Pharmacokinetics of estradiol and of estrone during application of a new 7-day estradiol transdermal patch with active matrix.

The pharmacokinetic patterns of estradiol (CAS 50-28-2) and of estrone (CAS 53-16-7) were investigated in 18 women in natural or surgical menopause during the application of a new estradiol transdermal patch with active matrix and without absorption enhancers designed for epicutaneous applications of 7 days (hereinafter called "patch 7D"). The study was made with randomized and balanced sequences of applications in cross-over of either patch 7D or of an authorized estradiol transdermal patch with a nominal release rate of 50 micrograms/day estradiol designed for a twice-a-week epicutaneous application (hereinafter called "patch 50"). The sequences consisted of applications for 3 weeks either of 3 patches 7D or of 6 patches 50. The patches were applied on the skin of the hips or upper buttocks. The serum samples were obtained during the 1st and during the last week of application of the patches. Estradiol (E2) was assayed in serum by a double-antibody RIA method selective for free estradiol. Estrone (E1) was assayed in serum using a 3H-estrone RIA method. The steady state with regard to E2 and E1 was achieved already during the application of the 2nd patch. Patch 7D provided within 6 h an increase of the E2 concentrations in serum from the basal postmenopausal level of less than 3 pg/ml to therapeutically effective concentrations. The Cmax of E2 of 45 pg/ml was reached on average after 25 h, the concentrations of E2 remaining at sustained and therapeutically effective levels during the whole application of patch 7D. At steady state, during the 3rd week of application, the Cav was on average 31 pg/ml. With a small delay, E1 also increased from the basal 15 pg/ml to a Cmax of 41 pg/ml after 44 h. At steady state, during the 3rd week of application, the Cav was on average 38 pg/ml. Patch 7D provided a similar bioavailability as patch 50 with regard to the rate and the extent of absorption of E2, as shown by the AUCs during the 7-day applications of one patch 7D compared to those during the 7-day applications of 2 patches 50. The release of E2 from patch 7D is therefore similar to that of patch 50, i.e. on an average of 50 micrograms/day over a 7-day period of application. The E2/E1 ratio increased from the postmenopausal values lower than 0.2 found before the application of patch 7D to average values of 0.67, i.e., to values that are normally found during the fertile life of the woman. The improvement of the E2/E1 ratio occurred already in the first 6-12 h of application of patch 7D. The E2/E1 ratio returned rapidly to the initial low postmenopausal levels after removal of the patch. Patch 7D was well tolerated by the skin, probably because it does not contain absorption enhancers. It provoked, however, some systemic adverse reactions typical of E2 overdosing. In the therapeutic practice these adverse reactions can easily be avoided using patches 7D of lower strength. No drop-out due to systemic or local intolerance occurred. The adhesion of patch 7D on the skin was good. During the application of a total of 54 patches, only in one occasion one patch became partially detached (about 40% of the total area) from the 3rd to the 7th day during the first 7-day period of application.