SKIN PENETRATION 625 vehicle itself. The bulk of evidence now indicates that unless an applied material is capable of passage either through the skin barrier or follicles the vehicle is of subsidiary importance. However, experimental and clinical evidence is now appearing which points the way to vehicles which may materially affect skin penetration (54, 56, 60, 62, 69-71, 87, 88). The previous physico-chemical discussion of solubility and partition coefficients, as well as in vivo (54) and in vitro (25) studies, has supported the postulate that the release of a substance will be favored by the selection of vehicles having a low affinity for the penetrant, or in which the drug is least soluble. This is consistent with the view that the rate of release is governed by the vehicle to receptor phase (stratum comeurn) partition coefficient. For a given concentration of drug in certain vehicles, the activity coefficient of the drug, and consequently the thermodynamic activity of the drug in the vehicle at that concentration, may vary by a factor as much as a thousandfold from one vehicle to the next. Solutes held firmly by the vehicle, such as when the drug forms a soluble complex with the vehicle, exhibit low activity coefficients hence, the rate of release from such drug-vehicle combinations will be slow. Solutes held "loosely" by the vehicle (less affinity of the vehicle for the drug or solute) exhibit high activity coefficients therefore, the rate of release from such drug- vehicle combinations will be faster (11). This was shown by Blank and Scheuplein (24, 25) in a study of the penetration of polar ethanol and nonpolar heptanol t/tom water and lipid solvents. Ethanol penetrates better from oils than from water, but the reverse is true for heptanol. The polar alcohol tends to stay in the polar vehicle and not be transferred to the skin, but it is transferred from oily vehicles the reverse occurs for the nonpolar alcohol. Dempski et al. (71) noted that dexamethasone was released more rapidly from gelled isopropyl myristate than t/tom petrolatum and two other nonaqueous vehicles. Their studies demonstrated that the in vitro release of a medicinal agent is a function of the degree of solubility of that agent in both the base and its surrounding media. The medicinal must be sufficiently soluble in a nonaqueous base to allow for its release into an aqueous medium but not so soluble to preferentially remain in that base. If the drug is insoluble in its vehicle, it appears that only the drug particles available at the surface of the vehicle will dissolve into an aqueous medium. If the drug is partly soluble in the vehicle, it seems to dissolve and diffuse throughout the medium as it dissolves

626 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS from the surface, and then returns to the surface for release into the surrounding medium. All the studies cited deal with the use of a skin membrane either in vitro or in vivo. Recently, solvents have been used to act as receptor phases to simulate the skin. Chloroform (54, 62) and isopropyl myristate (62, 69) have served as "sinks." Since they are immiscible with the alcohol-water it is not necessary to introduce an artificial membrane to separate them from the vehicles. Poulsen and coworkers (69) measured the release of fluocinolone acetonide and its acetate ester into an isopropyl myristate phase. The vehicles used were mixtures of propylene glycol and water gelled with Carbopol 934 and diisopropanolamine. The studies showed that optimal release was obtained from vehicles containing the minimum concentra- tion of propylene glycol required for complete solubilization of the corticosteroid. The poorest release rates were obtained with very high concentrations of propylene glycol. The results indicated that the im- portant factors influencing the release into the receptor phase were the solubility in the vehicle and the partition coefficient of the steroid be- tween the vehicle and the receptor phase. The findings appear to indi- cate that each compound requires individual formulation based on its solubility characteristics and the formulation may also need modification for different concentrations of the agent to obtain maximal release rates. Busse et al. (62) used both chloroform and isopropyl myristate (IPM) as separate receptor phases in studies of betamethasone valerate in oint- ment bases. The rate of release of the steroid into the chloroform phase from a paraffin ointment was about 4.5 times that from a similar ointment containing 10% hydrogenated lanolin. Conversely, in the IPM system, the reverse occurred. The in vitro results suggest the IPM system more adequately represents the skin. "A cceleran t" Solyen ts In the past ten years attention has focused on methods of increasing the rate of absorption of topically applied drugs. So far, the one method that has come into everyday use is the application of topical corticosteroids under thin plastic film (46, 47, 89, 90). This method of treatment now has widespread application in the treatment of recalcitrant psoriasis. The other method is to add materials which can combine with, or dissolve in the structures of, substances which make up the barrier. These agents have come to be known as "accelerants." To increase permeability the