PERCUTANEOUS ABSORPTION 501 The marked acceleration in the rate of percutaneous absorption pro- duced by DMSO prompted a number of investigations into the local changes produced by this compound. This 'accelerant' effect is not thought to be due to increased skin circulation because this can be increased without increasing the penetration rate (115) or the skin 'clearance rate' (137). Furthermore, the accelerant effect can be observed in vitro with isolated non-perfused skin preparations (137). This in vitro effect was studied in detail by Sweeney, Downes and Matoltsy (138). Their results show that there was no significant change in the rate of passage of water through the skin when the epidermis was treated for 30 min with aqueous DMSO in concentrations up to 50•o. At a concentration of 60•o a two-fold increase was observed, at 80•o and 90•o the increase was 10-fold and 90-fold respectively. The changes in permeability in this study were irreversible and the authors concluded that permanent damage to the stratum corneum had resulted from this treatment. The fact that the concentration of DMSO was far more significant than the actual time of exposure in producing this effect was thought to be particularly relevant. The in vivo work indicating a faster rate of absorption of corticosteroids dissolved in 25•o DMSO appear to contradict the results of this in vitro experiment. It would seem possible, however, that the steroids and DMSO may have penetrated the stratum corneum because of a favourable water/ lipid partition coefficient without producing damage. Further in vivo studies failed to support the conclusion of Sweeney et al (138) that the damage produced by DMSO on the stratum corneum was irreversible. Exposure of the flexor aspect of mid-forearm to pure DMSO for 30 min in three volunteers increased the water loss 8-, 11-and 17-fold respectively but the effect was reversed within 6-8 h (139). This discrepancy may be a reflection of the ability of normal skin to repair the damaged stratum corneum. Baker (139) attributed the effect of DMSO to its strongly hygroscopic properties so that its presence in the stratum corneum greatly increases the permeability properties by increasing the water content of this layer. How- ever, the detailed studies of Allenby et al (137) indicate that profound chemical changes occur. DMSO extracted lipoproteins from the stratum corneum, an effect which is likely to disorganize its fibrillar structure. Electron-microscopic studies on the guinea-pig skin treated with neat DMSO show considerable structural damage (62). Compared with the data available on DMSO, information on the mode of action of other 'accelerants' is sparse. Organic solvents, such as benzene,

502 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS ether and to a lesser extent, alcohol, have been shown to facilitate absorp- tion of both water-soluble and lipid-soluble substances (107). According to Rothman (21) these solvents increase the permeability of the skin by 'attacking lipid building stones of the cell membrane'. Valette, Cavier and Savel (140) investigated another series of organic solvents with respect to their ability to enhance the percutaneous absorption of physiostigrnine. The solvents belonged to eight classes of organic compounds: saturated aliphatic hydrocarbons, aromatic hydrocarbons, cyclic hydrocarbons, terpenes, primary saturated alcohols, ethylesters of saturated aliphatic acids and acetate esters of primary saturated alcohols. In this series, those solvents with the longer aliphatic chains were more efficient accelerants, while the presence of hydroxyl groups made the solvent less efficient. Baker (139) studied the effects of dimethylformamide and dimethylacetamide on the cutaneous barrier to water and thought that both these agents promoted percutaneous absorption by enhancing the state of hydration of the stratum corneum as a consequence of their hygroscopic properties. Allenby et al (137) compared the in vitro effect of a number of 'accelerants' on the pene- tration ofsaP-tri-n-propylphosphate (TPD), on the swelling of the skin and on its electrical conductivity. In this series, isopropanol, xylene, 0.9•o NaC1 in water, 8 M urea, methanol, chloroform, DMSO and phenol were studied. The most effective agents in promoting absorption of 8aP-TPD, in causing skin swelling and in reducing skin impedance were 8 M urea and DMSO, the least effective was isopropanol. All the substances which induced an accelerated absorption of oaP-TPD extracted some organic component from the epidermis. In previous studies, Elfbaum and Laden (141-143) using picrate ions showed that some accelerants cause swelling of the stratum corneum as well as increased penetration, while Vinson et al (60) and Montes et al (62) showed that accelerants may extract structural material from the stratum corneum. These results, according to Allenby et al (137) suggest that accelerants owe their effectiveness, at least in part, to their ability to lower the barrier properties of the stratum corneum by modifying its natural structure. The ease with which lipids dissolve in the organic solvents mentioned might suggest that these increase the rate of percutaneous absorption by removing the lipids from the stratum corneum, and Szakall (144) showed that in vivo, defatting human skin by swabbing with ether for 3 rain resulted in an increase in the amount of water absorbed lasting for 2 h. However, Winsor and Burch (145) have been unable to show an increase in the