CORTICOID, VEHICLE, AND SKIN INTERACTION 583 concomitant use of penetration enhancers probably can be partially at- tributed to an action other than a specific barrier effect. It is extremely difficult to separate the effect of an agent on a single parameter, such as skin integrity, from its other effects on the drug and its delivery system. While a large number of materials have been reported to act as penetra- tion enhancers, only a few have been found that appear to significantly enhance penetration without severe skin damage or irritation. It should be noted that, from the standpoint of both effectiveness and safety, per- haps the best peneiration enhancer of all is water. The effect of skin hydration on percutaneous absorption has been previously discussed in this report. Since 1964, dimethyl sulfoxide (DMSO) has been exten- sively investigated as a potential penetration enhancer. It has been shown, in numerous in vitro and in vivo experiments, to enhance the percutaneous pentration of many drugs (33, 34). DMSO seems to exert its effect on skin permeability by producing structural changes, such as swelling of the stratum comeurn, and by possible replacement of water as the continuous membrane phase of the skin barri.er. The Shin The skin is an effective barrier to the penetration of a wide variety of substances. This barrier function is of the utmost importance in man's physiological adaptation to his environment and has obvious applications to the practical problems of topical therapy with drugs. The absorp- tion of drugs depends primarily upon their physical properties and, to a lesser degree, their chemical properties, as well as on the normal or ab- normal state of the skin. Absorption Pathways Penetration through the stratum corneum is not primarily inter- cellular or appendageal. The hydrated stratum corneum seems to be best described as a dense, effectively homogeneous phase into which small molecular weight, polar n, onelectrolytes dissolve with strong chemical interaction and through which diffusion occurs remarkably slowly. For substances which pen'etrate relatively rapidly, the major pathway through the skin for steady-state conditions is directly through the cells of the stratum corneum. The entire stratum corneum functions as the rate- limiting barrier in the skin. Once through the stratum comeurn, dif- fusion in the dennis increases rapidly. Percutaneous absorption of the steroids and probably other large molecules appears to occur via appendages as well as through the un-

584 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS broken s•ratum corneum. The importance of appendages or other dif- fusion shunts for a specific steroid depends upon the magnitude of the membrane diffusion constant. These are so low [or the polar steroids as to increase the likelihood of steady-state penetration through sweat ducts, follicles, or other shunt pathways (17). Physiology Age, Disease, In]itry, Er•v.'ronment--The physiological condition of the skin is of major importance in determining drug penetration. Fac- tors such as age, disease, injury, and environment which affect the in- tegrity or hydration state of the stratum comeurn will have a significant effect on percutaneous absorption. Excessive keratinization (corns, calluses), reduced keratin sloughing (ichthyosis), and increased stratum granulesum activity (lichen planus) can all be expected to result in a denser stratum comeurn and reduced percutaneous absorption. In these cases, occlusive vehicles which en- han.ce hydration or "penetration enhancers" might prove of value. In- fection, abrasion, penetrating wounds, and decreased stratum granulesum activity, such as seen in psoriasis, damage the integrity of the stratum comeurn and result in greatly increased percutaneous absorption. If the barrier is absent, the skin acts as a perfect "sink" or receptor and the release from the vehicle is ,the rate-limiting step. Similarly, the partial ravages of age and environment which lead to dehydration can inhibit drug absorption. Either insult, carried to ex- treme, can result in sufficient damage to destroy the skin barrier. FORMULATION DEVELOPMENT--A CASE HISTORY Solubility Considerations An actual case history of the development of a highly efficacious topi- cal corticoid product will now be considered. Earlier in this paper were described the various biological screens such as the thymelyric, antigranu- loma, fibreblast, rat ear, and vaseconstrictor assays which were used to help select the highly potent corticoid, fluocinonide. By means of the in vitro release, skin diffusion studies and the vaseconstrictor assay, it was possible to determine the effect of the physical-chemical properties of fluocinonide on release and penetration. The next ste,• was to design vehicles which would provide maximum therapeutic efficacy. Several different formulations were investigated. From previous studies, we arrived at a general goal for topical corticoid