`for a long time inthe cutaneous and sub-
`cutaneous structures in the treated zone.
`One must remember that only normal skin
`is jrnpermeable. Lesions,-:.irritatiion' and
`pathological states increase permeability
`of the skin. Its alteration-can produce toxic-
`effects when applying preparations designed
`for normal skin.
`..
`1‘
`J '
`._
`Until now, the percutaneous route has
`been little used to obtain systemic effects,
`because these effects appear only with
`
`.
`
`_
`
`A
`_
`I
`‘vReadi11glist“
`A l._Blank, ,1; H. (1964) "J. Invest. Dermatol. 43,
`l._
`,
`’..V>::...,_.
`7-.~
`.
`7'2.‘Dugard, P. H. (1977)'1n‘: F. N. Marzulli and
`.
`.. H.
`I. Maibach ~(eds),' Dermatotoxicology and
`. Pharmacology, John Wiley. and Sons, New
`York,pp.525—_560.
`.
`.
`Hi
`.'oa1ey, w. 11., Lonsdale,’ H. K. and Natcht, s.
`(1976)J.Invest.Dermalol.67,7l3—7l7.,
`'
`. Idson, ’n.(197s)J. Pharm. Sci. 64, 901-924." ‘ ‘f
`'
`. Matoltsy, A. G. (1976) J. Invest. Dermatol. 67;
`.
`"'f.,' 20~25—yr..
`;""‘ .
`i.
`.‘
`'.
`(
`..Poulsen, B. J.
`(1973) In: 13. J. Ariens (ed.)
`_, Drug Design, Vol. 4,: Academic Press, New
`V"-York. 149-192- ‘
`'1
`-‘o
`t‘
`. Scheuplein, R. J. and Blank, 1. H. (197l)‘Ph)/siol.
`Rev.51,7O2-747..
`.
`._ ;
`1
`_‘
`. .8. —*r?ége'ar, RJT. (1966) Physical Function of Skin,
`Academic Press, London, Vol. 1, 185 pp. - 1
`9.
`Treherne, J. E. (1956) J. Physiol. (London) 133,
`171-181,. 1.
`-
`_ ..
`.;
`.
`:,_1
`f0.
`Viclcers, C. F. H. (1972) In: W. Montagna, R. B.
`I ‘' Stoughton and_E. J. VanAScott’(eds), Pharma-
`' cology andrthe Skin,'Appleton Century Crofts,
`NewYork,l77~l89.'
`1
`'
`‘
`"11. Wepierre, J.
`(1977)
`In: J. Polderman (cd.),
`Formulation and Preparation Dosage Forms,
`Elsevier/North-Holland
`Biomedical
`Press,
`.
`Amsterdam, pp. 237-257.
`'
`12.‘ Wepierre, J. (1979) Actualilés Pharmacologiques,
`~
`-A 31;‘: série, Masson, Paris, pp. 169-202.
`
`_.
`steroid at the eonceiitration selected.
`Surfactants, often included in pharma-
`ceutical formulations, act on percutaneous
`
`
`
`PERMEABlLlTYCONSTANT
`
`p(KP=cm.h~‘.1o-3;
`
`0
`
`20
`
`30
`
`.
`TWEEN 80 (PER CENT)
`Fig. 8. Surface active effect on percurar1eousubsorp-
`tion of drugs dissolved in a mixture water-Tween
`80 —_*.~- ~ .-~.' ethanol
`_
`_
`——-————————: butanol _ -V---A:
`octanol.
`'
`—
`
`Jacques Wepierre, 47ycars old is Professor of Phar-
`macology at the University of Paris-Sud. Centre
`d’Erudes Pharrnaceutiques. He has performed
`research on Dcrmopharmacolagy and biology of the
`skin and written works on pharnracokinetics and
`mechanism of action o_/antihyperlensive agents.
`:* '
`
`is Professor of
`Jean-Paul Marty, 32 years old,
`Pharmaceutical Technology at
`the Umversity of
`Amiens, Pharmaceutical Sciences Unit. He has per-
`formed research on bioavailabillty and pharmaco-
`kinetics of topical drug products and peroral solid
`dosageforms with prolonged action.
`
`4
`
`