SKIN PENETRATION 489 lipid solubility and slight water solubility which enables them to pass rapidly through the skin to produce cholinergic side effects. Fitzpatrick, Griswold and Hicks (8) reported five instances of increased weight and ankle oedema in patients applying 0.2% fluorohydrocortisone acetate lotion for the treatment of eczematous dermatosis. The fluoro- hydrocortisone had penetrated the skin sufficiently to produce systemic mineralocorticoid effects. Boric acid, although now deleted from official pharmacopoeial prepara- tions, has been widely used as a topical antiseptic for many years yet Meyler (9) describes several cases of fatal poisoning due to its penetration through the skin. This is a substance which does not penetrate normal skin in significant amounts but will penetrate inflamed or abraded skin to produce serious systemic toxic effects. Occlusion with plastic film is now widely used to promote the absorption into the skin of topically applied anti-inflammatory corticosteroids. Plastic film dressings, however, must be used with care where the drug applied may produce toxic systemic effects. Vickers and Fritsch (10) reported six cases of toxic reactions after the application of naphazoline to the skin under polyethylene film. PATHWAYS AND MECHANISMS OF PENETRATION A substance may penetrate the skin either transepidermally or trans- appendageally. Palmar skin has been shown to be less permeable than other skin sites in man, even though it contains three times as many sweat glands per unit area. It seeIns unlikely, therefore, that the sweat glands represent a significant pathway of penetration. In rodents, the number of hair follicles and therefore the relative area of invaginated epithelium within hair follicles per unit area of skin is greater than in man. Yet it has been shown for many substances that penetration of rodent skin is not correspondingly higher. Autoradiographic techniques have shown that substances do penetrate down the hair follicles {11). This suggests that penetration of the epithelium within the hair follicles is similar to that surrounding them. Tregear (12) showed that tri-n-butyl phosphate penetrated pig skin equally well, whether it contained hair follicles or not. As the stratified system constitutes the major area of the epidermis in man this is undoubtedly the major route of penetration. With the exception of sodium ions and water which may be actively pulled into the skin(13) most substances are thought to penetrate the skin

4,6)0 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS by passive diffusion. This conclusion has been reached because most penerrants obey Fick's law, excised skin retains its impermeability for many days after it has been removed (14) and the stratum corneum, which is composed of metabolically inactive cells, is considered to be the major barrier to penetration. A substance may cross the stratum corneum by passing either through or between the cells. Although much work has been carried out to discover which path is followed (13, 15-17) the question still remains unresolved. FACTORS INFLUENCING PENETRATION The factors influencing percutaneous absorption have been reviewed by Shelmire (18), Higuchi (19), Wagner (20), Barr (21) and Tregear (13). The following variables may be considered:- 1. Species differences. 2. Skin age and site. 3. Skin temperature and peripheral circulation. 4. The state of the skin (normal, abraded, or diseased). 5. The area of application, contact time and frequency of re-application. t3. The degree of hydration of the skin. 7. Pretreatment of the skin. 8. The physical characteristics of the penetrant. 9. The vehicle. 10. The penerrant vehicle relationship. It has been shown that skin permeability varies between species. Thus rabbit skin is more permeable than that of the guinea-pig, while human skin is less permeable than both. This is a factor which must be considered when laboratory animals are used to evaluate the performance of new compounds. Cronin and Stoughton (22) and Marzulli (2:3) have shown that sub- stances penetrate different skin sites at different rates. Tregear (1•3) has shown that the permeability of rat skin to 5% aqueous triethyl phosphate solution decreases quite sharply during the seven days before birth, and more slowly after birth, even after the epidermis appears histologically mature. Human skin, which is sparsely covered with hair, is subject to quite rapid variations in surface temperature depending on the environment. It has been shown that the penetration rate of some substances is significantly altered by this change in temperature. The state of the peripheral circula-