Article

Pharmacokinetics of the Transdermal Reservoir Membrane System Delivering β-Estradiol: In Vitro/In Vivo-Correlation

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Abstract

Purpose. 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). Methods. 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. Results. The transdermal in vitro E2 flux rate out of a complete MCRS, claimed to deliver 25 g/day, increased steadily, reaching a maximum value of 2.06 0.58 (g/h at 30 to 40 hours and decreased to a rate of about 0.5 (g/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. Conclusions. 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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... Indeed, although the in vitro permeation data do not always fit the expected one-to-one relation with the in vivo data ( Franz et al., 2009), a certain proportionality between the in vitro and in vivo fluxes is maintained. Therefore a direct in vitro-in vivo correlation of the biopharmaceutical performances has been postulated and well established, either for local ( Minghetti et al., 2000) and systemic administration ( Rohr et al., 1998). ...
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... As is evident from this study, unsaturated 4-HT solution in 66.66% alcohol showed significantly lower penetration compared to saturated 4-HT solution in 66.66% alcohol. The proportion of ethanol used in this study is similar to the ethanol used in the commercial transdermal patches (41). However, given that the nipple is a sensitive area, the effects of repeated topical application of high alcohol concentration on the nipple need further investigation. ...
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Chapter
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Chapter
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Peer Reviewed http://deepblue.lib.umich.edu/bitstream/2027.42/41577/1/11095_2004_Article_305246.pdf
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Estrogen-replacement therapy is important for the prevention of postmenopausal osteoporosis. However, oral synthetic and conjugated estrogens increase biliary cholesterol saturation index and risk of gallstone disease. To examine whether transdermal estrogen administration could avoid these adverse effects, 17 postmenopausal women were treated with transdermal estradiol (Estraderm TTS; Ciba-Geigy, Arnhem, The Netherlands), 100 μg/day for 4 weeks, and after 1 month without therapy, with oral estradiol (Progynova; Schering, Weesp, The Netherlands), 2 mg/day for 4 weeks. The increase in the serum estradiol level was much higher during transdermal than oral estradiol administration. On the contrary, the increase in the serum estrone level was much more pronounced during oral treatment. Both modes of treatment led to a similar reduction of urinary calcium excretion. A highly significant decrease in serum phosphate levels was found during transdermal therapy. Biliary cholesterol saturation index did not change during transdermal therapy (mean ± SEM, 1.25 ± 0.06 before and 1.22 ± 0.07 at the end of transdermal therapy; P = NS). A slight increase in cholesterol saturation index that did not reach statistical significance was found during oral therapy (1.28 ± 0.09 before and 1.36 ± 0.09 during oral treatment). However, the subgroup of women with strong increases in serum estrone levels during oral estradiol therapy (>0.5 pmol/mL; n = 8) generally had increased biliary cholesterol saturation index, a decrease in relative percentage chenodeoxycholic acid in bile, and increased serum sex hormone-binding globulin levels during oral treatment. Cholesterol monohydrate crystals were never found in duodenal biles during either treatment. This study indicates that transdermal estradiol does not induce lithogenic bile. On the contrary, oral estradiol leads to lithogenic bile in a subgroup of women with strong increases in serum estrone levels during oral treatment.
Article
The pharmacokinetics of three transdermal estradiol (E2) replacement regimens were studied following establishment of steady-state dynamics. Oestrogel 3.0 mg, Oestrogel 1.5 mg, and Estraderm transdermal delivery system 4 mg (0.05 mg/day) were administered for 14 days each to 15 postmenopausal volunteers, with a 14-day washout period between each regimen. The percutaneous E2 pharmacokinetics were compared with an oral micronized E2 preparation. Venous samples were obtained at 0, 1, 2, 4, 8, 12, and 24 hours on 3 sequential days 11 days after initial application of the Oestrogel and the transdermal delivery system, and at the same times after oral E2 ingestion. All three percutaneous regimens provided nearly constant serum E2 and estrone (E1) levels throughout their use. The mean serum E2 levels were 102.9 +/- 39.9, 68.1 +/- 27.4, and 41.1 +/- 13.5 pg/mL for Oestrogel 3.0 mg, Oestrogel 1.5 mg, and Estraderm, respectively. Oral E2 resulted in a mean serum E2 level of 114.0 +/- 65.2 pg/mL with marked peak and nadir values. The E1/E2 ratio was comparable with all three percutaneous regimens (1.08-1.33) and was significantly lower than that found with oral Estrace (5.05).
Article
The estradiol transdermal therapeutic system is a cutaneous delivery device which delivers estradiol into the systemic circulation via the stratum corneum at a constant rate for up to 4 days. Physiological levels of estradiol (the major estrogen secreted by the ovaries in premenopausal women) can therefore be maintained in postmenopausal women with low daily doses because first-pass hepatic metabolism is avoided. In short term clinical studies, the beneficial effects of transdermal estradiol on plasma gonadotrophins, maturation of the vaginal epithelium, metabolic parameters of bone resorption and menopausal symptoms (hot flushes, sleep disturbance, genitourinary discomfort and mood alteration) appear to be comparable to those of oral and subcutaneous estrogens, while the undesirable effects of oral estrogens on hepatic metabolism are avoided. As with oral or injectable estrogen replacement therapy, concomitant sequential progestagen is recommended for patients with an intact uterus during transdermal estradiol administration, in order to reduce endometrial stimulation. Transdermal estradiol has been well tolerated in clinical trials, with local irritation at the site of application being the most common adverse effect. The incidence of systemic estrogenic effects appears to be comparable to that observed with oral therapy. Thus, transdermal estradiol offers near-physiological estrogen replacement in postmenopausal women in a convenient low-dose form which may avoid some of the complications of higher dose oral therapy. Long term epidemiological studies are warranted to determine whether transdermal estradiol therapy provides protection against osteoporosis and fractures and cardiovascular disease equivalent to that offered by oral and injectable estrogens. However, despite the importance of such data, it seems reasonable to conclude at this stage of its development that transdermal estradiol represents an important advance in hormone replacement therapy.
Article
The in vitro release profiles of two sizes of estradiol patches were determined by the paddle method, where the patch was held in position at the bottom of the dissolution vessel by sandwiching it between a watch glass and an aluminum wire mesh or Teflon screen, and also by the manufacturer's paddle-over-disk method. The estradiol content of test aliquots of the dissolution medium was determined by HPLC. The release profiles by both procedures were comparable and showed that approximately 10% of the labeled drug was released in 4 days.
Article
To determine whether post-menopausal oestrogen use affects the risk of dying from stroke. Postal questionnaire survey to elicit details of oestrogen replacement therapy and potential risk modifiers. Californian retirement community. All 22,781 residents of community (white, affluent, well educated) contacted by mail and phone; 13,986 (61%, median age 73) responded, including 8882 women. These formed cohort for mortality follow up, using health department death certification. Only 13 lost to follow up, apparently not deceased, but 34 excluded because no information on oestrogen use. None. Mortality rate from stroke compared in women who did and did not receive oestrogen replacement treatment. Age adjusted mortality rates were computed using internal standard and four age groups. By January 1987 there had been 1019 deaths in the cohort. Twenty out of 4962 women who used oestrogen replacement treatment died from stroke compared with 43 out of 3845 women who did not use oestrogen replacement treatment: relative risk 0.53, 95% confidence interval 0.31 to 0.91. Protection was found in all age groups except the youngest and was unaffected by adjustment for possible confounding factors (hypertension, smoking, alcohol, body mass index, exercise). Oestrogen replacement treatment protects against death due to stroke.
Article
The metabolism of estrone sulfate has been studied in normal, young males by single injections of 6,7-³H-estrone sulfate (9 subjects); by constant infusions of 6,7-³H-estrone sulfate (8 subjects), 6,7-³H-estrone (5 subjects), and 6,7-³H-estradiol (5 subjects); and by the measurement of the concentration of radioactivity in plasma as estrone sulfate, estrone, and estradiol. The disappearance of radioactivity as estrone sulfate following the single injections of 6,7-³H-estrone sulfate can be described as a function which is the sum of two exponentials. The initial rapid component (T½ = 3 min) represents spread into and transfer from a space, with a volume of 7.2 rh 0.6 (se) L. The mean value for the rate constant of total removal (reversible and irreversible) from this space is 266 ± 2 7 (se) units/day of which 11.1 ± 2.4 (se) % is irreversible. The mean metabolic clearance rate (MCR R) is 105 ± 20 (se) L/day/m² Using the constant infusion technique the mean MCRr is 80 ± 10 (se) L/day/m². The overall mean MCR of estrone sulfate is 90 ± 10 (se) L/day/m². The mean transfer constant or fraction of ³H-estrone sulfate infused which is measured as estrone in the blood is 0.15 with 95% confidence limits of 0.12 to 0.18. In the two subjects in whom ³H-estradiol was measured the was 0.022 and 0.044. For the infusion of ³H-estrone and ³H-estradiol the mean and (95% confidence limits) were 0.40 (0.21 to 0.81) and 0.42 (0.30 to 0.58). Using the available data for and [ρ]bb values, it is probable that most of the estrone sulfate entering the blood each day does so as a result of conversion from the free estrogens and little, if any, arises as a result of direct secretion.
Article
We have attempted to measure the metabolic clearance rates (MCR) and the transfer factors of estradiol (E(2)) and estrone (E(1)) during 2-hr and 12-hr infusions. When estradiol-(3)H was infused for 2 hr, apparent equilibrium was reached at 70 min; the 12-hr infusions showed that plasma estradiol-(3)H levels increased slowly throughout the infusion. When estrone-(3)H was infused, constancy of estrone-(3)H levels was not attained in either the 2-hr infusions or in the two 12-hr infusions. The tritium level in the metabolite of the infused estrogen did not become constant in 50% of the short infusions and increased during all the long infusions. Thus, the conversion ratios C(E1E2) and C(E2E1) continually changed and transfer factors could not be calculated. The apparent "MCR'S" calculated on the basis of the 2-hr studies expressed as liters/24 hr per m(2) +/-SD were: "MCR(E1)" (women) 980 +/-94, (men) 1170 +/-95; "MCR(E2)" (women) 615 +/-17, (men) 830 +/-30. The estradiol "MCR's" differed significantly between men and women. "MCR(E2)" was the same using either estradiol-(14)C or -(3)H and was unchanged by the infusion of 170 mug of estradiol daily. Postmenopausal women had estrogen "MCR's" in the same range as premenopausal women. Excess glucocorticoids increased the "MCR(E2)."
Article
To determine whether the nonoral administration of estradiol (E2) might provide physiologic replacement without alteration of hepatic function, 20 postmenopausal women were studied before and after 3 weeks of treatment with either E2-containing transdermal therapeutic systems or placebo. Twenty premenopausal women were also studied. With E2-containing systems, serum E2 and estrone levels were restored to the premenopausal range. Variable responses of the different biochemical and biologic markers of the actions of E2 were observed. The most sensitive marker was vaginal cytology, with the E2 dosage reverting the maturation index to premenopausal values. Hot flashes, measured objectively, were reduced in frequency but not abolished. Serum levels of follicle-stimulating hormone and luteinizing hormone were lowered but remained higher than the premenopausal range. No significant changes were noted in urinary calcium/creatinine and hydroxyproline/creatinine ratios, which were used as markers of bone resorption. With active systems, no significant changes were noted in the concentrations of the hepatic proteins renin substrate and thyroxine-binding globulin or in the binding capacities of cortisol-binding globulin and sex hormone-binding globulin. These results indicate that transdermal E2 administration may be used to provide estrogen replacement while exerting limited effects on hepatic function.
Article
To describe the efficacy, safety, and wearability of estrogen replacement therapy of a 7-day estradiol transdermal system (Climara), developed using new drug-in-adhesive technology. The pharmacokinetics of the 7-day system were investigated in single- and multiple-dose studies, a relative bioavailability study of the two patch sizes, and comparative studies with the twice-weekly transdermal system (Estraderm). Safety and efficacy in the treatment of vasomotor symptoms compared with conjugated equine estrogens (Premarin) and placebo were evaluated in two 11-week, randomized, double-blind, multicenter trials in 603 women; the data are combined in this report. Irritation and adhesion were also evaluated in comparative studies with Estraderm, Micropore (an inert once-weekly tape), and placebo controls. Blood levels were sustained for the full 7 days of patch wear, there was no drug accumulation, and a physiologic estrone to estradiol ratio was maintained. Pharmacokinetics studies showed dose proportionality of the 0.05 and 0.1 mg/day patches. Both patch sizes significantly decreased the frequency of hot flushes compared with placebo and were comparable with conjugated equine estrogens. There was a statistically significant difference between the two patch sizes. The mean overall decline in the hot flush rate was 74.6% for the 0.1 mg patch versus 64.5% for the 0.05 mg patch (p < or = 0.05). The combined data also showed that the onset of efficacy is within 1 to 2 weeks after the start of therapy and that efficacy is fully sustained during the 7-day patch wear period with some diminution of effect during the treatment-free week of each cycle. Treatment was well tolerated. Adverse events led to withdrawal from the studies in 8.9% of subjects. In most of these (6.8% of subjects), the cause was adverse skin reactions. Skin irritation was similar to Estraderm in comparative studies, whereas adhesion was significantly better with Climara. The Climara patch delivers estradiol for a full 7 days. Clinical efficacy of both patch sizes is comparable with currently accepted therapy and is sustained for the entire week of patch wear. A significant difference in response between the two doses supports dose titration. The patch is well tolerated and has excellent adhesion.
Article
Circumstantial evidence links endogenous estrogens to increased risk of breast cancer in women, but direct epidemiologic support is limited. In particular, only a few small prospective studies have addressed this issue. Our purpose was to assess breast cancer risk in relation to circulating levels of the two major endogenous estrogens, estrone and estradiol, measured before the clinical onset of the disease. The association between serum levels of estrogens and the risk of breast cancer was examined in a prospective cohort study of 14,291 New York City women, 35-65 years of age, who received screening for breast cancer at the time of blood sampling and who had not been diagnosed with breast cancer. During the first 5 1/2 years of study, we identified 130 breast cancers among the postmenopausal group (7063 women, 35,509 person-years). The case subjects and twice as many postmenopausal control subjects were included in a case-control study nested within the cohort. Biochemical analyses for percent free estradiol, percent estradiol bound to sex hormone-binding globulin (SHBG), total estradiol, estrone, and follicle-stimulating hormone were performed on sera that had been kept at -80 degrees C since sampling. For increasing quartiles of total estradiol, the odds ratio (ORs) of breast cancer, as adjusted for Quetelet index (weight in kilograms divided by the square of the height in meters), were 1.0, 0.9, 1.8, and 1.8 (P value for trend = .06); the ORs for increasing quartiles of estrone were 1.0, 2.2, 3.7, and 2.5 (P value for trend = .06). For increasing quartiles of free estradiol, defined as the fraction of estradiol that is not bound to proteins, the Quetelet index-adjusted ORs of breast cancer were 1.0, 1.4, 3.0, and 2.9 (P value for trend < .01). When we considered the percent of estradiol bound to SHBG, the Quetelet index-adjusted ORs were 1.0, 0.70, 0.40, and 0.32 (P value for trend < .01), thus suggesting a strong protective effect. These associations persisted or became even stronger when analyses were restricted to women whose samples had been drawn 2 or more years before breast cancer diagnosis. These data represent the first confirmation in a large prospective epidemiologic study of a link between circulating estrogens and breast cancer risk. Although estrogen levels appeared to fall within the conventional limits of normality in all women under study, those who subsequently developed breast cancer tended to show higher levels of estrone, total estradiol, and free estradiol, and a lower percent of estradiol bound to SHBG than women who remained free of cancer. Factors that increase endogenous estrogen production or reduce the binding of estradiol to SHBG may increase a woman's risk of developing breast cancer later in life.
Article
The report differentiates between dermatological and transdermal products, identifies and discusses the principles involved in the development and optimization of topical drug products. The regulatory concerns in the evaluation of topical dermatological products with respect to bioequivalence and quality control are also discussed.
Article
The permeabilities of many steroids through human skin have been previously measured and reported in the literature. Analysis of these data reveals that significant discrepancies exist between the measurements of Scheuplein et al. and those of other groups. Six of the 14 steroids which were examined by Scheuplein et al., aldosterone, corticosterone, estradiol, hydrocortisone, progesterone, and testosterone, have also been examined by other groups. For each of these steroids, the permeability measurements of Scheuplein et al. are lower than those reported by other groups by factors of between 5.0 and 77. Eight independent measurements of the permeability of estradiol are in good agreement with one another, but are greater than the value reported by Scheuplein et al. by factors of between 11 and 20. Several possible sources of experimental error, including the variability of the skin samples, the differences in the experimental temperature, the establishment of steady-state conditions, the use of radiolabeled drugs, and the skin preparation technique, have been considered and do not appear to account for the magnitude of the observed discrepancies nor for the fact that the data of Scheuplein et al. are consistently lower than those reported by other groups.
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.
Article
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.
Article
The continuous infusion of (3)H-6,7-estrone and (3)H-6,7-estradiol has been used to study the metabolic clearance rate (MCR), the interconversions, and the red cell uptake of these steroids in normal males and females. The whole blood MCR of estrone is 1,990 +/- 120 liters per day/m(2) (SE) in males and 1,910 +/- 100 liters per day/m(2) in females. The whole blood MCR of estradiol is 1,600 +/- 80 liters per day/m(2) in males and 1,360 +/- 40 liters per day/m(2) in females. The values in females do not vary significantly when studied in the follicular or luteal phase of the cycle. At least 35% of the total estrone metabolism in both sexes is extrasplanchnic and at least 25% of the total estradiol metabolism in males, and 15% in females is extrasplanchnic. The [rho](BB) (2,1) [transfer constant of estradiol to estrone, which is equivalent to the fraction of the precursor (estradiol) converted to the product (estrone) when both the infusion of the precursor and the measurement of the product are in peripheral blood] is 15%; and the [rho](BB) (1,2) [transfer constant of estrone to estradiol, which is equivalent to the fraction of the precursor (estrone) converted to product (estradiol) when both the infusion of the precusor and the measurement of the product are in peripheral blood] is 5% in both males and females. Our findings concerning the radioactivity in whole blood, as measured by our procedure, were the following: 15-20% of estrone in both sexes and 15% of estradiol in males is associated with red cells. Only 2% of the whole blood radioactivity of estradiol in females is associated with red cells. Changes in the distribution of radioactivity between plasma and red cells will influence the MCR as calculated from plasma, but not as calculated from whole blood.
New delivery systems for hormone replacement therapy
  • J S Frazer
Comparative efficacy and tolerability of transdermal Estradiol and conjugated estrogens,-a double blind multi center study
  • W L E H Nachtigall
  • Utian
Compliance of postmenopausal women under ERT
  • S A Campbell
  • Crawford
Kinetik eines neuen Pflaters zur transdermalen Applikation von 17-β-Estradiol
  • C U D Rohr
  • A M Nauert
  • Ehrly
In vitro model for intramuscular drug bioavailability I: Can membranes mimic muscle capillary wall permeability
  • U G D Schmittmann
  • T Rohr
  • Kissel
Physical chemical analysis of percutaneous absorption process from creams and ointments
  • T Higuchi