PLASMA PROFILES OF TRANSDERMAL 17-BETA-ESTRADIOL DELIVERED BY 2 DIFFERENT MATRIX PATCHES - A 4-WAY CROSS-OVER STUDY IN POSTMENOPAUSAL WOMEN

The aim of this study was to investigate the systemic bioavailability and plasma profiles of 17 beta-estradiol (CAS 50-28-2, E-2) after the application of two types of matrix patches for the transdermal deliver y of E-2: Menorest (TM) (the test patch) with delivery rates of 37.5, 50 and 75 mu g E-2/day and a reference patch with a delivery rate of 5 0 mu g E-2/day. All 3 test patches were identical in composition, achi eving different transdermal E-2 delivery rates by variations in the su rface area (11.0, 14.5 and 22.5 cm(2)). All 4 patches were each worn b y 24 postmenopausal women over a 4-day period (i.e. 96 h), each of the 4 treatment periods being separated by a 7-day wash-out period accord ing to a randomized, 1-way crossover design. Blood samples were collec ted before and 3, 6, 9, 12, 24, 34, 48, 58, 72, 84, and 96 h after eac h patch application. Plasma E-2 concentrations were determined by a sp ecific direct radioimmunoassay method. The following pharmacokinetic p arameters were evaluated: AUC(O-96h), C-max, t(max), C-min, C-average The course of the E-2 plasma levels over the total test period (96 h) was relatively constant for all patches. For the test patch, a linear relationship between the pharmacokinetic parameters and the different patch areas (i.e. dosages of 37.5, 50, 75 mu g E-2/d) could be shown ( correlation coefficient 0.99). The resulting C-max values for the test patch were: 44.2, 58.3, and 92.1 pg E-2/ml, corresponding to C-averag e values of 39.5, 45.5, and 70.6 pg E-2/ml. The reference patch and th e test patch, at a dose of 50 mu g E-2/d, were similar in terms of C-m ax, while the C-average, AUC(0-->96h) and C-min were significantly hig her with the test patch. The systemic bioavailability of the reference patch was comparable to that of the test patch at a dose of 37.5 mu g E-2/d: AUC(0-->96h) 3017.5 +/- 1312.4 pg/ml h for the reference patch and 3375.9 +/- 1254.7 pg/ml.h for the test patch. A physical model fo r the calculation of the course of the E-2 levels was used to describe the experimentally determined data. However, in the evening, periodic ally higher E-2 plasma levels were observed for all patches than in th e morning. From these results it can be concluded that E-2 plasma prof iles produced by the test patch are reproducible, and in the physiolom cal range consistent with the early to mid follicular level in the pre menopausal woman over 4 days (96 h), correlating with the doses admini stered (37.5-50-75 mu g E-2/d). Additionally, the systemic bioavailabi lity of the test patch at a dose of 37.5 mu g E-2/d is comparable to t hat of the reference patch at a dose of 50 mu g E-2/d.