PERCUTANEOUS ABSORPTION 507 preparations in which the valerate was incorporated in aqueous cream BP, oily cream BP, and white soft paraffin BP. The reverse effect was found when fluocinolone acetonide was used in these vehicles instead of the valerate. The most marked vasoconstrictor effect was observed when fluocinolone acetonide was incorporated in aqueous cream BP and in the oily cream, it was less with white soft paraffin as an ointment base and markedly less with Carbo•vax 1500. Further work carried out by the authors (159) showed that the physical state of the steroid may have been responsible for this difference. Thus, using the microcrystalline rather than the coarse granular form improved skin absorption from white soft paraffin so that the degree of vasoconstriction produced was equal to that observed with the steroid incorporated in aqueous or oily cream BP. The improved absorption which accompanied this change in the physical state may be due to an improved contact with the skin surface since incorporating the steroid dissolved in 5•o propylene glycol, thus improving still further skin contact, increased skin penetration from these two ointments and still further from white soft paraffin. Christie and Moore-Robinson (160) also found that fluclorolone acetonide produces a better vasoconstrictor effect when dissolved in propylene glycol and then incorporated into a 'petrola- tum' ointment base. They found furthermore that the presence of 15•o or 30• cetyl alcohol further increased the vasoconstrictor effect. According to the authors the addition of cetyl alcohol has the effect of increasing the concentration of the steroid in the propylene glycol and since it is this liquid phase that is likely to have the most intimate contact with the skin, enhanced penetration of the steroid is to be expected. Experiments in which sodium salicylate or salicylic acid were applied to the intact rabbit skin in petrolatum USP XV or hydrated petrolatum USP XV provide further illustrations of the influence of the nature of the oint- ment on percutaneous absorption (161). 4-6 h after percutaneous applica- tion of petrolatum containing 6•o salicylic acid, a concentration of 6 mg 100 ml -• blood salicylic acid could be detected. When the hydrated ointment was used, the blood concentration reached a level of 9 mg 100 ml -• blood. On substituting the sodium salt for the acid in these preparations, a peak concentration of only 1 mg 100 ml -• could be detected in the blood. Addition of the surfactants, sorbitan monostearate, polyoxyethylene 20 or 40 sorbitan monostearate to petrolatum, enhanced the absorption of salicylic acid but did not affect that of sodium salicylate. Addition of these surfactants to the hydrophilic ointment reduced the absorption of salicylic acid but improved that of sodium salicylate. Salicylic acid is primarily an oil-soluble

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'.