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`J . Pharm. Pharmacol. 1983, 35: 28-33
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`Received June 18, 1982
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`0022-3573/83/010028-06 $02.50/0
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`© 1983 J. Pharm. Pharmacol.
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`Physicochemical characterization of the human nail:
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`permeation pattern for water and the homologous
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`alcohols and differences with respect to the stratum
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`corneum*
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`KENNETH A. WALTERST, GORDON L. FLYNN*, AND JOHN R. MARVEL:
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`College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, U. S.A., and i Dermatological Division, Ortho
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`Pharmaceutical Corporation, Raritan, New Jersey, U. S.A.
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`In order to develop a basic concept of the permeability of the human nail plate and thus
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`create a better understanding of the toxic potentials and therapeutic possibilities of
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`substances a plied to the nail, avulsed cadaver nails have been placed in specially
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`constructed iffusion chambers and their permeation by water and the n—alkanols through
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`dodecanol, all in high agueous dilution, has been investigated. The permeability coefficient
`of water is 16-5 X 10'
`cm h-1 and that for methanol is 5-6 X 104 cm h'1. Ethanol’s
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`permeability coefficient measured 5-8 X 10—3 cm h-1. Permeability coefficients decreased
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`systematically thereafter to a low value of 0-27 X 1&3 cm h-1 at n-octanol. The middle
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`chain length alkanols, n-pentanol through n—octanol, have similar ermeability coefficients
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`but n-decanol and n-dodecanol show higher rates of permeation. The data suggest that, as a
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`membrane, the hydrated human nail plate behaves like a hydrogel of high ionic strength to
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`the polar and semipolar alcohols. Declining permeability rates appear linked to decreased
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`partitioning into the complex matrix of the plate as the compounds become hydrophobic.
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`The results for n-decanol and n-dodecanol introduce the possibility that a parallel lipid
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`pathway exists which favours the permeation of these exceedingly hydrophobic species.
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`coefficients. Such structural influences on physico—
`Apparently, no evidence exists concerning funda-
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`mental permeation mechanisms and possible influ-
`chemical properties, when considered together with
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`ences of chemical structure on transport across the
`relative permeabilities, have helped decipher the
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`barrier mechanisms of several membranes (Blank
`nail plate. To an extent its permeability properties
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`have been inferred without foundation from the
`1964; Scheuplein 1965; Hwang et al 1976; Ho et al
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`1977: Behl et al 1980; Durrheim et al 1980; Flynn et
`behaviour of other horny tissues. In order to make a
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`al 1981). Previous studies of the a1kanol’s permea-
`priori judgements concerning toxic risk and thera-
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`peutic benefit of substances brought in contact with
`tion of skin are especially notable as these provide
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`evidence that the stratum corneum acts to some
`the nail, some baseline information on this tissue is
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`needed.
`extent as a hydrophobic continuum (barrier) (Blank
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`1964; Scheuplein 1965; Behl et al 1980; Durrheim et
`We have shown it possible to determine nail plate
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`al 1980; Flynn et al 1981). Similar studies on the
`permeability coefficients using standard diffusion
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`human nail plate presented here are comparably
`cell techniques (Walters et al 1981). Results obtained
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`for water agreed well with literature data on water
`revealing as, unlike the stratum corneum, the nail
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`becomes less permeable to the n—alkanols as their
`transpiration through the nail plate (Burch & Winsor
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`hydrophobicity is
`increased. At extreme hydro-
`1946; Spruit 1971; Baden et al 1973). In pursuant
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`phobicity there is
`increased permeability. The
`studies the techniques have been extended to the
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`permeation of some n—alkanols. These are useful
`mechanistic significance of these general observa-
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`tions is considered.
`prototype compounds with systematically varying
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`oil/water (o/W) distribution coefficients and diffusion
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`* Correspondence. This work su ported through the
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`generosity of Ortho Pharmaceutical orporation, Raritan,
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`N.J., U.S.A.
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`1' Present address, Fisons Limited, Pharmaceutical Divi-
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`sion, Research & Development Laboratories, Bakewell
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`Road, Loughborough, Leicestershire LE1l OQY, UK.
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`Materials
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`Tritiated water and radiolabelled alcohols were
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`obtained from New England Nuclear ([3H]water,
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`[3H]methanol,
`[14C]ethanol,
`[1“C]butanol), Cali-
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`fornia Bionuclear
`([14C]propanol,
`[14C]pentano1,
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`MATERIALS AND METHODS
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`Page 1 of 6
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`Kaken Exhibit 2020
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`Acrux V. Kaken
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`IPR2017-00190
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`Page 1 of 6
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`Kaken Exhibit 2020
`Acrux v. Kaken
`IPR2017-00190
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`

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`
`29
`NAIL PERMEATION BY HOMOLOGOUS ALCOHOLS
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`[14C]heptanol, [14C]dodecanol) and ICN ([1“C]hex- compound, h is the nail plate thickness and tL is the
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`diffusional lag time obtained by linear regression of
`anol, [14C]octanol, [14C]decanol). All radiolabelled
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`the steady state slope of uptake versus time plots.
`compounds were diluted with saline (0-9% NaCl
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`The nail plates used in these studies were measured
`Irrigation Solution, Abbott Labs) before use. The
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`alkanols were diluted to trace concentrations, 104
`with a micrometer and averaged 0-54 mm in thick-
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`ness.
`molar or less.
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`Permeation procedures
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`Details of the diffusion cell and permeation pro-
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`cedures have been given previously (Walters et al
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`1981). Briefly, trimmed human nail plate sections*
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`were placed between two halves of a diffusion cell. A
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`known amount of a radiolabelled permeant was
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`placed in the donor chamber and samples were taken
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`at predetermined intervals from the receptor cham-
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`ber. Isotope activity was monitored using a Beckman
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`LS 9000 liquid scintillation counter.
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`The permeation behaviours of [3H]water and
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`[3H]methanol and [14C]alkanols in dilute solution
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`were followed as a function of time at 37 °C. In all
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`cases two permeants were applied with different
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`radiolabels. Generally methanol was run as a tri-
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`tiated compound along with a 14C-labelled co-
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`permeant. Methanol thus sewed as a reference and it
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`is important to note that the increased values for the
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`permeability coefficient of decanol and dodecanol
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`were obtained concurrently with normal methanol
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`data.
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`Permeability coefficients
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`from:
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`(P) were calculated
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`(1)
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`P _v dC/dt
`' A.A C
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`where V is the volume of the receiver half cell, dC/dt
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`the rate of change in concentration in the
`is
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`pseudo-steady state portion of the receiver concen-
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`tration versus time plot, A is the diffusional area and
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`AC is the concentration differential of permeant
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`across the membrane. V(dC/dt) gives the diffusional
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`flux in mass per unit time. The diffusion cells with
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`nail plate membranes in place were scrupulously
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`checked for intercompartmental leakage using sol-
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`uble but impenetrable polyethyleneglycol markers
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`and no leaks were evident.
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`Diffusivities of the permeants in the nail plate
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`tissue were calculated from the non-stationary state
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`periods using:
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`hz
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`Where Deff is the effective diffusivity for a given
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`* Fresh cadaver nails generously supplied by Dr T. M.
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`Oelrich, University of Michigan, School of Medicine.
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`Page 2 of 6
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`RESULTS AND DISCUSSION
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`Permeability coefficients of water and the saline
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`diluted n-alkanols are given along with diffusion lag
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`times in Table 1. Fig.
`1 shows the relationship
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`between the logarithms of the permeability coeffi-
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`cients and the alkyl chain lengths of the alcohols. An
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`unusual pattern is observed with minimum per-
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`meability coefficient values at intermediate alkyl
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`chain length.
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`Table 1. Nail plate permeability data for water and
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`n-alkanols.
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`Lag. time
`Permeability“
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`(t,_)
`coefficient
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`(s)
`(cm h-1 X 103)
`Permeant
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`900 i 100
`16-5 i 5-9
`Water
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`5-6 i 1-2
`26) 1790 i 200
`Methanol
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`5 8 i 3-1
`2730 i 200
`Ethanol
`8
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`0-83 1 0-15 4
`4020 i 350
`n-Propanol
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`0-61 i 0-27 4
`3470 i 350
`n-Butanol
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`0-35 i 0-07 6
`2700 1- 250
`n-Pentanol
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`0-36 : 0-23 5
`3540 1' 300
`n-Hexanol
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`0-42 i 0-12 4
`2520 i 300
`n-Heptanol
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`0-27 i 0-03 4
`2120 i 150
`n-Octanol
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`‘L 1-7
`10) 2090 i 150
`2-5
`n-Decanol
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`n-Dodecanol 4 1 i 2-7
`2300 i 150
`8)
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`Effective
`diffusion”
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`constant
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`(Den) cm2 s*
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`X 107
`5-4
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`2-7
`1-3
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`1-2
`1-4
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`1-8
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`1-4
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`1-9
`2-2
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`2-1
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`2-1
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`a. Data include standard deviation and (
`) number of
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`experiments.
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`b. From t,_ = l—12— (Mean value for h = 0-54 mm)
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`6D
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`Fig. 2 shows the effective diffusivities of the
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`permeants in the nail plate tissue as a function of
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`alkyl chain length.
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`Theoretical considerations
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`The nail plate’s barrier properties are governed by its
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`anatomical construction and its physicochemical
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`properties and a proposed model must be support-
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`able in terms of both. The model developed here,
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`although speculative,
`fulfills these requirements.
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`The plate consists of a laminate of sheets of
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`keratinized cells (Caputo & Dadati 1968; Forslind
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`1970; Forslind & Thyresson 1975). Like the stratum
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`Page 2 of 6
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`

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`K. A. WALTERS ET AL
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`The above picture allows consideration of diffu-
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`first
`its
`sion across
`the nail plate at
`level of
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`organizational complexity. For a given permeant,
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`the principle mass current may either pass directly
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`through the cell units stacked upon one another and
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`separated by the intercellular substance, or may flow
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`mainly around the cell contents by way of the
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`interconnecting, extra—cellular lipid network. The
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`first of these possibilities involves alternating pas-
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`sages through two distinctly different domains.
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`Based on the lipid content of the nail being totally
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`extracellular and 1% of the total volume and on
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`individual cell dimensions of 30 um diameter (hexa-
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`gonal) and 1 pm thickness, the latter route would
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`offer a fractional area for diffusion of 5 X 10-4. At
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`this percentage composition and with these cell
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`dimensions,
`the calculated width of the region
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`between cells is approximately 100 A, in reasonable
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`agreement with ultra-microscopic estimates (Zaias &
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`Alvarez 1968; Hashimoto 1971b). Allowance has to
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`be made for diffusional path of the extracellular
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`route to be tortuous, having a path length up to, but
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`not exceeding, 15 times (1/2 cell diameter), the nail’s
`width.
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`30
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`N) O
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`5
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`The following equation can be formulated to
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`describe flux across the nail plate as described using
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`the general principles outlined by Flynn et al (1974):
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`J __
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`fc
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`f_;_
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`(3)
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`A "[212, + ERM + RL JAG
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`Here J is the total flux (mass/time), A, is the area of
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`application, and fa and fL are the fractional areas
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`available for
`the transcellular and lipid routes
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`respectively. The terms RC and RM are the summed
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`resistances of the two types of lamina encountered
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`
`
`
`
`transcellularly while RL is the resistance of the
`
`
`
`
`
`
`
`
`
`extracellular lipid route. The term AC is the driving
`
`
`
`
`
`
`
`
`
`force for the mass transfer process measured as the
`
`
`
`
`
`
`concentration difference across the nail plate.
`
`
`
`
`
`
`
`Equation 3 can be made more explicit by including
`
`
`
`
`
`
`
`the estimated fractional areas and by defining the
`
`
`
`
`
`
`resistances in terms of effective thicknesses (h),
`
`
`
`
`
`
`diffusivities within phases (D), and partition coeffi—
`
`
`cients (K):
`
`
`
`
`
`
`i z
`A
`
`0-9995DcDMKcKM
`DMKM2hc +DcKc2hM-
`
`+
`
`(4)
`
`5 x 10-4DMKM—:.hLll c
`
`
`
`
`
`
`
`
`The subscript c is used to indicate the intracellular
`
`
`
`
`
`
`
`protein domain and the subscript M the extracellular
`
`
`
`
`x103(cmh-‘) 5'
`Logpermeabilitycoefficient
`
`
`0-1
`
`
`
`1
`
`
`
`
`
`
`
`3
`2
`
`
`456789101112
`
`
`
`
`
`
`
`Alcohol alkyl chain length
`
`
`
`
`
`
`
`
`
`FIG. 1. Relationship between the logarithm of the per-
`
`
`
`
`
`
`
`
`
`meability coefficient and alkyl chain length of the alcohol.
`
`
`
`
`
`
`
`
`
`
`corneum, the cytoplasmic keratin mass is partially
`
`
`
`
`
`
`
`crystalline and partially amorphous. In section, thin
`
`
`
`
`
`
`
`
`
`
`lipid seams are seen to separate the cell layers. This
`
`
`
`
`
`
`
`
`
`lipid is from the original cell membranes and is
`
`
`
`
`
`apparently supplemented by intercellular deposition
`
`
`
`
`
`
`
`of so-called membrane coating granules during the
`
`
`
`
`
`
`
`plate’s formation (Hashimoto et al 1966; Hashimoto
`
`1971a,b).
`
`6
`
`0
`
`[Water
`
`(J
`
`
`
`
`
`Effectivediffusionconstant(cmz
`sec-'x10'7) N
`
`
`
`123456789101112
`
`
`
`
`
`
`
`
`
`
`
`Alcohol alkyl chain length
`
`
`
`
`
`
`
`
`
`
`
`FIG. 2. Effecive diffusivities of the permeants as a function
`
`
`
`
`
`
`
`of alkyl chain length of the alcohol.
`
`
`
`Page 3 of 6
`
`Page 3 of 6
`
`

`

`
`
`31
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`
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`
`
`
`log KM,“ = log KM_0 + nn
`
`
`
`(6)
`
`
`
`
`
`
`
`(09995 DCKC + 5 x 10-4DMKM
`JAC (5)
`
`
`Eh,
`hL
`
`
`
`
`
`
`
`
`
`Equation 5 gives the flux per unit area for typical
`
`
`
`
`
`
`
`permeants in terms of physically meaningful mass
`
`
`
`
`
`
`
`transfer parameters. The bracketed quality is a
`
`
`
`
`
`
`complex mass transfer coefficient or ‘permeability
`
`
`
`
`
`
`
`
`coefficient’. Using the symbol P for the permeability
`
`
`
`
`
`
`
`the statement J/A = PAC, applies
`coefficient,
`
`
`
`
`
`
`
`
`generally for such mass transfer systems. The opera-
`
`
`
`
`
`
`
`
`tive parallel pathways are indicated by the two
`
`
`
`
`
`
`separate collections of terms comprising P.
`
`
`
`
`
`
`The permeability coefficient profile for a homolo-
`
`
`
`
`
`
`
`
`
`gous series of permeants will depend upon how the
`
`
`
`
`
`
`
`diffusivities and partition coefficients in equation 5
`
`
`
`
`
`
`
`
`
`
`are affected by variation of length of the alkyl chain.
`
`
`
`
`
`
`
`
`
`
`
`It is impossible to predict how DC and Kc might be
`
`
`
`
`
`
`
`
`
`affected as very little is known about solubility and
`
`
`
`
`
`
`
`molecular mobility in the nails dense, semicrystal—
`
`
`
`
`
`
`
`line protein phases. Based on general considerations
`
`
`
`
`
`
`
`
`
`(Flynn et al 1974) and on partitioning behaviour of
`
`
`
`
`
`
`
`
`
`long chain fatty acids between the nail plate and
`
`
`
`
`
`
`
`
`
`water (Baden 1970), KM may be assumed to follow
`
`
`
`
`
`
`the general o/w homologue partitioning pattern:
`
`
`
`
`NAIL PERMEATION BY HOMOLOGOUS ALCOHOLS
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`of the n-alkanols (including water at n = 0) is shown
`lipid domain. The quantities he and hM are the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`summed thicknesses of the cytoplasmic laminae and
`in Fig. 1. From water to n-octanol permeability
`
`
`
`
`
`
`
`
`
`
`
`
`coefficients decrease systematically and by an overall
`membrane lamellae passed through transcellularly.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`factor of about 60. This observation rules out the
`Added together these yield the total nail plate
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`thickness. Common values of diffusivity (DM) and
`possibility that a lipid pathway is involved for these
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`permeants. Over the same alkyl chain length span
`partition coefficient (KM) are given for the lipid
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`elements of the two distinct routes but the 2hM<<hL
`diffusivities are also decreasing, but only several-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`even in the absence of a significant tortuosity factor.
`fold. The lag time based diffusivities are on the order
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`10'7 cm2 S‘1,
`a magnitude which is physically
`Finally,
`for all but
`the most polar permeants,
`
`
`
`
`
`
`plausible.
`DMKM2hC>>DCKc2hM as Dc<DM (likely) and
`
`
`
`
`
`
`
`
`
`A nominal molecular size sensitivity for diffusivity
`EhM<<2hc. Therefore:
`
`
`
`
`
`
`
`
`is evident considering the narrow spread in apparent
`
`
`
`
`
`
`
`
`Dc (Deffective) values. Thus, there must be another
`
`
`
`
`
`
`
`
`cause for the decline in the permeability coefficients
`
`
`
`
`
`
`
`with increasing chain length. According to equation
`
`
`
`
`
`
`
`
`5 partitioning provides the only alternative basis for
`
`
`
`
`
`
`
`
`
`the declining trend; it would be necessary for the
`
`
`
`
`
`
`
`partition coefficients between the protein domain of
`
`
`
`
`
`
`
`
`
`the nail (keratin) and the external water to decrease
`
`
`
`
`
`
`
`
`about 25-fold. To our knowledge there is no
`
`
`
`
`
`
`
`
`precedent for such behaviour in a mass transfer
`
`
`
`
`
`
`framework under circumstances where the external
`
`
`
`
`
`
`
`media are aqueous. There are, however, some
`
`
`
`
`
`
`
`observations supporting the concept that the keratin
`
`
`
`
`
`
`
`
`matrix has a decreasing ability to dissolve the
`
`
`
`
`
`
`
`alkanols as the homologous series is ascended.
`
`
`
`
`
`
`
`
`
`Tillman & Higuchi (1961) note that the solvating and
`
`
`
`
`
`
`
`
`
`softening abilities of solvents for callus strips are in
`
`
`
`
`
`
`
`
`
`the order water > methanol >> ethanol. A great
`
`
`
`
`
`
`
`
`
`
`deal of work has been done on the sorption of
`
`
`
`
`
`
`
`
`
`solvents into hair and wool fibres and, according to
`
`
`
`
`
`
`
`
`Harrison & Speakman (1958), the fine structure of
`
`
`
`
`
`
`
`
`wool seems to be inaccessible to molecules larger
`
`
`
`
`
`
`
`
`
`
`than n-propanol. On the basis of the present work, it
`
`
`
`
`
`
`
`would appear that exclusion associated with increas-
`
`
`
`
`
`
`ing hydrophobicity is more a thermodynamic than a
`
`
`
`
`
`
`kinetic (molecular size) phenomenon. Hair (wool),
`
`
`
`
`
`
`
`
`
`callus and nail seem to have more in common
`
`
`
`
`
`
`
`
`chemically and physically with each other than they
`
`
`
`
`
`
`
`
`
`do with the stratum corneum (Baden 1970; Baden et
`
`
`
`
`
`
`
`
`
`al 1973) and thus inferences drawn from the cited
`
`
`
`
`
`
`
`
`works have good probability of being applicable to
`
`
`
`
`
`
`
`
`
`the nail. Furthermore, at 10-7 cm2 s-1 the effective
`
`
`
`
`
`
`
`diffusivities are too large for an approximately
`
`
`
`
`
`
`
`
`
`25-fold factor to be incorporated and hidden in some
`
`
`
`
`
`
`
`
`complex way. It therefore appears that, to a rough
`
`
`
`
`
`
`
`
`
`first approximation, the nail plate acts as a concen-
`
`
`
`
`
`
`
`trated hydrogel to the alkanol permeants through
`
`
`
`
`
`
`
`n-octanol. The behaviour suggests there is a positive
`
`
`
`
`
`
`
`
`free energy change accompanying the transfer of a
`
`
`
`
`
`
`
`methylene group from the external. water medium
`
`
`
`
`
`to the intracellular protein phase.
`
`
`
`
`
`
`
`Skin permeation of the alkanols through n-octanol
`
`
`J
`A
`
`"7
`
`
`
`
`
`
`
`
`
`where KM_,, is the partition coefficient of the homo-
`
`
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`
`
`
`
`
`
`logue of chain length n between a water immiscible
`
`
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`
`
`phase and water and log KM_0 is the Y-intercept of a
`
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`
`
`
`plot KM,“ versus n. The term, 31?, is the slope of the
`
`
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`
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`
`
`
`
`log K versus n plot. The nature of the intercellular
`
`
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`
`
`
`
`
`material is such that 3120-3 and therefore KM_,, can
`
`
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`
`
`
`
`
`
`be expected to grow in an exponential fashion as the
`
`
`
`
`alkyl chain is extended.
`
`
`
`
`
`
`
`
`Relative permeability of the n-alkanols through nail
`
`
`
`
`plate and stratum corneum
`
`
`
`
`
`
`
`The alkyl chain length dependency of permeability
`
`Page 4 of 6
`
`Page 4 of 6
`
`

`

`
`
`
`
`32
`
`
`
`K. A. WALTERS ET AL
`
`
`
`
`
`
`
`
`
`
`
`is strikingly different (Blank 1964; Scheuplein 1965;
`
`
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`
`
`
`
`
`
`
`Behl et al 1980; Durrheim et al 1980; Flynn et al
`
`
`
`
`
`
`
`
`1981). As the alkyl chain length is
`increased,
`
`
`
`
`
`
`permeability coefficients also increase, with the
`
`
`
`
`
`
`increase being essentially exponential past ethanol.
`
`
`
`
`
`
`
`Such behaviour signifies that the stratum corneum
`
`
`
`
`
`
`
`
`
`functions for the most part as a hydrophobic mem-
`
`
`
`
`
`
`
`brane to these permeants, with increased perme-
`
`
`
`
`
`
`
`ability coefficients the result of increased partition-
`
`
`
`
`
`
`
`
`ing into some critical hydrophobic phase within the
`
`
`
`
`
`
`
`horny structure. The stratum corneum’s far greater
`
`
`
`
`
`
`
`
`lipid content undoubtedly plays a role here, setting
`
`
`
`
`
`
`
`
`
`its membrane behaviour apart from that of the nail
`
`
`
`
`
`and perhaps other cornified tissues.
`
`
`
`
`
`
`
`The striking increase in nail plate permeability
`
`
`
`
`
`
`coefficients from n-octanol to n-dodecanol signals a
`
`
`
`
`
`
`change in diffusional mechanism. Now permeability
`
`
`
`
`
`
`
`is increasing with increased hydrophobicity of the
`
`
`
`
`
`
`permeants,
`an unmistakable indication of
`the
`
`
`
`
`
`
`
`emergence of a functionally lipid pathway. Equa-
`
`
`
`
`
`
`
`
`
`
`
`tions 4 and 5 were formulated with such a route in
`
`
`
`
`
`
`
`mind, namely a route through the intercellular
`
`
`
`
`
`
`seams,
`with
`collection
`of
`the
`terms,
`
`
`
`
`
`
`
`5 X 10-4DMKM,hL, representing the route’s diffusive
`
`
`
`
`
`
`contribution. Regardless of whether the placement
`
`
`
`
`
`
`
`
`of the lipid pathway is anatomically proper,
`the
`
`
`
`
`
`
`
`route’s essential trait is an exponentially increasing
`
`
`
`
`
`
`
`distributioning with increased alkyl chain length, as
`
`
`
`
`
`
`
`
`described in equation 6. Even a fractionally minor
`
`
`
`
`
`
`lipid route will assume rate-controlling proportions
`
`
`
`
`
`
`
`
`at an appropriately long alkyl chain length providing
`
`
`
`
`
`
`
`no other competitive pathway has a partitioning
`
`
`
`
`
`
`
`sensitivity. The transition to lipid pathway control
`
`
`
`
`
`
`
`
`
`occurs with but a slight increase in effective diffusiv-
`
`
`
`
`
`
`
`
`ity based on the effective diffusivities of n-decanol
`
`
`
`
`
`
`
`
`
`and n-dodecanol. It would appear that the route is
`
`
`
`
`
`
`
`
`not tortuous as these effective diffusivities do not
`
`
`
`
`
`
`
`
`allow for great non—linearity in path. The appearance
`
`
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`
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`
`
`
`
`
`
`of this route so late on the alkyl chain length profile is
`
`
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`
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`
`
`
`consistent with its limited fractional area, which we
`
`
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`
`
`
`
`
`
`
`estimate to be about 1/100 of that of the same
`
`
`
`
`
`
`
`pathway in stratum corneum. With a methylene unit
`
`
`
`
`
`
`
`partitioning factor (115) of 20-3 as suggested by
`
`
`
`
`
`
`
`literature data (Baden 1970),
`the alkyl fragment
`
`
`
`
`
`
`
`necessary to place the permeation process into
`
`
`
`
`
`
`
`
`
`extracellular control would have to be five to six
`
`
`
`
`
`
`
`
`
`carbons longer than it would for the stratum cor-
`
`
`
`
`
`
`
`
`
`
`neum, and this is very close to what is experimentally
`
`
`
`
`
`
`
`
`
`observed. Assuming a fractional area of 5 X 10-4
`
`
`
`
`
`
`
`
`
`and otherwise using the permeability data in Table 1,
`
`
`
`
`
`
`the partition coefficient between the extracellular
`
`
`
`
`
`
`
`
`lipid substance and water necessary to account for
`
`
`
`
`
`
`dodecanol’s high permeability coefficient can be
`
`
`
`
`
`
`
`
`
`
`estimated,
`ie, P z fLDMKM/hM, and KM is about
`
`
`
`
`
`
`
`
`
`6000. This value is certainly not too large considering
`
`
`
`
`
`
`
`the extended length of the alkyl chain.
`
`
`
`
`
`
`
`
`
`
`It is thus evident that the nail plate as a membrane
`
`
`
`
`
`
`
`
`behaves in a manner widely different from the
`
`
`
`
`
`
`
`epidermis (stratum corneum). There are other dif-
`
`
`
`
`
`
`
`ferences. The absolute rate of water transpiration
`
`
`
`
`
`
`
`
`
`
`through the nail is faster than through the intact skin
`
`
`
`
`
`
`
`
`(~10 times) and, if the rate is thickness-normalized,
`
`
`
`
`
`
`
`
`
`
`the ratio is approximately 1000 in favour of the nail.
`
`
`
`
`
`
`
`
`Over a wide polarity range nail plate permeability is
`
`
`
`
`
`
`
`
`
`inversely related to polarity while the reverse is true
`
`
`
`
`
`
`
`
`for the stratum corneum. The declining nail plate
`
`
`
`
`
`
`
`permeability appears related to decreasing affinity of
`
`
`
`
`
`
`
`
`the keratin matrix for the higher alkanols. Attempts
`
`
`
`
`
`
`
`
`to confirm this supposition by way of equilibrium
`
`
`
`
`
`partitioning were not entirely successful.
`
`
`
`
`
`
`At extreme hydrophobicities (ZC8) a new path-
`
`
`
`
`
`
`
`
`way for diffusion through the nail becomes evident.
`
`
`
`
`
`
`And from n-octanol
`to n-dodecanol equilibrium
`
`
`
`
`
`partition coefficients
`increased exponentially,
`a
`
`
`
`
`
`
`
`
`trend generally supportive of the lipid character of
`
`
`
`
`
`
`
`
`the route. A partition coefficient for n-dodecanol of
`
`
`
`
`
`
`
`
`
`131 i 24 was obtained. If it is assumed that this C12
`
`
`
`
`
`
`
`homologue is concentrated exclusively in the lipid
`
`
`
`
`
`
`
`domain, which overall
`is estimated to occupy
`
`
`
`
`
`
`approximately 0-01 volume fraction, then dodecan-
`
`
`
`
`
`
`
`
`ol’s intrinsic partition coefficient would be 13 000.
`
`
`
`
`
`
`
`
`
`
`This value is only a little over twice the value
`
`
`
`
`
`
`
`computed from the permeability coefficient using a
`
`
`
`
`
`
`
`
`
`
`fractional area for diffusion of 5 X 104. Given all
`
`
`
`
`
`
`
`
`uncertainties, this is in reasonable if not fortuitous
`
`accord.
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`It seems likely to us that the alkanol permeability
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`pattern of the nail plate reflects general nail behav-
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`iour and thus suggests how other low molecular
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`weight organics might permeate. If this supposition
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`is true, then very polar compounds might be surpris-
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`ingly easily delivered through the nail plate to
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`underlying tissues. The fact that urea can be used to
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`chemically loosen and separate the nail plate from its
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`bed is a supporting observation (Farber & South
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`1978). The low incidence of problems associated
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`with the use of powerful hydrophobic organic
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`solvents in nail laquer seems equally reinforcing.
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`Certainly toxic and irritant properties of substances
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`measured via patch tests on skin cannot be extrapol-
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`ated to the nail. Moreover, physicochemical criteria
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`governing the selection of therapeutic candidates to
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`treat nail disorders would seem to be very different
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`from the established criteria used for drug selection
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`for the skin.
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`Page 5 of 6
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`Page 5 of 6
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`

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`NAIL PERMEATION BY HOMOLOGOUS ALCOHOLS
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`REFERENCES
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`Harrison, D., Speakman, J. B. (1958) Textile Res. J. 28:
`1005-1007
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`Hashimoto, K. (1971a) Ultrastructure Res. 36: 391-410
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`Hashimoto, K. (1971b) Arch. Derm. Forsch. 240: 1-22
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`Hashimoto, K., Bernard, G. G., Nelson, R., Lever, W. F.
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`(1966) J. Invest. Derm. 47: 205-217
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`Ho, N. F. H., Park, J. Y., Morozowich, W., Higuchi, W. I.
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`(1977) In: Roche, E. B. (ed.) ‘Design of Biopharmaceut-
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`ical Properties through Prodrugs & Analogs. American
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`Pharmaceutical Association, Washington, pp 136-227
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`Hwang, S., Owada, E., Yotsunganagi, T., Suhardja, L.,
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`Ho, N. F. H., Flynn, G. L., Higuchi, W. I. (1976) J.
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`Pharm. Sci. 65: 1574-1578
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`Scheuplein, R. J. (1965) J. Invest. Derm. 45: 334-346
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`Spruit, D. (1971) Ibid. 56: 359-361
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`Tilgr/112191; W. J., Higuchi, T. (1961) J. Invest. Derm. 37:
`
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`Walters, K. A., Flynn, G. L., Marvel, J. R. (1981) J.
`Invest. Derm. 76: 76-79
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`Zaias, N., Alvarez, J. (1968) J. Invest. Derm. 51: 120-136
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`Baden, H. P. (1970) J. Invest. Derm. 55: 115-122
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`Baden, H. P., Goldsmith, L. A., Fleming, B.
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`Biochim. Biophys. Acta. 322: 269-278
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`Behl, C. R., Flynn, G. L., Kurihara, T., Smith, W.,
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`Higuchi, W. I., Ho, N. F. H., Pierson, C. L. (1980) J.
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`Invest. Derm. 75: 346-352
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`Blank, I. H. (1964) Ibid. 43: 415-420
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`Burch, G. E., Winsor, T. (1946) Arch. Derm. Syph. 51:
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`39-41
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`Ca uto, R., Dadati, E. (1968) Arch. Klin. Exp. Derm. 231:
`44-354
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`Durrheim, H., Flynn, G. L., Higuchi, W. I., Behl, C. R.
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`(1980) J. Pharm. Sci., 69: 781-786
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`Farber, E. M., South, D. A. (1978) Cutis 22. 689-692
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`Flynn, G. L., Durrheim, H., Higuchi, W.
`I.
`(1981) J.
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`Pharm. Sci. 70: 52-56
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`Flynn, G. L., Yalkowsky, S. H., Roseman, T. J. (1974)
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`Ibid. 63: 479-510
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`Forslind, B. (1970) Acta. Derm. Venereol 50: 161-168
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`Forslind, B., Thyresson, N. (1975) Arch. Derm. Forsch.
`254: 199-204
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`(1973)
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`33
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`Page 6 of 6
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`Page 6 of 6
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