SKIN PENETRATION 623 Cronin and Stoughton (66), studying the penetration of nicotinic acid and ethyl nicotinate, were able to show a very dramatic difference (37,000-fold) between the penetration rates of the two materials. They postulated that the differing ether/water partition coefficients of the two com?ounds were at least in part responsible for the difference. Aprotic molecules such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF), and dimethylacetamide (DMA), with high lipid and water solubility and the capacity to form strong hydrogen bonds, penetrate skin themselves and aid in the penetration of other agents. The positive permeation effects of solubility and partition coefficient characteristics are perhaps best illustrated with the corticosteroids. Triamcinolone possesses five times the systemic activity of hydrocortisone but only one-tenth its topical activity. Conversion of triamcinolone to its acetonide yields a more favorable lipid/water partition coefficient and enhances the topical activity one-thousandfold (67). Similarly, betamethasone has 30 times the systemic activity of hydrocortisone, but only ten times its topical activity. Conversion to betamethasone-17- valerate, with a more balanced lipid/water coefficient, increased topical activi_ty over tenfold (68). The effects of steroid solubility are also major factors in penetration from varied vehicles (60, 69-71). Molecular Characteristics of Penetrant An inverse relationship appears to exist between absorption rate and molecular weight (16, 25, 65, 72-74). Small molecules penetrate more rapidly than large molecules, but within a narrow range of mo- lecular size there is little correlation between size and penetration rate. Diffusion constants through hydrated stratum corneum for many low molecular weight compounds appear approximately the same (75). Yet, when Feldmann and Maibach (19) determined the human urinary ex- cretion of a series of topically applied molecules of relatively similar molecular weight (ca. 200), there was a large difference in penetration of the compounds tested. The specific effect on penetration rate of the size and shape of the penetrating molecules can be determined only if the effect of size and shape can be separated from the effect of solubility characteristics. Blank and Scheuplein (25), in studies of homologous alcohols from methanol to octanol, noted that water solubility decreases and lipid solubility in- creases with increasing molecular weight, and the rate of penetration in- creases as the molecular weight increases.

624 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS Higher molecular weight materials also show variable penetration. Very large molecules such as proteins and polysaccharides go through very poorly, if at all. The use of DMSO as a penetration carrier indi- cated that substances which have molecular weights of 3000 or more cannot be transported into the skin (76). There are few published re- ports in which permeability coefficients are correlated with the size of penetrating molecules. Virtually nothing is known of the effect of molecular shape. Miscellaneous Physical Factors Other drug-vehicle factors of importance are the particle size of poorly suspended drugs, the viscosity of the vehicle, and the drug con- centration in the vehicle. A reduction in the particle size of fluocino- lone acetonide has been shown to enhance its penetration (77, 78). Where a drug exists in more than one crystalline form, the one with the highest thermodynamic activity would be expected to penetrate most rapidly, provided it is stable (11, 53). VEHICLES Factors in Release o[ Penetrant The literature on the influence of vehicles on skin penetration is con- fusing and often contradictory. The variety of experimental animals and methods of estimating penetration renders correlation of results tenuous. A lack of awareness of possible drug-vehicle interactions and of the func- tions of different vehicles (18, 79, 80), as well as a lack of consideration of the thermodynamics involved in the interpretation of results (11, 18, 53, 81), has added to the difficulties. In general, the emphasis in de- veloping vehicles has generally been placed on the compatibility, stability, and appearance of the product, rather than on the influence which the components in the vehicle had on enhancing or hindering the movement of the drug through the skin (82). Rothman (83) reviewed the literature on vehicles up to 1954, and Barr (84) to 1962. More recent reviews are those of Malkinson (1, 2), Vickers (21), Barrett et al. (79, 80), Busse et al. (62), Munro (85), and Sarkany and Hadgraft (86). Physiological availability of a topically applied drug depends on both the rate of release from the vehicle and the permeability through the skin. The drug, incorporated in the vehicle, should reach the skin sur- face at an adequate rate and in sufficient amounts. Earlier belief held that the primary factor influencing penetration through the skin was the