406 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS z z z lo o BENZOICACID ß NICOTINIC ACID * ACETYLSALICYLIC ACID ß THEOPHYLLINE {amount applied 1000 nm.cm -2 ) s NANOMOLES IN THE STRATUM CORNEUM AFTER 30 MINUTES OF CONTACT Figure 6. Correlation between the amount of material in the stratum corneum at the end of application (30 min) and its overall penetration within four days in the hairless rat. have shown (18) that when applied concentration was increased, penetration was in- creased up to a certain point, at which a plateau was reached. Within the range of concentration used in the present study, this phenomenon does not appear. This tends to indicate that the horny layer is unaffected by the concentrated solutions. Therefore, the permeability constant should be unaltered over the entire concentration range. Con- sidering the differences in physicochemical properties of the tested molecules, it seems that, at least for a range of concentrations, the linear relationship between dose applied and percutaneous absorption level might be taken as a general rule. Independent of the physicochemical nature of the chemical and whatever the dose ad- ministrated, there exists (Figure 8) a highly significant correlation between the total amounts that penetrated over a four-day period and the amounts recovered in the stratum corneum at the end of application time (r = 0.98, p 0.001). From a toxicological point of view, the influence of applied concentration on the overall penetration of a drug can therefore be predicted using the stripping method. From a pharmacological viewpoint, Sheth and coworkers have recently shown that the therapeutic efficacy of increasing doses of an antiviral (iododeoxyuridine) on herpes sim- plex infection can be predicted by the stripping method (19).

PREDICTING PERCUTANEOUS ABSORPTION 407 20- z 15- z uJ 10- '7 O O z z 0 BENZOIC ACID ,• . ACETYLSALICYLIC ACID /• ß NICOTINIC ACID // ß THEOPHYLLINE i i i i 125 250 500 1000 DOSES APPLIED IN NANOMOLES.CM -2 Figure 7. Relationship between dose applied and penetration rate of the test materials in the hairless rat. INFLUENCE OF VEHICLE In recent years, increasing attention has been devoted to the influence that components of a vehicle may have on enhancing or hindering skin absorption of drugs. The effects of vehicles have been reviewed in detail by several authors (20-23). It is well established that substances added to formulations as excipients and other factors, such as the physical form of the drug, not only affect its release and absorption but also its action. Unfortunately, few techniques can be used routinely to rapidly elucidate the role that a vehicle or a component in a vehicle may have on the overall absorption of a drug in vivo. The influence of nine vehicles on the in vivo percutaneous absorption of •4C benzoic acid was studied in the hairless rat using the stripping method. Twenty }xl of each vehicle contained 200 nmol of (ring •4C) benzoic acid (specific activity 40 mCi/mmol, purity 98%). After this time, the total percutaneous absorption and stratum corneum reservoir were assessed as previously described (see Part I). As shown in Table IV and Figure 9, although the vehicles that were used were simple in composition, the total amount of benzoic acid that penetrated over four days varied by a factor of 50, demonstrating the importance of vehicle in skin absorption.