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Pharmacokinetics of the transdermal reservoir membrane system delivering beta-estradiol: in vitro/in vivo-correlation

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Abstract

The aim of our study was to investigate the high fluctuations of Estradiol (E2) plasma levels transdermally delivered in postmenopausal women by a commercially available membrane controlled reservoir system (MCRS). The transdermal E2 flux either out of a complete MCRS or across its membrane out of defined ethanol water mixtures was determined, as well as E2 plasma profiles in 6 postmenopausal women produced by a MCRS. The transdermal in vitro E2 flux rate out of a complete MCRS, claimed to deliver 25 microg/day, increased steadily, reaching a maximum value of 2.06 +/- 0.58 microg/h at 30 to 40 hours and decreased to a rate of about 0.5 microg/h from 60 to 90 hours. No statistically significant differences between plasma profiles calculated from the in vitro investigation and derived from a clinical study could be identified. The E2 flux in defined ethanol/water mixtures across MCRS-membrane, adhesive and skin layer increased with increasing ethanol concentrations up to a maximum of 227 +/- 34 ng/cm2/h at an ethanol concentration of 62.5% (V/V) and decreased with further increase in the volume fraction of ethanol. In vitro as well as in vivo investigations showed high fluctuation of E2 plasma profiles in postmenopausal women produced by the MCRS. These fluctuations are caused by a non-constant input rate of E2 which may be due to changing ethanol concentrations in the reservoir of the MCRS.

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... It was also shown that the three in vitro models are equivalent regarding in vitro LFS studies with hydrophilic drugs and all could be used to predict the permeability of mannitol across in vivo skin during LFS [82]. Rohr et al. found good IVIVC based on different pharmacokinetic plasma profiles parameters for β-estradiol (E2) after the application of a commercially available drug-loaded membrane controlled reservoir system to postmenopausal women [83]. Schaefer et al. compared the Saarbruecken penetration model (SB-M) and vertical Franz diffusion cells for IVIVC of the lipophilic drug flufenamic acid using human skin. ...
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