498 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS Brauner and McFarlane (119) showed that it has some relevance in the absorption of steroids. The steroids were chosen to span as wide a range as possible in the presence of polar groups within a restricted range of molecular weights (oestrone mw 270.3 to hydrocorfisone mw 360.4). Nevertheless, a thousand- fold difference between these two compounds was observed in permeability studies in vitro with human cadaver skin. Skin permeability of the other steroids in the series (progesterone, pregnenolone, hydroxypregnenolone, hydroxyprogesterone, cortexone, testosterone, cortexolone, corticosterone, cortisone, hydro-cortisone and aldosterone) were of an intermediate degree between that of oestrone and hydrocortisone. The rate of permeability in this series, as in the examples quoted in previous paragraphs, correlated with the lipid solubility of the compounds and was inversely related to the polarity. But the difference in lipid solubility between the extremes in this series of steroids was 50-fold which is in strong contrast to the 1 000- fold difference in permeability so that the authors could attribute only a small part of this difference to their lipid solubility. They postulated that the more polar molecules possessed a decreased mobility not only because they were less lipid soluble but also because of a stronger chemical binding with the stratum corneum. Thus, in the case of steroids, the chemical structure influenced to a significant extent the absorption through the stratum corneum. This possibility of a chemical binding with components of the stratum corneum may explain the formation of a corticosteroid 'reservoir' in this layer (120). Chemical binding may also explain the failure of a series of synthetic artionic surfactants to penetrate the stratum corneum from low concentra- tions of aqueous solutions (121-123). The slower rates of absorption of trivalent compared with hexavalent chromium at concentrations of 0.017-0.239 M (124) is also probably due to a difference in the ability of these two compounds to interact with the proteins of the stratum corneum. In the trivalent form, chromium binds with the proteins of the stratum corneum three times as much as its hexa- valent form (125, 126). Hexavalent chromium is, however, reduced to the trivalent form in the skin (125) and it is thought likely that any Cr bound to the stratum corneum on the application of hexavalent compounds is largely in the trivalent form. Molecular size The percutaneous absorption of molecules much larger than those of

?ERCUTANEOUS ABSORPTION 499 steroids was studied by Tregear (127), Kastin, Arimura and Schally (128) and by Iunin (129). According to these authors such macromolecules as colloidal sulphur, albumin, dextrans, polyvinyl pyrrolidone and poly- peptides can penetrate the barrier readily if applied in solvents which possess a high lipid solubility, although they hardly penetrate at all if applied in an aqueous solvent. The studies outlined above indicate that water and electrolytes exhibit the slowest rate of penetration through the stratum corneum. In the case of other compounds, the closer to unity the water/lipid partition coefficient the greater is their rate of percutaneous absorption. Chemical structure appears to be important because of its influence on the water lipid partition coefficient and on the interaction between test compound and stratum corneum. Molecular size does not appear to be relevant unless it is of macromolecular dimensions. Solvents and vehicles DMSO and other ' accelerants' A variety of organic solvents are known to influence the percutaneous passage of chemical agents but few have been studied as intensively as di- methylsulphioxide (DMSO). It is a colourless liquid, and an excellent solvent for a variety of organi6 chemicals (130). Soon after the publication of its synthesis and of its physical properties it was realized that it had a great potential use in pharmacology because of the ease with which it traversed biological membranes (85, 131). Stoughton and Fritsch (130) investigated its effect on the percutaneous absorption in vivo of hexapyrronium bromide, naphazoline hydrochloride, flucinolone acetonide, and in vitro of hexopyrronium chloride and 4-x4C-hydrocortisone. Hexapyrronium bromide is a quaternary ammonium compound possessing anticholinergic properties and, dissolved in 95•o alcohol, inhibits sweating at the site of application at concentrations of 0.2•o and above. The addition of 20• DMSO to the solvent reduced the effective concentration to 0.008• thus increasing the potency by a factor of about 30-fold. A considerable increase in the pharmacological activity of naphazoline was observed by the addition of DMSO to the solvent. At a 0.04•o concentration in 95• alcohol, no vaso- constriction and no pilo-erection was observed at the site of topical applica- tion in 16 volunteers. Presence of DMSO in concentration of 10 %, 25 % and 50•o in the solvent produced a pharmacological effect in four out of 14, eight out of 24, 10 out of 14 treated subjects. To establish whether this