PHARMACOKINETICS OF THE TRANSDERMAL RESERVOIR MEMBRANE SYSTEM DELIVERING BETA-ESTRADIOL - IN-VITRO IN-VIVO CORRELATION

Purpose. The aim of our study was to investigate the high fluctuations of Estradiol (E-2) plasma levels transdermally delivered in postmenop ausal women by a commercially available membrane controlled reservoir system (MCRS). Methods. The transdermal E-2 flux either out of a compl ete MCRS or across its membrane out of defined ethanol water mixtures was determined, as well as E-2 plasma profiles in 6 postmenopausal wom en produced by a MCRS. Results. The transdermal in vitro E-2 flux rate out of a complete MCRS, claimed to deliver 25 mu g/day, increased ste adily, reaching a maximum value of 2.06 +/- 0.58 mu g/h at 30 to 40 ho urs and decreased to a rate of about 0.5 mu g/h from 60 to 90 hours. N o statistically significant differences between plasma profiles calcul ated from the in vitro investigation and derived from a clinical study could be identified. The E-2 flux in defined ethanol/water mixtures a cross MCRS-membrane, adhesive and skin layer increased with increasing ethanol concentrations up to a maximum of 227 +/- 34 ng/cm(2)/h at an ethanol concentration of 62.5% (VN) and decreased with further increa se in the volume fraction of ethanol. Conclusions. In vitro as well as in vivo investigations showed high fluctuation of E-2 plasma profiles in postmenopausal women produced by the MCRS. These fluctuations are caused by a non-constant input rare of E-2 which may be due to changin g ethanol concentrations in the reservoir of the MCRS.