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[Kinetics of a new patch for transdermal administration of 17 beta-estradiol]
Abstract
A novel patch containing 17 beta-Estradiol exhibits improved kinetic profiles compared to the currently available leading transdermal product. The blood concentrations produced by the newly developed matrix patch are stable over 3 to 4 days, thus avoiding the occurrence of 17 beta-Estradiol peaks in the blood. In an additional clinical study an almost linear relationship could be identified between the patch size (Test patch: 7.25, 14.5 and 29.0 cm2) and the obtained 17-estradiol bioavailability (judged on AUC, cmax, c(ave), Cmin). These results are corroborated by the additional in vitro experiments. An almost constant drug delivery rate of 48 micrograms +/- 15 micrograms/day of 17 beta-Estradiol per 13.85 cm2 patch over 4 days can be detected through excised human skin. No statistically significantly different transdermal flux rates of 17 beta-Estradiol were detected in 3 different batches of the transdermal drug delivery system in vitro. Statistical evaluations were performed with the 3-Way-Anova test on the 0.05 significance level. This newly developed product presents a kinetically optimized transdermal 17 beta-estradiol patch for hormone substitution therapy.
Purpose. The aim of our study was to clarify the kinetic performance of a membrane controlled reservoir system (MCRS) for -estradiol (E2) under in vitroconditions by determination of the role of membrane and adhesive layer on E2flux control.
Methods. E2and ethanol fluxes across EVA membrane or membrane coated with adhesive from saturated solutions in defined ethanol/PBS mixtures were measured in the symmetric and asymmetric configuration. Physicochemical parameters of the EVA membrane were determined.
Results. The E2flux across the 9% EVA membrane steadily increased with increasing ethanol concentrations in both configurations, due to enhanced uptake of E2by the polymer and increasing membrane diffusivity. Permeation across the EVA membrane coated with an adhesive layer in the symmetric and asymmetric configuration increased up to maximum values of 0.80 0.14 (g cm–2 h–1and 0.37 0.02 g cm–2 h–1, respectively, at 62.5% (v/v) ethanol. The fluxes then decreased with further increase in the volume fraction of ethanol due to a dramatically reduced permeability of the adhesive layer. For the asymmetric case, a linear dependence of E2on ethanol fluxes was observed.
Conclusions. The E2flux from MCRS is strictly dependent on reservoir ethanol concentrations, whereas the adhesive layer represents the rate controlling barrier at high ethanol levels (>70% v/v).
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).
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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