DEPLETION EFFECTS IN TOPICAL PREPARATIONS 171 11 10. 9. 8. 7. 6. Latency time n=10 Penetration measurement n=12 ...."" DIM ... ..' ... ..' ... ... .. Duration n--11 4: IPM ...'" DIM ß ... .. .•.." CCT .: 0 T' T' T'""'"'"'"' ...... T'" ...... 0 5 6 7 8 90 I 6 90 6 9 ¾T/ST Figure 3. Bioavailability factors fh as a function of the relative effective activity coefficient •/T/s-r. The dotted line represents the function fh -- YT/s•r - Error bars are 95% confidence intervals. R values, this time period, i.e., the duration of the effect, is reduced. As mentioned earlier, the most accurate bioavailability factors may be determined from the low-dose range of the curves where the duration of the effect is rather short (Figure 2b). However, even in the low-dose range of the curves, the theoretical f values will never be reached, leading to the conclusion that the duration of the effect is an unsuitable parameter of response. The response parameter 1/LT is only marginally influenced by decreased penetration rates because the onset of the erythema occurs within minutes after appli- cation of the ointment. Thus, permeant depletion will only become obvious if the permeant penetration rate is markedly reduced. High penetration rate constants may lead to an underestimation of the response values in the low response region of the concentration-response curves, which is the reason for the deviation of the fh values from the theoretical or the infinite-dose values as shown with DIM (Figure 3). With increas- ing permeant concentration in the vehicle and thus decreasing latency time, this devia- tion becomes less evident and even disappears at high permeant concentrations (Figure 2a). Theoretical or infinite-dose values can only be obtained from the upper parts of the curves right below the plateau where parallelism is given (12). Generally, the higher the horizontal distance between the dose-response curves of a test and a standard preparation, i.e., the higher the RT/RsT ratio, the more pronounced permeant depletion will become, which manifests itself in underestimated bioavailabil- ity factors. It is therefore preferable to determine the horizontal distances between dose-response curves instead of concentration- or activity-response curves in order to get a better impression of the extent of permeant depletion. The greater bioavailability factors resulting from the infinite-dose penetration rate data are not only a result of the minimized permeant depletion but are also due to penetration enhancement in the case of IPM and MO. From concentration-response curves, no specific vehicle effects can be detected with MO because of an interference of penetration enhancement with permeant depletion (Figure 3). For this reason, no penetration- enhancing effect could be found with MO in a recent study (9).

172 JOURNAL OF COSMETIC SCIENCE Enhancement factors obtained with the different vehicles under infinite- and finite-dose conditions, respectively, are shown in Figure 4. In the past, enhancement factors de- scribing only the specific effects of vehicles on the properties of the barrier stratum corneum were determined by several investigators (17-19). These factors correspond to the enhancement ratio introduced by Goodman and Barry (20) and to the so-called activity-standardized bioavailability factor f•, which can be determined from activity- response curves (14). The data presented in Figure 4 again show very pronounced MN depletion for MO and DIM, which is less obvious with the parameter 1/LT. In contrast to the pharmacody- namic response data, the results of the penetration rate data clearly show that IPM and MO act as penetration enhancers. Although MO is considered to be an inert vehicle, it has been shown to fluidize the lipid bilayers of the stratum corneum to some extent, possibly a result of its branched structure (21). Depletion factors calculated as the ratio of the enhancement factors obtained under infinite-dose conditions to those obtained under finite-dose conditions are shown in Figure 5. From the data it is obvious that with both response parameters a statistically significant MN depletion may be observed. From the fact that MN depletion is sig- nificant with the response parameter 1/LT, one may conclude that the determination of the relative bioavailability was not done in the high-response region of the concentra- tion-response curves. MN depletion seems to be more pronounced with MO than with DIM. This is due to the fact that MO causes penetration enhancement in addition to the high MN activity in this vehicle. It behaves like a vehicle with a thermodynamic activity of MN, even higher than that with the vehicle DIM, which does not cause penetration enhancement of the model compound. This indicates that, among others, a high ther- modynamic activity of the permeant and penetration-enhancing properties of the vehicle may lead to permeant depletion in the vehicle. 2.4 2.2' 2- 1.8- '" 1.6- 1.4- 1.2- 1- 0.8- 0.6- 0.4' 0 n=10 CCT IPM MO DIM CCT n=12 IPM MO DIM n=11 I i CCT IPM MO DIM ........... Latency time ........... Penetration measurement .............. Duration .......... Figure 4. Enhancement factors EF calculated from response measurements and flux data according to Eqs. 4a/e. Error bars are 95% confidence intervals.