508 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS coml•ound while sodium salicylate is predominantly water soluble (161). The greater absorption of this acid from the hydrated ointment is probably a consequence of its greater affinity for the stratum corneum. The lower degree of absorption of the sodium salt is probably due to its much lower lipid solubility. The increased absorption of sodium salicylate from the hydrated ointment on the addition of surfactants is in conformity with their known ability to enhance percutaneous absorption when applied in an aqueous vehicle. The effects of surfactants on salicylic acid absorption is more difficult to explain. Salicylic acid has been shown to interact with substances containing polyoxyethylene groups (162) and this interaction may be expected to yield compounds with different solubilities, and con- sequently different rates of absorption. So far only the physico-chemical interactions between the test substance and the constituents of the ointment have been considered in relation to their influence on percutaneous absorption of the active agents. Physiological factors are also involved. Baker (163) points out that the application of an ointment on the skin surface may lead to 'occlusion' of the skin surface so that the normal evaporation of water is prevented. This leads in turn to an increase in the water content of the stratum corneum and as a consequence to an increased permeability of this 'barrier' layer. In his experiments Baker (163) showed that the ointments differ considerably in their ability to achieve complete suppression of epidermal evaporation of water. Soft white paraffin with or without 55/o propylene glycol was effective in this respect in the majority of patients tested. Ung. emulsificans BP and com- pound zinc paste achieved only partial suppression while anhydrous lanolin, and polyethylene glycol 1 500 failed completely in suppress- ing water evaporation. The evidence reviewed indicates that the degree to which the test substance is soluble in the continuous phase is of primary importance since this determines the extent to which it comes into contact with the epidermis. Substances that are in solution in the dispersed phase do so only to a much more limited extent. Other factors of importance are the degree of partition between the continuous and dispersed phase and between these and the stratum corneum. The former eventually determines the available concen- tration at the skin/ointment interface while the latter influences to a con- siderable extent the passage of the test substances from the ointment into the skin. Ointments, pastes and creams may enhance percutaneous absorp- tion by preventing evaporation of water from the stratum corneum thereby increasing its water content or its 'state of hydration'.

PERCUTANEOUS ABSORPTION 509 Sulphonamides do not appear to follow these general rules. Thus, the determination of the rate of penetration of sulphanilamide, sulphathiazole, sulphadiazine and sodium sulphacetamide applied to the shaved backs of guinea-pigs revealed that there was no difference in the rate of absorption when o/w or w/o emulsions were used (164, 165). Clearly, absorption of the compound from ointment bases is impossible to predict with any reasonable degree of accuracy. Only experimentation using the compound and the base intended for its incorporation can be of assistance in this respect. 'State of hydration' of stratum corneum Observations on human beings have shown that conditions of high relative humidity enhance the damage produced to the skin by toxic chemi- cals. Cullumbine (18) and Kenshaw (166)observed that the vesicant pro- perties of certain war gases was greater when the persons exposed were sweating freely. The influence of the water content of the stratum corneum on percutaneous absorption was studied in detail using both in vitro and in vivo techniques. Cronin and Stoughton (167) investigated the passage of •4C-labelled ethylnicotinate through excised human skin supported over a chamber containing saline. They found that immersion of the skin in water of varying temperatures prior to mounting on the chamber resulted in a five-fold increase in the passage of ethyl nicotinate. In vivo experiments are in agreement with these observations. The concentration of topically applied ethylnicotinate necessary to produce a predetermined degree of erythema on the forearm of human volunteers was reduced by 5-10 times if the forearm was previously soaked in warm or cool water (168). Soaking of the forearm of human volunteers has also been shown to increase the percutaneous absorption of steroids. In a study (132, 169) •4C-labelled trimethalone in 95• alcohol was applied to a small area of the forearm, allowed to remain for 30 min and then washed off with a standard washing procedure. Previous hydration of the arm resulted in a five-fold increase in the absorption of the glucocorticosteroid. A more effective absorption of other steroids also takes place if they are applied under occlusive dressings. A suspicion that this might be so was expressed by clinicians who observed a better clinical response to topical glucocorticosteroids when the site of application was covered by a water- impermeable covering (170, 171). This suspicion was confirmed quantita- tively (79, 80). Using graded concentrations of a glucocorticosteroid on