j. Cosmet. Sci., 49, 165-174 (May/June 1998) Ouantification of depletion in solution-type topical preparations in vivo CLAUDIA S. LEOPOLD, Department of Pharmacez/tical Strafie Technology, Heinrich Heine University, Universiti/tsstrasse 1, 40225 Di/sseldorf Germany. Accepted for publication May 15, 1998. Part of this paper was presented as a poster at the AAPS Annual Meeting and Exposition, Miami Beach, FL, November 5-9, 1995. Synopsis To distinguish between thermodynamic, penetration-enhancing, and permeant depletion effects of solution- type transdermal preparations, two sets of human in vivo permeant penetration data obtained under finite- dose and infinite-dose conditions, respectively, were compared. The measurement of the pharmacodynamic response of a permeant or the determination of permeant penetration rates under finite-dose conditions includes all three types of vehicle effects, whereas under infinite-dose conditions permeant depletion does not play a significant role. Four lipophilic liquids (caprylic/capric triglyceride, isopropyl myristate, light mineral oil, and dimethicone 100) were used as vehicles. The reciprocal of the time of onset of an erythema (1/LT) and the duration of the erythema D induced by the model compound methyl nicotinate served as response parameters. Steady-state penetration rate measurements were made with a recently developed glass chamber system. Bioavailability factors f and enhancement factors EF were determined from both methyl nicotinate penetration rates (infinite-dose conditions) and the horizontal distances between concentration- response curves (finite-dose conditions), with caprylic/capric triglyceride as the standard vehicle. Permeant depletion was quantified by dividing the enhancement factors determined under infinite-dose conditions by those under finite-dose conditions. These ratios were called depletion factors DF. Significant methyl nico- tinate depletion was observed with both response parameters. However, the most accurate bioavailability factors may be obtained with the response parameter 1/LT, especially if they are determined from the horizontal distances between the curves in the high-response region where parallelism is given. INTRODUCTION With solution-type permeant preparations applied to the skin, three types of penetra- tion-influencing effects may be observed: (a) thermodynamic effects resulting from different permeant solubilities in the vehicles, (b) penetration-enhancing effects caused by an interaction of the vehicle with the barrier stratum corneum, and (c) permeant depletion in the vehicle in the case of finite-dose conditions. Permeant depletion may result from a high thermodynamic activity of the permeant in the vehicle and/or from pronounced penetration enhancement caused by vehicle com- ponents or by the vehicle itself. The extent of this effect depends on the thickness of the

166 JOURNAL OF COSMETIC SCIENCE applied ointment layer. Because ointments are usually applied to the skin as thin films, decreased permeant penetration rates always have to be taken into consideration (1). Permeant depletion may lead to a pronounced reduction of the permeant-induced re- sponse and thus have a major impact on the quantification of vehicle effects using pharmacodynamic response data. More or less sophisticated mathematical models have been developed to describe per- meant depletion (1-7). The relationship between the applied drug dose and the phar- macodynamic response using the response parameters' duration and time until onset of the effect has been described mathematically by Levy (8). It was found that under certain conditions a linear relationship between drug dose and response may be obtained. The objective of this study was to quantify vehicle effects, in particular permeant depletion in the vehicle, using data from two recently conducted human i, v/vo pen- etration studies that were performed under finite-dose and infinite-dose conditions, respectively (9,10). MATERIALS AND METHODS Both in vivo studies included the following lipophilic vehicles: dimethicone (DIM Baysilone M 100 ©, Bayer AG, Leverkusen, Germany), light mineral oil (MO Parafiuid Minerali31gesellschaft, Hamburg, Germany), isopropyl myristate (IPM: Henkel KGaA, Dtisseldorf, Germany), and caprylic/capric triglyceride (CCT Hills Troisdorf AG, Trois- doff, Germany). CCT was chosen as the standard because it was expected to show the least pronounced depletion due to the high solubility of the model compound in this vehicle and its inert behavior with regard to skin penetration enhancement (10). The rubefacient methyl nicotinate (MN Janssen Chimica, Beerse, Belgium) was used as a model compound. The measurements of the response and the determination of the MN penetration rate were done with 11 (response parameter duration), 10 (response parameter 1/time of onset) and 12 (penetration rate measurements) healthy volunteers, respectively. All experiments were done under occlusion conditions under the assumptions that the MN preparations do not undergo significant changes in composition and that the influence of boundary layers is negligible (11). MEASUREMENT OF THE RESPONSE (FINITE DOSE) Solution-type ointment formulations of the above-mentioned lipophilic liquids were prepared by adding either 10% polyethylene (10 kdaltons) or, in the case of DIM, dimethicone (1,000 kdaltons) as gelling agents. Five ointment preparations, containing different amounts of MN, depending on its solubility, and two placebo formulations were applied to the ventral side of each forearm in a double-blind manner under occlusion conditions as described previously (9). The thickness of the applied ointment films was 50 12m, and the area of application amounted to 3.14 cm 2. For every applied preparation, the time of onset of the erythema LT and the duration of the erythema D were determined visually (9). With the resulting data, concentration-response curves were plotted, which allowed the determination of the relative bioavailability as the horizontal distances between the standard curve and the test curves.