Article

Plasma profiles of transdermal 17β-estradiol delivered by two different matrix patches: A four-way cross-over study in postmenopausal women

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Abstract

The aim of this study was to investigate the systemic bioavailability and plasma profiles of 17 beta-estradiol (CAS 50-28-2, E2) after the application of two types of matrix patches for the transdermal delivery of E2: MenorestTM (the test patch) with delivery rates of 37.5, 50 and 75 micrograms E2/day and a reference patch with a delivery rate of 50 micrograms E2/day. All 3 test patches were identical in composition, achieving different transdermal E2 delivery rates by variations in the surface area (11.0, 14.5 and 22.5 cm2). All 4 patches were each worn by 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 according to a randomized, 4-way crossover design. Blood samples were collected before and 3, 6, 9, 12, 24, 34, 48, 58, 72, 84, and 96 h after each patch application. Plasma E2 concentrations were determined by a specific direct radioimmunoassay method. The following pharmacokinetic parameters were evaluated: AUC0-96h; Cmax, tmax, Cmin, Caverage. The course of the E2 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 micrograms E2/d) could be shown (correlation coefficient 0.99). The resulting Cmax values for the patch were: 44.2, 58.3, and 92.1 pg E2/ml, corresponding to Caverage values of 39.5, 45.5, and 70.6 pg E2/ml. The reference patch and the test patch, at a dose of 50 micrograms E2/d, were similar in terms of Cmax, while the Caverage, AUC0-96h and Cmin were significantly higher 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 micrograms E2/d: AUC0-->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 for the calculation of the course of the E2 levels was used to describe the experimentally determined data. However, in the evening, periodically higher E2 plasma levels were observed for all patches than in the morning. From these results it can be concluded that E2 plasma profiles produced by the test patch are reproducible, and in the physiological range consistent with the early to mid follicular level in the premenopausal woman over 4 days (96 h), correlating with the doses administered (37.5-50-75 micrograms E2/d). Additionally, the systemic bioavailability of the test patch at a dose of 37.5 micrograms E2/d is comparable to that of the reference patch at a dose of 50 micrograms E2/d.

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... ). Auch hier gibt es größere kurzzeitige Schwankungen des Estradiolspiegels. Da die Hautdurchblutung einer zirkadianen Rhythmik unterliegt und aufgrund dieser Tagesschwankungen die Hormonabsorption variiert, beobachtet man unter transdermaler Therapie am Abend erheblich höhere Estradiolkonzentrationen als am Morgen(Rohr et al. 1997).Der Serumspiegel wird auch von der Umgebungstemperatur, durch körperliche Belastung, Stress und Emotionen oder durch die Aufnahme von Nahrungs-und Genussmitteln, welche die Tagen) aufgebaut(Feige et al. 2001). Deshalb beobachtet man bei klimakterischen Beschwerden häufig ein verzögertes Ansprechen. ...
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Article
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To compare two estradiol transdermal matrix systems with regard to bioavailability, pharmacokinetics and tolerability. A single centre, open, randomized, comparative cross-over study in 20 healthy postmenopausal women. Menorest with 3 or 4 days of suggested use and Climara with 7 days of suggested use (both 50 microg/24 h) were compared at steady state. Two 14-day treatment periods were separated by a 4 week washout. Plasma levels of estradiol were monitored during the second week of each treatment. Tolerability was assessed by open questions and inspection of the application site. There were no differences between the two treatments with regards to AUC, Cmax, Cmin, Caverage or fluctuations of plasma estradiol. Tmax was significantly shorter for Menorest than Climara. Cmax and Cmin were significantly higher for the second Menorest patch during the monitoring period compared to the first. All local reactions were mild and there were three cases of erythema with Menorest and a total of 21 skin reactions in 15 subjects with Climara. Systemic tolerability was similar between treatments with eight estrogen-related adverse events in eight subjects (period pains, uterine bleeding, mastodynia, headache and vaginal discharge) with Menorest and 13 events in ten subjects with Climara. The bioavailability of estradiol from the two matrix transdermal delivery systems Menorest and Climara was similar, but the products were not bioequivalent because Tmax was significantly shorter for Menorest than for Climara. Tolerability of treatment was good for both patches but with a higher number of local reactions and estrogen related adverse events for Climara.
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The feasibility of transdermal controlled delivery system of 17beta-estradiol was investigated by conducting in vitro release studies. Several new 17beta-estradiol unilaminate adhesive devices capable of releasing 17beta-estradiol in a controlled fashion over a 24-h, 36-h, 96-h, 104-h, 168-h, and 216-h period have been developed using acrylic resins (Eudragits E100, RSPO, and RLPO) as adhesive and rate-controlling polymers. The in vitro release profiles of 17beta-estradiol from various TDS unilaminate devices were characterized in a new developed dissolution tester vessel (total volume 200 ml), using a new paddle. The release of drug from different formulations was measured by a sensitive high-performance liquid chromatographic (HPLC) method. The release of drug from all prepared adhesive devices seems to obey zero-order kinetics (r > 0.98). The effect of two different plasticizers (acetyltriburyl citrate [ATBC] and triethyl citrate [TEC]) on the release patterns of 17beta-estradiol from TDS formulations was studied, and they were almost identical. The effect of two different release modifiers, propylene glycol (PG) and myristic acid (MA), on the release pattern of 17beta-estradiol from prepared unilaminate devices was evaluated. It was shown that the use of these release modifiers significantly increased the release of 17beta-estradiol from a TDS unilaminate patch. Furthermore, these data clearly demonstrated that the acrylic resins are suitable polymers for the preparation of 17beta-estradiol TDS adhesive devices.
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The pharmacokinetic performance of a matrix system for transdermal beta-estradiol (E(2)) delivery after multiple consecutive dosing in postmenopausal women undergoing hormone replacement therapy was investigated. The E(2) plasma profiles determined during the third application in 16 postmenopausal women were compared with results obtained in a published clinical study using the same patch in 24 postmenopausal women without E(2) pretreatment; they were compared with a theoretical diffusion/pharmacokinetic model. A conventional theoretical model with constant model parameter (CPM) obtained from in vitro mass balance experiments in a Franz cell type set up described successfully the transdermal E(2) bioavailability parameter AUC(0-96h) (4341.9 +/- 1513.1; calculated 4250.8) and C(average) (45.0 +/- 13.2; calculated 41.2). Also, experimentally, there was no significant drop in E(2) plasma values after patch removal and reapplication; this was corroborated by calculations. Accumulation of E(2) did not occur when several patches were applied consecutively over a period of 3 weeks. Steady state was achieved following application of the first patch. However, the differences between recorded E(2) plasma profiles and theoretical results detected at specific measurement points cannot be explained by the CPM model. Experimentally obtained plasma profiles were always lower in the morning and higher in the evening than predicted on the basis of the model. Measurements of in vivo skin temperature in the postmenopausal women showed oscillating temperature profiles in the form of a cosinor function: The temperature mesor of untreated postmenopausal women was 34.8 degrees C with an acrophase at 17.0 o'clock (95% CI: 14.30-19.30) and an amplitude of +/- 0.4 degrees C (p = 0.1). During the application of the patch the average temperature next to a patch rose 0.3 degrees C, which was statistically significant (p = 0.1). In the skin under the application of the matrix patch a mesor temperature was detected as 35.6 degrees C with an amplitude of +/- 0.5 degrees C with an acrophase at 17.51 o'clock (95% CI: 14.30-21.00) (p = 0.05). The temperature period was 24 h for all measurements and the maximum temperature was observed at about 16.30 h, and a minimum at about 5.00 h. A linear dependency was detected in in vitro experiments between the log of E(2) permeability and the temperature for stripped skin, epidermis/dermis layer, as well as for the matrix. Modeling of E(2) plasma profiles with oscillating diffusion coefficients (ODM1) with a sine wave function results in this equation: D(1) = D(0x) + Da(x).sin(k.t). D(0x) is the diffusion coefficient determined at 35.6 degrees C, k is 1/24 h, D(a) is the diffusion coefficient of the temperature amplitude, h is hour, and x stands for the respective diffusion layer. It was shown that the experimental E(2) plasma profile variations are more pronounced than can simply be explained by skin temperature variations alone (ODM1 model). A simplex fit with an oscillating diffusion coefficient in the form of a sine wave function for the stratum corneum (ODM2 model) resulted in a temperature amplitude of 1.1 degrees C, about twice as high as was determined in the in vivo measurements (ODM2 model). Therefore, other circadian parameterlike blood flow might superimpose the temperature profile. The improvement in data analysis by incorporating oscillating diffusion coefficients (ODM1 and 2) over CPM was judged from a comparison of experimental data with the calculated plasma profiles with the AIC, Akaikes model selection criterion, which allows ranking between models because it is independent of the scaling of the data points. ODM1 and ODM2 improved the data analysis over CPM by allowing better calculation of experimental C(max), t(max), the time to reach to C(max), and the fluctuation, f. No difference between CPM, ODM1, or ODM2 was found for the bioavailability parameter C(average) and AUC(0-96h).
Article
This study compares the pharmacokinetic performance of a matrix system for transdermal 17-beta-estradiol (E(2)) delivery using multiple consecutive dosing with a first application in postmenopausal women undergoing hormone replacement therapy. A clinical study (SI) was conducted over a treatment period of 11 days in 16 postmenopausal women receiving three consecutively applied matrix patches for the delivery of E(2). The first patch was worn for 4 days, the second for 3 days, and the third patch for 4 days. The E(2) plasma profiles determined during the third application were compared with results obtained by a published clinical study (SII) using the same patch in the same group of postmenopausal women without E(2) pretreatment. Additionally, the 24 h plasma profiles of E(2) and estrone were determined before and on day 4 during patch application of the third patch. Comparison of the mean pharmacokinetic parameters from the two studies showed no significant difference in E(2) plasma levels: AUC(0-->96h) [pg/mL h] SI: 4342 +/- 1513 and SII: 4512 +/- 1229; C(max)[pg/mL] SI: 51.3 +/- 28.8 and SII: 54.2 +/- 22.3; C(average) [pg/mL] SI: 45.0 +/- 13.2 and SII: 47.0 +/- 9.4; C(min) [pg/mL] SI: 31.4 +/- 5.9 and SII: 32.2 +/- 8.1. Over 96 h, fluctuation, f, defined as (C(max) - C(min)) / C(average), was 0.44 in SI and 0.47 in SII. Individual comparison of E(2)-C(max), -AUC, and -C(min) revealed that more than 87.5% of all patients showed a variation between SI and SII of less than 10%. The mean of the individual AUC(0-->96h) variation between the first and the third patch was only 4.7%. There was no significant drop in E(2) plasma values after patch removal and reapplication, and accumulation of E(2) did not occur after several patches were applied consecutively. Plasma E(2) showed a circadian rhythm that was lower in the morning and higher in the evening. No circadian rhythm was observed in untreated basal plasma E(2) in the group of postmenopausal women. The transdermal matrix system yielded sustained E(2) plasma levels in postmenopausal women in the initial application period. In long-term dosing there was no accumulation of E(2) in plasma and no significant drop after patch removal. It is presently not known why the circadian variation in the experimentally obtained E(2) plasma values exists.
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This review comprises the pharmacokinetics and pharmacodynamics of natural and synthetic estrogens and progestogens used in contraception and therapy, with special consideration of hormone replacement therapy. The paper describes the mechanisms of action, the relation between structure and hormonal activity, differences in hormonal pattern and potency, peculiarities in the properties of certain steroids, tissue-specific effects, and the metabolism of the available estrogens and progestogens. The influence of the route of administration on pharmacokinetics, hormonal activity and metabolism is presented, and the effects of oral and transdermal treatment with estrogens on tissues, clinical and serum parameters are compared. The effects of oral, transdermal (patch and gel), intranasal, sublingual, buccal, vaginal, subcutaneous and intramuscular administration of estrogens, as well as of oral, vaginal, transdermal, intranasal, buccal, intramuscular and intrauterine application of progestogens are discussed. The various types of progestogens, their receptor interaction, hormonal pattern and the hormonal activity of certain metabolites are described in detail. The structural formulae, serum concentrations, binding affinities to steroid receptors and serum binding globulins, and the relative potencies of the available estrogens and progestins are presented. Differences in the tissue-specific effects of the various compounds and regimens and their potential implications with the risks and benefits of hormone replacement therapy are discussed.
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The bioavailability of estradiol from Oesclim® 50 and Systen® 50, two matrix-type estradiol transdermal systems with the same nominal delivery rate of 50 μg per 24 hours, was compared in a randomized, crossover pilot study of 12 healthy postmenopausal women. A 7-day washout separated the two 4-day application periods. Serum estradiol levels were determined by using radioimmunoassay before application of the transdermal system and at defined intervals thereafter. Higher serum estradiol levels were observed with Oesclim 50 than with Systen 50. Analysis of log-transformed, baseline-corrected pharmacokinetic values showed significant differences between the two transdermal systems. Except for the maximum serum concentration and concentration at 72 hours, all Oesclim 50 pharmacokinetic values were significantly higher than those of Systen 50 (P < 0.05). Estradiol bioavailability was approximately 1.5 to 2 times higher after application of Oesclim 50 than after application of Systen 50.
Article
Circulating plasma levels of 17β-estradiol after the administration of fixed dosages of 17β-estradiol show great variability depending upon product formulation, route of administration, and interindividual variation in absorption and metabolism. Two new 17β-estradiol transdermal delivery systems, Systen 50 (also called Evorel®) and Menorest®50 have recently been approved in Europe for the treatment of climacteric symptoms. Both transdermal systems deliver 17β-estradiol at a rate of 50 µg/day. The present study was undertaken to compare the plasma profiles of 17β-estradiol delivered by these 2 products in 30 healthy postmenopausal women according to a randomised, monocentric, single-blind, crossover protocol. Two 4-day patch application periods were separated by a 7-day washout period. Plasma 17β-estradiol concentrations were determined 24 hours and 30 minutes before and then 0, 2, 4, 8, 12, 24, 48, 60, 72, 84 and 96 hours after the first patch administration. 17β-Estradiol measurements were performed using a specific direct radioimmunoassay developed at the French Fondation de Recherche en Hormonologie laboratory. Bioequivalence was assessed by analysis of variance. The results demonstrated that the 2 products were similar in terms of maximum plasma concentration; however, mean concentration, concentration at 96 hours and area under the concentration-time curve were significantly (p < 0.05) greater with Menorest®50. Furthermore, 17β-estradiol concentrations decreased more rapidly with Systen®50 than with Menorest®50. These differences in the plasma profiles of 2 transdermal systems both delivering 50 µg/day of 17β-estradiol may have important clinical consequences both in terms of tolerance and effectiveness.
Article
The aim of this study was to compare the bioavailability and plasma profiles of estradiol and estrone after repeated applications of 2 types of estradiol transdermal systems: a new adhesive matrix system (Menorest®) compared with a reference membrane/reservoir system (Estraderm®) and to evaluate their short term safety. This was an open, randomised, crossover study, with 2 treatment periods of 10.5 days separated by a 10-day washout period and with a 1-week follow-up. Participants were studied at Institut Aster, Paris, and Association de Recherche Thérapeutique (ART), Lyon, France, and included 31 healthy postmenopausal women, all volunteers aged between 49 and 67 years (mean 58 years). Each transdermal system was applied for three successive 3.5 day-wear periods (10.5 days) on the lower abdominal skin. Plasma estradiol and estrone concentrations were measured at steady-state, before and after the third application of each transdermal system at regular intervals over 106 hours. Cutaneous tolerance was assessed after each transdermal system removal. Although the extent of availability [area under the plasma concentration-time curve (AUC) and average plasma concentration (Cav)] was similar with both transdermal systems, their pharmacokinetic profiles were different, with Menorest® producing less fluctuating and more sustained plasma estradiol levels than the reference system. The mean estradiol to estrone Cav ratio was similar with the 2 transdermal systems and in the physiological range of premenopausal status. The incidence of adverse events was similar for both treatments, but a lower incidence of local erythema was observed with Menorest® (8.9%) than with the reference system (18.3%). In conclusion, during the entire wear period, Menorest® produced more sustained plasma estradiol levels with less fluctuations (40 to 72 ng/L) than the reservoir/ membrane system (18 to 102 ng/L). Menorest® gave estradiol plasma levels approximating the concentrations observed during the early to mid-follicular premenopausal stage, with a 2-fold lower incidence of erythema than with the reservoir/membrane system.
Article
The objective of this study was to evaluate the pharmacokinetics of estradiol and estrone, at steady-state, after repeated applications of Menorest® delivering 0.025, 0.050 and 0.100mg estradiol daily, and to determine the plasma concentration/administered dose relationship. It was an open randomised crossover study, with 3 treatment periods of 10.5 days separated by two 12-day intervening washout periods. Randomisation was conducted according to a latin square design. The clinical part of the study was carried out at CAP (Centre d’Activité Pharmacologique), Montpellier, and plasma estradiol and estrone concentrations were determined at CEPHAC (Centre d’Etudes et de Recherche en Pharmacie Clinique), St Benoit, France. The study included 30 healthy postmenopausal women, volunteers aged between 42 and 70 years (mean 59.13 ± 6.90 years). Each transdermal system dosage was applied for 3 successive 3.5-day wear periods (10.5 days) on the lower abdominal skin. Plasma estradiol and estrone concentrations were measured at steady-state, before and after the third application of each transdermal system dosage at regular intervals over 106 hours. Cutaneous tolerance was assessed after each transdermal system removal. After the third application of patches releasing 0.025, 0.050 and 0.100 mg/day, a linear relationship was established between the administered dose and the estradiol pharmacokinetic parameters [area under the plasma concentration-time curve from time 0 to 84 hours (AUC0–84h), maximum plasma concentration (Cmax), minimum plasma concentration (Cmin) and average plasma concentration (Cav)]. This relationship did not exist between plasma estrone concentrations and estradiol administered doses, although these concentrations increased with the increased dosage. Adverse events were neither serious nor unexpected; none required discontinuation of the treatment, and their incidence was higher with the highest doses. Erythema and skin wrinkling were the most frequent cutaneous reactions — their frequency (related to the number of applications) was increased from 26 to 44% for erythema and from 2 to 40% for skin wrinkling when the administered dose increased from 0.025 to 0.100 mg/day. It was concluded that the linear relationship established between plasma estradiol concentrations and administered doses constitutes the basis for the dosage adjustment to the individual needs of postmenopausal women in the range 0.025 to 0.100 mg/day, and allows adjustment of the dose to deliver the minimum effective level of estrogen.
Article
The bioavailability of estradiol (CAS 50-28-2; E2) from a new "matrix type" estradiol transdermal patch (Dermestril; Test patch) was compared to that of the widely used "liquid-reservoir, membrane-controlled type" transdermal patch (Reference patch) in a two-way randomized cross-over study on 28 healthy postmenopausal women, during a single 4-day application of 2 patches (total content 8 mg E2, total nominal release rate 100 micrograms E2 in 24 h). Evaluated from the AUC0-96h, the extent of bioavailability was practically the same for the two patch types. Conversely the rate of bioavailability was significantly different, because from the Reference patch the release rate is fast in the first 24 h, leading to an E2 peak at 8 h and to a Cmax in average at 23 h. But after the 2nd day the release/absorption rate declines markedly, leading to E2 serum concentrations at the 3rd and 4th days possibly below the effective threshold. From the Test patch the release/absorption rate of E2 is more constant, leading to sustained E2 concentrations during the 4 days of application, with smaller fluctuations than during application of the Reference patch. In conclusion the Test patch can be considered practically bioequivalent to the Reference patch with regard to the extent of absorption, but not with regard to the rate of absorption, because the E2 concentrations in serum are more constant during the application of the Test transdermal patch than during the application of the Reference.