"-mg‘
`
`--u
`
`—
`
`-
`
`,
`
`1
`
`.
`
`,,
`
`PHYSICAL CHEMICAL ANALYSIS OF PERCUTANEOUS ABSORPTION PROCESS 85
`
`(11). Cosmetics applied to skin previously exposed to solvents may be
`expected to penetrate more readily and possibly cause irritation. Depil—
`atory creams and cold-wave solutions may be alkaline; only if their pH is
`greater than 11.5 will the barrier be sufficiently damaged to alter permea-
`bility.
`
`REFERENCES
`
`(1) Griesemer, R. D., “Protection Against the Transfer of Matter Through the Skin,” In
`The Human Integument, Am. Assoc. Advance. Sci. Pub. No. 54 (1959), pp. 25-46.
`(2) Mali,
`VV. H.,
`Invest. Dermatol., 27, 451 (1956).
`(3) Blank, I. H., I&z'd., 18, 433 (1952).
`(4) Higuchi, T.,
`Soe Cosmetic Chemists, 11, 85 (1960).
`I. Penc-
`(5) Blank, I. H., and Gould, E., “Penetration of Anionic Surfactants into Skin.
`tration of Sodium Laurate and Sodium Dodecyl Sulfate into Excised Human Skin,” 7.
`Invest. Dermatol., 33, 327 (1959).
`(6) Szakall, A., Fette, Sezfen, ./Imtric/zmittel, 53, 399 (1951).
`(7) Stoughton, R. B., “Relation of the Anatom) of Normal and Abnormal Skin to its Pro-
`tective Function,” In The Human Integument, Am. Assoc. Advance. Sci. Pub. No. 54
`(1959), pp. 3—24.
`(8) Selby, C. C., :7. Invest. Dermatol., 29, 131 (1957).
`(9) Treherne, J. E., :7. P/zysiol. (London), 133, 171 (1956).
`(10) Blank, I. H., Personal communication.
`(11) Blank, I. I-I., Personal communication.
`
`PHYSICAL CHEMICAL ANALYSIS OF PERCUTA-
`
`NEOUS ABSORPTION PROCESS FROM CREAMS
`
`AND OINTMENTS
`
`BY T. H1GUcHI*
`
`Presented September 23~-24, 1959, Seminar, New York City
`
`PROBLEMS ASSOCIATED with penetration of intact skin are, of course,
`of great interest to both pharmaceutical and cosmetic chemists. Not only
`are we concerned with maximizing the rate of penetration of beneficial
`drugs from ointments and lotions but also in minimizing the rate of entry
`of toxic chemicals, as such, or from drug and cosmetic preparations.
`In
`this brief discussion I hope to review from the viewpoint of a PIIYSICEII
`chemist some‘of the factors which may govern the rate of the penetration
`process.
`Despite the large amount of work already carried out in this field, there
`is very little agreement on the basis process which is largely responsible for
`percutaneous absorption through the intact skin. Many workers feel that
`essentially all penetration occurs through the transfollicular route. Other
`equally recognized investigators support the view that the major pathway
`of entry is
`transepidermal
`through the intact cornified and transition
`
`* School of Pharmacy, University of Wisconsin, Madison, Wis.
`
`ALL 2013
`MYLAN PHARMACEUTICALS V. ALLERGAN
`IPRZO16-01128
`
`1
`
`ALL 2013
`MYLAN PHARMACEUTICALS V. ALLERGAN
`IPR2016-01128
`
`

`

`86
`
`JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS
`
`layers. A third and growing group is inclined to accept both routes, rela-
`tive importance depending on the chemical nature of the penetrating agent.
`In this treatment little attempt will be made to resolve this controversy.
`Rather, general aspects of the problem which embrace largely both mecha-
`nisms will be presentedbased on laws of thermodynamics and diffusion,
`the only restriction being that the absorption.process is not energetically
`coupled to any biological process.
`Despite the dissimilarity in the two modes of drug movement through
`the skin structure (shown schematically in Fig. 1) there are relationships
`which are Valid irrespective of the correct absolute mechanism. The rate
`
`Transfollicular
`
`Transepidermal
`
`///
`92
`
`Figure 1.—Schematic diagram of two routes of percutaneous penetration.
`
`of penetration by both pathways can be set up mathematically by employ-
`ing as a model the dificusional process through a passive membrane. Result-
`ing relationships, which appear to have received only partial attention in
`pharmaceutical and dermatological literature, should prove useful guides to
`those entrusted with development of new medicinal and cosmetic prepara-
`tions.
`
`Because of the nature and the complexity of the problem, it is convenient
`to divide the discussion into two parts.
`In the first we will analyze situa-
`tions Where the rate-controlling step or steps are in the skin.
`In the second
`part we will consider those cases where the thermodynamic potential drop
`of the percutaneously absorbed materials is largely in the applied phase
`such as an ointment base.
`.
`
`RELATIONSHIPS FOR SYSTEMS VVHERE THE RATE CONTROLLING BARRIER
`
`Is IN THE SKIN
`
`The majority of the cases of interest to us fall into this category. The
`skin is a wonderfully resistant cover and it is penetrated only with difliculty
`by most noncaustic substances.
`In our discussion of this aspect of the
`problem of percutaneous absorption, we will treat it initially in its simplest
`aspects, then attempt to see what additions and modifications must be
`made in our formulation to better fit the real systems.
`
`2
`
`

`

`‘T -‘
`
`w I
`
`I“ u
`
`i
`
`I
`
`I
`
`‘f
`
`"
`
`PHYSICAL CHEMICAL ANALYSIS OF PERCUTANEOUS ABSORPTION PROCESS 87
`
`If it is assumed that the vehicle containing the pene-
`Simpler! Mode/.
`trating chemical does not appreciably affect the skin, We can set up the
`following approximate relationship for an idealized system, such as shown
`in Fig. 2, between the steady state rate of penetration (dq//it) and various
`properties of a fairly water soluble drug:
`
`ciq _
`df — (P.C.)
`
`(Cone. of Drug) DAV
`,
`L
`
`(1)
`
`where (P.C.) is the effective distribution coefficient of the penetration agent
`between the vehicle and the barrier of the skin, (Cone. of Drug), the con-
`centration of the agent in the vehicle, D, the effective average diffusivity
`of the agent in the barrier phase, /1, the effective cross section area, and L,
`the effective thickness of the barrier phase.
`
`Penetrant in«
`
`Aqueous Vehicle
`
`Aqueous
`Receptor
`
`
`
`E - D[pc]A _ —A£_m
`UL
`L
`s
`dt
`Figure 2.—Schematic plot showing simple steady state difiusion
`across a barrier layer of thickness L.
`
`The main characteristics of the penetrating agent which determine
`its rate of entry through the skin, according to this equation, are its effective
`partition coefficient and diffusivity in the barrier phase. The product of
`these two
`
`(P.C.) (D)
`
`If the barrier phase were
`is often spoken of as the permeability constant.
`available in the form of a film, the two constants can be separated and
`individually determined by a technique known as the lag time method.
`Actually the important variable in the permeability constant is the (P.C.)
`factor since diffusivity of a substance of similar molecular weight and
`shape usually differ only slightly. According to the Stokes—Einstein
`equation, D varies approximately only as the cube root of molecular weight.
`The partition coefficient, on the other hand, is an extremely sensitive func-
`tion of molecular structure and size.
`
`Another useful but equivalent form expresses the same equation in terms
`
`3
`
`

`

`a
`
`as
`
`:
`
`v
`
`I
`
`......
`
`,.
`
`88
`
`JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS
`
`of the thermodynamic activity of the penetrating agent in itsivehicle:
`
`‘Z4 = 1&4
`(fl
`7 L
`
`(2)
`
`is the thermodynamic activity of the drug in its vehicle and 7
`where oz
`is the effective activity coeflicient of the agent in the skin barrier phase.
`The significance of the second relationship is apparent in Fig. 3 where
`both activity and concentration under steady state conditions of a hypo-
`thetical penetrating drug having a partition coeH-icient of 1/2 and 2 have
`been plotted as a function of depth.
`’
`In the activity plot there is a discontinuity in the slope but not in the
`absolute value at the interphase. VVhereas in the concentration plot there
`are usually sharp breaks in both.
`Since the driving force behind the drug
`movement is the diH'erence in the thermodynamic potential between the
`Vehicle and the deeper tissues, activity plots always show a decrease with
`depth. This is not necessarily true with concentration plots since favor-
`able partition coefficients may result in an increase as shown in one of the
`examples in Fig. 3.
`I
`
`tissues
`
`n
`
`oint.
`Ibase
`
`I Skin I
`:barr ie r
`lower]
`
`COHC -
`
`lower,
`tissues
`
`_L\
`
`PENETfiATION (effective depth)
`Figure 3.—Plots showing schematically the changes in concentration and ac-
`tivity Wlth effective depth of penetration.
`
`Although for thermodynamic reasons the direction of flow is always in the
`direction of negative concentration gradient for passive systems, one may
`conceivably obtain a net flow against the gradient if there exists an energy
`transfer mechanism.
`If Buettner’s contention that water is readily ab—
`sorbed through human skin from highly hypertonic solutions is correct,
`there must be a pump mechanism which will push water molecules against
`the gradient into body fluid.
`In equation 2 only the
`T/zermodymzmic flclivizy and Rate of Penetmtion.
`activity of the drug in its vehicle appears, the properties of the base itself
`seem to play no part. For such systems the rate of percutaneous penetra-
`tion measured for different ointment bases would be approximately con-
`stant provided the thermodynamic activity of the drug in the vehicles
`
`4
`
`

`

`‘'7
`
`PHYSICAL CHEMICAL ANALYSIS OF PERCUTANEOUS ABSORPTION PROCESS 89
`
`was maintained constant. Thus all ointments containing finely ground
`suspensions of the drug (thermodynamic activity equal to that of the solid
`drug) will produce the same rate of penetration. This again presupposes
`that the rate determinining step is essentially in the passage of the barrier
`phase. For highly insoluble systems this would not be true as we will see
`later.
`
`In order to obtain the maximum rate of penetration it is evident that the
`highest thermodynamic potential possible for the penetrating substances
`must be used. For simple organic compounds the activity of the pure form
`of the material at environmental temperature places, however, an upper
`limit on the available thermodynamics activity. Any higher activity
`would represent supersaturation with respect
`to the form. With more
`complex compounds, however, difFerent crystalline modifications may exist
`having different free energies, thus different thermodynamic activities, at
`room temperature.
`In such instances the selection of the most energetic
`species will result in fastest penetration. These systems are, however,
`metastable and may show a gradual change in properties.
`
`TABLE l-—LIMITING ACTIVITY COEFFICIENTS or SARIN IN ORGANIC SOLVENTS AND WATER
`
`*
`
`Perfluorotributylamine .
`Hexadecane .
`,
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Water .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Tributylamine .
`.
`.
`.
`.
`.
`.
`.
`.
`Tetralin .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`2—Pyrro1idone .
`.
`.
`.
`.
`.
`.
`.
`.
`Diethylene glycol .
`.
`.
`.
`.
`Carbon tetrachloride .
`.
`.
`Phenyl ether .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`. .66.6
`. .15.6
`. .14
`. .10.4
`.
`. 4.3
`.
`. 2.8
`.
`. 2,4
`.
`. 2.4
`.
`. 2.38
`
`.
`Diisooctyl adipate .
`.
`Methyl salicylate .
`.
`N-methylacetam-ide .
`Dibutyl phthalate .
`.
`Butryolactone .
`.
`.
`.
`.
`.
`Isoamyl alcohol .
`.
`.
`.
`Ethyl lactate .
`.
`.
`.
`.
`.
`Benzyl alcohol .
`.
`.
`.
`.
`m—Cresol. .
`-.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`. .1.84
`. .1.74
`. .1.44
`.
`. 1 .42
`. .1.31
`. .1.07
`. .0. 536
`. .0.446
`. .0044
`
`Since activities are important rather than any absolute concentration,
`it is obvious that, for a given concentration of the penetrating substance,
`vehicles which have lower afiinity (poorer solvent power) will normally
`produce faster penetration.
`It is not commonly realized how dependent
`such activity coefiicients are on solvents.
`In Table 1, I have listed Values
`in some solvents for sarin, a nerve gas, which we determined a few years
`ago.
`It is evident that these values encompass three orders of magnitude.
`It is to be expected that the same degree of difierence will be found in the
`rates of absorption of the fluorophosphate from these solutions.
`In practical language one might say that solutes held firmly by the vehicle
`will exhibit low activity coefiicients and slow rates of penetration. Good
`pharmaceutical examples of this behavior are the relative rates of release
`(penetration) of phenols from mineral oil or petrolatum bases and from
`camphor or polypropylene glycol bases. The latter preparations are mild and
`bland whereas the former are quite corrosive at equal concentrations.
`This is du_e to the reduction in the thermodynamic activity of the phenols
`caused by the ketone or the polyethers. Such complex formations usually
`
`5
`
`

`

`V_.
`
`90
`
`JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS
`
`cause marked diminution in the rate of penetration of the bound compound.
`Similarly, the absorption rate of iodine has been greatly reduced by use of
`PVP to control its toxicity.
`-
`For the same reason the rates of absorption of acidic and basic drugs are
`strongly influenced by the effective pH of the vehicle. The activity co—.
`eflicient of the molecular form of such drugs is a rapidly changingfunction
`of pH for pH values greater than pKa for acidic compounds and less than
`pKw — pK,, for alkaloidal drugs. Thus, for example, the rate of absorption
`of histamine would be 10 times greater from a base buffered at pH = 7.5
`than from that at 6.5 and 100 times greater than that from base at 5.5.
`Such estimations are valid irrespective of the nature of the assumed barrier
`and mode of transfer provided only the nonionized species is involved in the
`absorption process.
`Substances showing lower melting points generally permit higher con-
`centration in solution and would thus tend to give faster penetrating
`systems.
`It is difficult,
`therefore,
`to produce rapid absorption of high
`melting chemicals such as sulfonamides whereas most semipolar, low melt-
`ing or liquid organic compounds are fairly rapidly absorbed.
`Efieclive Multilayer Bozrriem. These simple relationships are not valid
`for systems where the penetrating substance has an extremely low afiinity
`for the lower water—bearing tissues.
`In this instance the rate determining
`step no longer involves transition through the barrier but transfer from the
`barrier phase to the deeper tissues. The situation becomes evident by
`comparison of Fig. 2 with Fig. 4 where such a situation exists.
`In the latter
`
`2 Conc. plot
`
`Surface Layer
`
` Deeper Tissue
`
`Figure 4.—eSchematic diagram showing penetrating system having little or no
`gradient in the barrier layer.
`
`instance the drop in the chemical potential of..the penetrating agent occurs
`largely below the barrier layer.
`In the former case the drop occurred
`mainly in the barrier itself.
`Systems which follow Fig. 4 usually exhibit a relatively low rate of
`penetration. This is obviously due to the highly unfavorable partition
`coefficient in moving from the epidermal layers to the watery deeper tissues.
`
`6
`
`

`

`PHYSICAL CHEMICAL ANALYSIS OF PERCUTANEOUS ABSORPTION PROCESS 91
`
`In effect, for such systems we can look on the resistant barrier as being
`composed of two dissimilar layers, one largely lipoidal and the other effec-
`tively hydrous. Schematically we can represent such a system by a plot
`
`Hydrous Barrier
`
`Lipoid Barrier
`
`ctivity Plot
`
`_
`d.
`J‘ —
`d.t
`
`A
`L, 3
`F + P
`I
`2
`
`_ D
`R —-'-
`
`‘
`
`SLOPE oc —
`P
`
`Figure 5.—Schematic diagram of permeation through a double barrier
`layer.
`
`as shown in Fig. 5. Mathematically such double and multi-layer systems
`would obey the relationship:
`
`ad
`d§__
`all — U11/P1) + (/I2/P2)
`for a double layer where /z is the thickness and P = D/7 of the respective
`layers. And
`
`a/1
`dq __
`dz ‘ (721/P.) + (/22/P2) + .
`
`. .(/1,./P.)
`
`for an n-layer system.
`As one might expect these equations are quite analogous to electric cir-
`cuits where dq/dz‘ is the current, and P is the conductivity.
`It is also
`evident that the layer having the lowest conductivity will have dispropor-
`tionate effects on the flux analogous to the common series—connected resist-
`ance circuits.
`
`If we assume that diffusion coefficients in the several phases are approxi-
`mately the same as is often practically the case, we find
`\
`
`adD
`dq __
`dz ' hm + hm + .../1.».
`
`7
`
`

`

`92
`
`JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS
`
`/z, the thick-
`where D here refers to the effective mean diffusion coeflicient;
`ness of each layer and 7 the activity coefficient of the penetrant in that
`layer. For such a system and comparing a number of chemicals the pene-
`trant which minimizes the summation shown in the denominator will
`penetrate the fastest.
`' This may lead to selection of a compound having
`balanced hydrophilic lipophilic properties if the double barrier layer such as
`suggested above really exists.
`v
`~ If the activity coefficients in the above equation were such that all
`except that in the hydrous layer. the deeper aqueous tissues underlying the
`normal barrier layer, were very small the rate of agent penetration would be
`expected to be a sensitive function of the rate of capillary blood How.
`This assumes that the effective thickness of the hydrous barrier depends
`on the rate of How of blood through it. One would thus predict that the
`rate of absorption of highly hydrophobic solvents and materials would be
`influenced by capillary dilation and blood flow. On the other hand for
`systems showing low activity coeflicients in water, that is for penetrating
`materials which are at least partly hydrophilic in nature, the rate of per-
`fusion or capillary flow would have little or no effect.
`.
`Influence of Moisture and S0/vents.
`So far in our consideration we have
`assumed (I) that diffusion coeflicients are constants independent of con-
`centration and (2) that activity coefficients likewise were constant through-
`out the penetration process.
`In special instances these are poor assump-
`tions. This is particularly true where we are concerned with penetration of
`water molecules by a transepidermal route or any transepidermal pene-
`tration where there is concomitant imbibition of water. Sinceiwater is
`
`particularly well sorbed by protein and protein degradation products con-
`tained in the outer skin, the transfer properties of the several
`layers are
`probably strongly influenced by the presence of water. __.
`This sort of behavior, while diflicult to establish in viva, can be readily
`followed in vitro with certain artificial membranes.
`In Fig. 6 is shown an
`experimentally determined permeability of glyceryl monostearate to mois-
`ture as a function of relative humidity. At Very low humidity perme-
`ability (gm./cm.2 - hr - mm. Hg) is relatively insensitive to relative humidity,
`whereas near 100 per cent, the rate of penetration is acutely dependent on
`water activity. This is attributed to imbibition of water by the barrier
`phase exposed to saturated Water vapor and consequent changes both in the
`diffusion coefiicient and activity coefficient.
`The large effect on permeability of small decreases in the thermodynamic
`activity of water is evident for leather. Common leather normally offers
`little resistance to penetration by water vapor. Addition of salt to the
`penetrating aqueous phase, however, greatly decreases the rate. Leather
`has been found to be practically impermeable when exposed to 2.5 normal
`sodium chloride solution (approximately 90% relative humidity).
`
`8
`
`

`

`PHYSICAL CHEMICAL ANALYSIS OF PERCUTANEOUS ABSORPTION PROCESS 93
`
`Although the effect of variation of activity of Water over skin surface on
`the rate of percutaneous absorption has not been investigated as yet, one
`would strongly suspect that the effect would be considerable. This would
`be particularly true if the penetrating substance is being transported trans-
`epidermally rather than through the follicular route. Even in the latter
`case, hydration of the tissues may be expected to cause physical alteration in
`the passages sufficient to produce significant dependency on water.
`In any
`case, substances such as methyl salicylate appear to penetrate at a con-
`siderably altered rate under humid conditions.
`
`
`
`|2
`
`I
`
`CO
`O
`
`X
`
`3
`
`)‘
`':
`-1
`E5
`<
`UJ
`
`2 (
`
`I4
`LIJ
`Q
`
`00
`
`an
`O
`
`I90
`
`X >
`
`-
`
`neofi
`>
`(T)
`3
`l7OLL
`L:
`D
`
`|60|_
`
`5D
`
`C
`ISOE
`D.
`<
`
`I40
`
`2
`
`0
`
`0
`
`25
`
`50
`
`75
`
`I00
`
`°/o HUMlD|TY
`
`Figure 6.—P1ot showing variation of permeability
`and apparent diffusivity of glyceryl monostearate with
`change in relative humidity.
`
`Application of many solvents other than water also appears to cause
`marked alteration in the resistance of the skin barrier toward penetration.
`VVhether this is due to the efiect of such treatment on the follicular opening
`or modification of the barrier tissues underlying the outer layer has not
`been established.
`In either instance the phenomenon is possibly caused
`by marked changes produced by such solvents in the activity coefficient
`and diffusion constant of the penetrating agent in the barrier.
`
`9
`
`

`

`94
`
`JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS
`
`I CAsEs WHERE THE RA’1‘E CONTROLLING STEP Is IN_ THE APPLIED PHASE
`
`In the preceding section it was assumed that the thermodynamic activity
`of the species being absorbed was essentially uniform in all parts of the
`applied material at all times.
`If the concentration of the absorbed ma-
`terial changed in the applied cream or ointment, the assumption was made
`that only negligible concentration gradient developed in the direction
`normal to the skin surface;
`that is, any decrease in concentration occurred
`uniformly. This is never quite the case since some concentration gradient
`must exist
`to promote the necessary diffusional How. Because of the
`great resistance to penetration of intact skin, however, such gradients are
`usually very small and may normally be ignored. There are important
`instances, nevertheless, such as cases involving absorption by injured skin
`or Where highly insoluble, suspension-type ointments are used where large
`concentration gradients may develop in the applied phase. Mathematical
`relationships governing such situations are considered in the following
`section.
`
`In all cases to be considered it will be assumed that all the concentration
`
`gradient occurs in the applied material, a situation shown diagrammatically
`in Fig. 7. This is equivalent to assuming that the skin surface is a perfect
`
`RECEPTOR
`
`
` OINTMENT PHASE
`
`CONCENTRATION
`
`Figure 7.—Schematic diagram of diflfusional flow from homogeneous solution of finite
`thickness into a perfect receptor.
`
`sink and will maintain essentially zero concentration of the penetrating
`material by rapidly dissipating it to deeper tissues. This simplication is
`necessary since any attempt to distribute the activity gradient between the
`skin phase and the applied phase would lead to extremely complex mathe-
`
`10
`
`10
`
`

`

`PHYSICAL CHEMICAL ANALYSIS OF PERCUTANEOUS ABSORPTION PROCESS 95
`
`If essentially all of the gradient is in the skin, it is evident the
`matics.
`mathematics of the preceding section will apply.
`.
`/flsorptionfrom Solutions. For the simplest system of this type, where
`the penetrating substance is initially uniformly dissolved in a homogeneous
`base as shown in Fig. 7, it can be shown rigorously that the amount of
`material absorbed from the applied phase,
`
`Q.=hCn[1—;2.7E=0 e
`
`8
`
`0.,
`
`1
`
`—D(2m+1)21r2t
`
`4122
`
`]
`
`thickness of the applied phase,
`initial concentration of the penetrating solute,
`diffusion constant of the solute in the base, and
`elapsed time of application.
`
`where
`
`IIIIIIII
`
`/2
`Co
`
`D1
`
`It is evident that if an instantaneous rate is desired it is necessary only to
`differentiate the above with respect to time. These relationships are
`extensively treated by Barrer in his book on diffusion.
`flésorpiion from Suspensions. The case discussed above probably will
`rarely apply to percutaneous absorption through intact skin since the
`difiusion coefiicient of any chemical readily taken in through such a barrier
`will be so great as to maintain a uniform concentration in the applied phase.
`A more important case is the absorption of a drug, for example, which is
`used as an extremely fine solid dispersion in a homogeneous base. This
`can be, for example, an ointment consisting of pencillin in petrolatum base.
`
`Receptor
`
`
`
`Figure 8 .
`
`Diffusion from ointment
`
`base of suspension type
`
`L = h2
`ED
`
`+ Ah2
`QCSD
`
`For such a system, shown schematically in Fig. 8, we are able to derive
`rather simple relationships among the several variables. Thus
`
` V9- = W ‘ C”
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`

`96
`
`JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS
`
`where
`
`2 = the amount absorbed at time t per unit area of exposure,
`xi = the concentration of drug expressed in unit/cm.3,
`C, = the solubility of the drug as units/cm.3 in the external phase of the ointment, and
`D = the diffusion constant of the drug molecule in the external phase.
`
`Differentiating with respect to time we obtain for the instantaneous rate of
`absorption at time 2‘
`
`as _
`
`_
`
`E " 1/2 (M C“) \/1 +‘2(/1 — Ca)/C,
`
`Dr
`
`For the common case of C, < .4 we find the relationship further simplified to
`
`and
`
`.9; = x/2/1130.;
`
`£2 _
`dt _
`
`2D_Cs
`2;
`
`Derivation and bases for these equations will be reported elsewhere.
`According to these remarkably simple relationships, remarkable in View
`of the complexity of the situation treated, the amount of drug released from
`such suspension—type ointment (C, < .4) is proportional to the square roots
`of the amount of drug per unit Volume, diffusion constant, drug solubility
`and time.
`It is ofinterest to note that intuitively one might expect a direct
`relationship with concentration, but this is not the case.
`i
`It is evident that We can regulate the rate of release of drugs from such
`preparations by controlling 1, D, and Cs.
`If partly aqueous base is em-
`ployed, C, can be varied, for example, by changing the effective pH of the
`vehicle for insoluble acidic and basic drugs. Or it can be altered by addi-
`tion of complexing agent or cosolvent. D, the diffusion coefficient, is in— D
`versely proportional to the microscopic viscosity of the vehicle and may be
`varied in this manner.
`.4, the drug concentration, is, of course, susceptible
`to wide variations.
`
`There are a number of other similar situations which have been solved
`
`dealing with diffusional flow where all of the gradient is in the applied
`phase. We have worked out cases involving both emulsion—type ointments
`and ointments containing solid fillers such as zinc oxide. Nearly exact
`mathematical solutions to the behavior of these systems as drug sources are
`presently available.
`
`GENERAL DISCUSSION
`
`Although complete elucidation of the mechanism of percutaneous pene-
`tration is of great consequence in our fields, it is evident that much can be
`done without awaiting its complete solution. Thus, for example, we have
`seen that for cases involving situations where essentially all of the activity
`
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`

`THE PERCUTANEOUS ABSORPTION OF SALICYLATES
`
`97
`
`gradient is in the applied phase, skin properties play no part. For these
`systems drug concentration in the base, diffusion coefficient of the drug
`molecule in the vehicle, and solubility of the drug in the same are the im-
`portant factors. For the remaining cases these formulation variables are
`not directly important,
`the only significant factor involving the vehicle
`being the thermodynamic activity of the penetrating agent contained in it.
`More information concerning the exact route of penetration would be of
`considerable aid, however,
`in devising methods of increasing the perme-
`ability of the rate limiting barriers. Certain solvents significantly lower
`the resistance of the skin to penetration. Whether this is due to changes
`produced in the transepidermal barrier layer or to modification of the
`follicular and sebaceous route apparently has not been unequivocally
`established. Present treatment is not meant to discount the importance
`of studies along this line but to show what can be still done without them.
`
`THE PERCUTANEOUS ABSORPTION OF
`
`SALICYLATES AS MEASURED BY BLOOD PLASMA
`
`LEVELS IN THE RABBIT
`
`By VAL F. COT'I‘Y, JOHN SKERPAC, HEINZ M. EDERMA, FRANK ZURZOLA
`and MARTIN KUNA*
`
`Presented September 23—24, 1959, Seminar, New York City
`
`THE PERCUTANEOUS ABSORPTION of salicylates has been reviewed by
`Gross and Greenberg (1), by Valette and Cavier (2) and more recently by
`Rothman (3). Most of the studies of percutaneous absorption of salicylates
`have been carried out by measuring the total urinary excretion of salicyl-
`ates over relatively long periods of time following the topical application
`of the salicylate preparation. The validity of this method may be ques-
`tioned on the basis that a considerable proportion of administered salicylate
`is conjugated by the time it appears in the urine (Schachter and Manis)
`(4) and that this method does not take into account the loss of the drug
`from the skin surface (e.g., by evaporation). One may seriously question
`whether it is possible to make conclusions about the relative rates of ab-
`sorption of salicylates by measuring their excretion.
`In measuring the ab-
`sorption of a drug by its blood levels one is usually interested in its fate
`when it gets into the circulatory system. For this reason the changes in
`plasma level following the intravenous injection of methyl salicylate dis-
`solved in saline were studied.
`
`* Bristol—Myers Products Division, Hillside 5, N. I.
`
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