?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

500 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS increase was due to an enhancement of percutaneous absorption these authors measured the passage of the •4C-labelled compounds and found that the addition of DMSO increased absorption by a factor of 6.71 in the case of hydrocortisone and 27.4 in the case of hexopyrronium-methyl-•4C. Subsequent studies in vitro showed that DMSO not only enhances percu- taneous absorption but promotes the formation of asteroid reservoir in human skin (132). Comparative studies, in vitro, showed that DMSO is superior to other solvents both in enhancing penetration and in favouring dermal retention. This was clearly demonstrated in a study of the passage of •C-labelled griseofulvin, dissolved in neat DMSO, dimethylacetamide, dimethylform- amide, ethanol or benzene, through human skin in vitro. Taking the rate of penetration of griseofulvin dissolved in benzene as unity, the ratios of penetration when the other compounds were used as solvents were 60, 40, 7 and 3 respectively. The superior property of DMSO to enhance percu- taneous transit is seen even when its concentration is 50•o in water. Thus, the ratios of penetration of •C hydrocortisone dissolved in 50•o DMSO and in neat DMAC, DMFA and 95•o alcohol was 20, 6, 4, 1. The retention of both griseofulvin and hydrocortisone in the excised skin was found to be roughly parallel to their rate of penetration and DMSO, neat or in 60•o aqueous solution, was therefore superior to the other solvents in promoting skin penetration and retention. The retention ratios were approximately 25, 5, 5, 1 when DMSO, DMAC, DMFA or ethanol were used (133). Similar results were obtained using other criteria for percutaneous absorption. After topical application of •sC-labelled hydrocortisone or testosterone, 0.9•o or 11.8•o of the •sC label appears in the urine in 5 days. Presence of 25•o DMSO in the solvent increased the excretion rate of the label approximately four-fold. Dimethylformamide in the same concentra- tion increased the penetration approximately two-fold while propylene glycol and mineral oil in 25•o concentration slightly decreased penetration (134, 135). DMSO was found effective in enhancing the percutaneous absorption of HgCla in vivo in the guinea-pig. Using the 'disappearance measurements' technique, it was found that pretreating the exposure area with 1.0 ml of neat DMSO enhanced the absorption of HgCla from a 0.239 M aqueous solution. No significant change in the rate of absorption was found at lower concentrations. In a similar experiment employing the same concentrations of mercury, the use of 1• soap or alkyl aryl sulphonate were as effective as DMSO (136).