DEPLETION EFFECTS IN TOPICAL PREPARATIONS 173 0.9 0.5- , 0.4- . ß 0.2- Latency time Duration n=10 n=11 i i i i i i 0.1, 0 COT IPM MO DIM COT IPM MO DIM Figure 5. Depletion factors DF calculated for the response 1/LT and D according to Eq. 5. Error bars are 95% confidence intervals. From the presented results it may be concluded that any increase of the penetration rate constant may lead to permeant depletion. The mathematical elimination of parameters such as the thickness of the applied ointment formulation or the permeant solubility in the vehicle in order to differentiate between vehicle effects does not eliminate their influence on permeant depletion. Because of the insufficient parallelism of the dose- response curves, the duration of the erythema is an unsuitable parameter for the evalu- ation of thermodynamic or specific vehicle effects. In the case of the response parameter 1/latency time, correct estimations of the relative bioavailability can be expected only in the high-response region. Permeant depletion in the vehicle has to be considered par- ticularly if the permeant solubility in the vehicle is low and/or in the case of vehicles with penetration-enhancing properties. It can be avoided either by application of sus- pension-type preparations or by using vehicles with high dissolving capacities. REFERENCES (1) J. L. Zatz, "Percutaneous Absorption: Computer Simulation Using Multicompartmented Membrane Models," in Percgta,eogs Absorptio,, R. L. Bronaugh and H. I. Maibach, Eds. (Marcel Dekker, New York, 1985), pp. 165-181. (2) R. H. Guy and J. Hadgraft, A theoretical description relating skin penetration to the thickness of the applied medicament, I,t. J, Pharm., 6, 321-332 (1980). (3) E. R. Cooper and B. Berner, Finite dose pharmacokinetics of skin penetration, J. Pharm, ScL, 74, 1100-1102 (1985). (4) J. L. Zatz, Influence of depletion on percutaneous absorption characteristics,J. Soc. Cosmet. Chem., 36, 237-249 (1985). (5) W.J. Addicks, G, Flynn, N. Weiner, and R. Curl, A mathematical model to describe drug release from thin topical applications, Int. J. Pharm., 56, 243-248 (1989). (6) W. Addicks, N. Weiner, G. Flynn, R. Curl, and E. Topp, Topical drug delivery from thin applications: Theoretical predictions and experimental results, Pharm. Res., 7, 1048-1054 (1990).
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