498
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`COMMUNICATIONS
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`J,’Pharm. Pharmacol. 1985, 37:498--499
`Communicated December 17 1984
`Penetration of.the . uman hal!/plate: the effects of ovehicle pH on
`" ihe 15ermeation’of iniConazole
`
`(~) 1985 J. Pharm Pharmacol.
`
`.
`.. ..
`.
`. .- .
`KENNETH A. WAL’rER$*; GORDONL. FLYNNI J.ot-tt~R: MA~.VEL’~, Univemttv of Michigan, College of Pharmacy. Ann Arbor.
`Michigan 48109i ¢,DermaiologiCat Division. O)’rh’o Ph’armaceutical Corpo/’ation, Raritari. New-Jersey, USA
`o
`
`5
`
`In Order to assess the relative permeability of the nail plate
`tO ionized and Unionized drugs.the permeation of mtcon-
`azole ate varying pH has been followedas a function of tiihel
`’~a~ i~H was adjusted from 3.1 to’8.2 to obtain between 5
`~md 100% di~ssoeiation of the drug. No sigr~ificant difference
`; ¯ in. :the .-rate c~f permeation ,w, as~de~onst,rateu., The. data.
`su~ests that the ionic foi’rn Of mi~0nazoie disS61"~e~"as
`easdy in ihe nail plate aS the free. base and; therefore.
`topical bioavailabifity can be enhanced by decreasingthe
`formulation pH thereby increasing d~ug solubility¯ . . -
`
`-Prevtous studies on the physicochemical ptoperues of
`the htaman nail plate have ,indicated a marked difference
`between the permeability ~chara~teristics of this tissue
`and thatof~the epidermis t Waiters et al 1983). Whereas
`the straxum corneum behaves as .a lipid barrier.to the
`permeation’of low molecular weight chemicals (Scheu-
`plein 1965: Durrheim et al 1980~ the nail plate exhibits
`behaViour similar to:fhat of a,hydrogel of high~onic
`strength’. Furthermore chemicals, such ~s dimethylsul-
`phoxide, Which have been shown to be;remarkably
`effective as enhancers of skin penetration (Scheuplein
`& Ross 193’0: Astley & Levine 1976J have shown little
`promise as accelerators of nail plate permeability
`(Kligman 1965, Waiters & Flynn-1981). These differ-
`ences"betWeen tWO t~ssues Of such intimately related
`origins Cannot be attributed to any obvious differences
`in’morphogenests: rather the inconsistencies appear to
`¯ be due to differences in the relative amounts.of the lipid
`and protein~regimes (Walterset al 1983) and perhaps
`the~physieoehemical qualities of each of.these phases.
`Stratum corneUm contains ’at least 10% lipid, mo’gt of
`WhiCh ~s believed to be intercellular, whereas the nail
`- platte cont~ains no more than t°A; (Baden et al 1973). The
`low lipid fraction of the nail,As ¢onsistem in makeup and
`amount with lipids derived mostty from the residual cell
`membranes. In its- normal state ~the nail als~ contains
`less water than the’ stratum eorneum, about 10%
`moisttire by actual estimate,(Baden et al 1973) Permea-
`tion:data for the homologous nonelectrolytes, the
`n=alkanols,-indicate :the .relativi~ importance of the
`various regimes Of .the nail plate in determining its
`barrier properties andshow the nail to be a.far different
`membrane than the stratum corneum, In this communi-
`
`* Correspondeiice and present:address: Fisons pie,
`Pharmaceutical Division. Bakewell Road Loughborough,
`UK.
`
`cauon further evidence of unique behaviour of the nail
`plate membrane ts presehted. Specifically the permea-
`tion of a Weak electrolyte, miconazole, does not appear
`to be influenced bv its degree of iomzation.
`
`Tritiated mic0nazole(1-[2~a,-dichloro-13-(cid:128)2 a-dichloro-
`benzy 6xy)phenet~yl]imidaz01e) was supp’tied by O~ho
`:Ph:~rmaceutical Corporation.. The-radiolabelted chem-
`ica! was diluted with 0.9% NaCI before use. Detadsofthe
`diffusion cellafii5 permeation procecmres ha~’e been given
`elsewhere ~Waffers et al 1981). The permeation of
`[3.H]miconazole throdgh hydrated nail plate was followed
`as a function ofpH of the bathing medium at 37 °C. The
`pH.was adj usted’from 3-1 to8-2, with cit rate~ phosphate
`buffer¯,,to .obtain between 5 and t00% dissociation.
`During these experiments [i~C]ethanol (New England
`Nuclear) was the internal reference.
`
`O3
`
`OI
`
`!
`
`FIG. 1. pH-permeauon profile for mtconazole and ethanol
`data are mean x s.d in = 5.). Figures beneath the
`miconazole curve are % dissociations.
`
`Results and discussion
`The effect of pH on the permeability coefficients of
`miconazole and ethanol are shown m Fig. 1. It is
`expected that the permeability of a weak electrolyte
`should vary as a function of pH. providing the mem-
`brane behaves as a lipoidal structure¯ It has been
`~emonstrated~ for example, that orgamc ions can
`permeate the stratum corneum, but the rate of permea-
`tion is only a fraction of that Of the undissOciated form
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`COMMUNICATIONS
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`499
`This work was supported through the generosity of the
`Ortho Pharmaceutical Corporation, Raritan. New
`Jersey, USA.
`
`(Arita et al 1970; Wallace & Barnett 1978; Dyer et al
`1981). The low permeation rates of dissociated com-
`pounds through skin are assumed to be due to a relative
`inability of ions to partition into the lipid phases of the
`horny layer. The lack of importance of lipid phases as a
`medium of transport across the nail, as suggested
`previously (Waiters et al 1983), is reflected in the ability
`of both the dissociated and the undissociated species of
`miconazole to permeate at near equivalent rates (Fig,
`1). Miconazole is a weak base with a pK~ of 6-65 and,
`therefore, the more acidic the medium the greater is the
`degree of ionization. Yet the flux of miconazole,
`through different nail plates, is invariant at low pH
`where ionization is near complete. Moreover. the
`permeability coefficients of the reference compound.
`ethanol, follow the same pattern as a function of pH.
`The ratio, Pmiconazole/PethanoI is essentiallv invariant.
`Thus the ionic form of miconazole dissolves as easily in
`the nail plate as the free base. Since there is little or no
`dependency of permeability on pH. these data suggest
`that the overriding aspect in increasing topical bio-
`availability of miconazole, for the treatment of onycho-
`mycoses, is increasing the solubility of the drug in a
`formulation, which can be done by decreasing the pH.
`
`REFERENCES
`
`Arita. T.. Hori. R.. Anmo, T, Washitake. M.. Akatsu.
`M., Yajima. T. (1970) Chem. Pharm. Bull. 18: 1045-
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`Astley. J. P.. Levine, H. (1976) J. Pharm Sci. 65:210-215
`Baden, H, P., Goldsmith, L. A., Fleming. B. (1973)
`Biochim. Biophys. Acta 322:269-278
`Durrheim, H.. Flvnn. G. L., Hizuch W.I. Behl, C. R.
`1980) J. Pharm" Sci. 69:781-7"86
`Dyer, A.. Haves, G. G., Wilson. J. G., Catterall. R. (1981)
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`Scheuplein. R. J (1965) J Invest. Dermatol. 45:334-345
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`Wallace. S. M.. Barnett. G. (1978) J Pharmacokinet.
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`Wakers, K. A.. Flvnn.. G. L.. Marvel, J. R. (1981) J.
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