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Rate Control in Transdermal β-Estradiol Reservoir Membrane Systems: The Role of Membrane and Adhesive Layer
Abstract
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).
Fatty alcohols, fatty acids (saturated and unsaturated), and fatty acid esters have been extensively utilized as skin penetration enhancers in many research studies over the past 3 decades. Some of these compounds, for example, oleic acid, stearic acid, isopropyl palmitate, ethyl oleate, have been approved by the US Food and Drug Administration for their use in topical and transdermal products. It is generally believed that these agents increase skin permeation by disrupting the lipid organization in skin layers, forming solvated complexes, increasing the diffusivity and partitioning of drugs in/through the skin barrier. This chapter summarizes the utility of fatty alcohols, fatty acids, and their esters as promising percutaneous penetration enhancers for topical and transdermal delivery of drugs. The role of vehicle or other ingredients from the formulation on the enhancement effects of the topical or transdermal formulation and their skin irritation potential has also been presented.
Estradiol is an important pharmacologically active drug with good skin permeation. It does not induce side effects like an overproduction of unwanted hepatic proteins. In this study the feasibility of a new formulation for the local delivery of estradiol consisting of an anhydrous gel, with a high percentage of ethanol, forming an invisible and non-irritating film on the skin was tested. The formulation was designed in order to delay the liberation of estradiol and to slow down the skin estradiol permeation with a consequent prolonged drug action that would reduce the number of applications. For this reason, two different gel-forming polymers were added to the basic formulation: Klucel® HF (hydroxypropyl cellulose) and Polymer-Len®, a polymer made by copolymerization of lauryl methacrylate with N-vinyl pyrrolidone. From in vitro permeation studies it was pointed out that hydroxypropyl cellulose and the copolymer act on drug permeation in two opposite ways with respect to the basic formulation. In fact, the copolymer decreases drug permeation while hydroxypropyl cellulose increases it. Therefore, the copolymer of lauryl methacrylate with N-vinyl pyrrolidone is well suited to delay permeation and to achieve the desired formulation properties.
Fatty alcohols, fatty acids, and their derivatives are used in a variety of skin and general healthcare products, to name a few: moisturizing creams, shampoos, hair products, shaving products, bath oils, lipsticks, and perfumed products. The wide usage of these as topical ingredients implies that they are nontoxic and considered safe for topical use. Pimecrolimus 1% cream (Elidel1 cream), Tretinon cream (Renova1 cream), and Fluorouracil 0.5% cream are some examples of topical formulations employing fatty alcohols, or fatty acids, or both as dermatological ingredients. Alpha-lipoic acid, a ring containing fatty acid, is an active medicament for treating photo-damaged skin and is deemed safe as a topical agent. Fatty alcohols and fatty acids have been extensively investigated to characterize their interactions with stratum corneum (SC) and to describe their effects in modulating the skin barrier function.1 This chapter deals with the utility of fatty alcohols and fatty acids as promising skin penetration enhancers for topical and transdermal delivery of drugs. The role of vehicle or other ingredients on the enhancement effects of the topical or transdermal formulation and their skin irritation potential has also been discussed.
Analytical solutions based on the pseudo-steady state approximation (PSSA) were derived for the case of controlled dispersed-drug release from erodible and non-erodible planar matrices, through a membrane, and taking into account the existence of a diffusion boundary layer and a finite release medium. The solutions can be applied to a broad range of situations from drug release into finite or infinite medium, from erodible or non-erodible matrices, in the presence or absence of a membrane, and in the presence or absence of a stagnant liquid layer. The prediction is accurate for the cases in which the initial drug load is higher than the drug solubility in the polymer (e.g. A/Cs≥3) till the entire dispersed drug is dissolved. The dependence on the release kinetics with different parameters was simulated and provides a theoretical platform for the design of dispersed-drug release devices.
Purpose. The aim of our study was to investigate the kinetics of -estradiol (E2) metabolism in the human keratinocyte cell line HaCaT and to estimate the effect of the potential inhibitor ethanol on the biotransformation reaction.
Methods. The formation rates of estrone (E1) in dependence on substrate concentrations were determined in HaCaT cells using tritium labelled E2. Experiments were conducted with and without addition of dehydroepiandrosterone (DHEA) and ethanol. Possible toxic effects on the cells due to ethanol were investigated by cytotoxicity tests.
Results. The metabolism of E2 in HaCaT cells exhibited Michaelis-Menten kinetics with Km and Vmax values of 3.5 M and 216 pmol mg–1 protein h–1, respectively. The reaction was inhibited by DHEA and ethanol. The alcohol showed a reversible competitive inhibition mechanism for concentrations of 4 to 8% (v/v). Lower ethanol concentrations had no effect, whereas levels 10% significantly decreased cell viability leading to a different inhibition mechanism.
Conclusions. The HaCaT cell line seems to be a suitable model for studying enzyme kinetics equivalent to the human skin. The concentration dependent inhibitory effect of ethanol observed in this cell line may be relevant for the transdermal E2 application in patients.
Analytical solutions for the case of controlled dispersed-drug release from planar non-erodible polymeric matrices, based on Refined Integral Method, are presented. A new adjusting equation is used for the dissolved drug concentration profile in the depletion zone. The set of equations match the available exact solution. In order to illustrate the usefulness of this model, comparisons with experimental profiles reported in the literature are presented. The obtained results show that the model can be employed in a broad range of applicability.
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).
The purpose of this investigation was to study the effect of some penetration enhancers on in vitro permeation of glibenclamide and glipizide through mouse skin. Ethanol in various concentrations, N-methyl-2-pyrrolidinone, transcutol, propylene glycol and terpenes like citral, geraniol and eugenol were used as penetration enhancers. The in vitro skin permeation experiments were conducted by both simultaneous application of drug and enhancer solution and by pretreatment of the skin with neat enhancer. At the end of the experiment drug retained in the skin was estimated. The flux values (μg/cm2/h) of both drugs significantly (p < 0.05) increased in the presence of penetration enhancers, except transcutol and propylene glycol. The glibenclamide flux values ranged from 1.42 ± 0.09 without enhancer, to 18.25 ± 1.21 in a combination of 50% ethanol and 5% eugenol. Glipizide flux values ranged from 3.21 ± 0.51 without enhancer, to 57.21 ± 5.25 in a combination of 50% ethanol and 5% eugenol. Skin retention and solubility of both drugs increased with all penetration enhancers compared to control (except propylene glycol). As the target permeation rates for glibenclamide and glipizide were calculated to be 193.8 and 184.8 μg/h respectively, the present study showed that the required permeation rates for both drugs could be achieved with the aid of enhancers by increasing the area of application in an appreciable range.
Synopsis
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.
Pharmacodynamic Properties
17β-Estradiol is the predominant estrogen produced by the ovaries in premenopausal women. Administration of transdermal estradiol to postmenopausal women (in dosages of 0.05 to 0.2 mg/day) elevates plasma estradiol concentrations into the range observed in premenopausal women at the early to mid follicular stage. Plasma estrone concentrations are increased to a much lesser degree and a physiological plasma ratio of estradiol to estrone (approximately 1: 1) is thus produced. As a result of the increased plasma estradiol concentrations, plasma concentrations of follicle-stimulating hormone (FSH) and luteinising hormone (LH) are decreased and vaginal cytology is converted to a pattern resembling that found in premenopausal women, with improvement of the maturation and karyopyknotic indices. Bone resorption is inhibited, as evidenced by a reduction in the urinary ratios of calcium and hydroxyproline to creatinine, and an increase in bone mineral density has been achieved in patients receiving long term treatment. Transdermal estradiol has a less marked effect than oral estrogens on lipid and lipoprotein metabolism; the plasma lipid profile does not appear to be significantly altered by short term treatment, but some studies of ⩾ 6 months’ duration have reported potentially beneficial changes in various lipid and lipoprotein fractions.
Pharmacokinetic Properties
The estradiol transdermal therapeutic system is designed to deliver estradiol at a constant rate for up to 4 days. Currently, 3 sizes of delivery system are available, with nominal delivery rates of 0.025, 0.05 and 0.1 mg/24 hours. Following application of transdermal estradiol to intact skin, maximum plasma estradiol concentrations are attained in postmenopausal women within 2 to 8 hours. Steady-state plasma concentrations of estradiol are linearly proportional to the dose administered; mean levels of around 23, 40, 75 and 100 ng/L occur in women with pretreatment estradiol levels ⩽ 10 ng/L from administration of 0.025, 0.05, 0.1 and 0.2 mg/day, respectively. Plasma levels of estradiol during transdermal therapy and reduction in menopausal symptoms, plasma FSH concentrations and urinary excretion of calcium are closely related.
Estradiol is mainly metabolised in the liver, the major metabolites being estrone and estriol and their conjugates, which are considerably less potent than estradiol. The bulk of the metabolites are excreted in the urine as glucuronides and sulphates, although some enterohepatic recirculation may occur. Within 24 hours of removal of transdermal delivery systems, plasma concentrations of estradiol and estrone, and urinary excretion of estradiol and estrone conjugates, return to pretreatment levels. The plasma elimination half-life of estradiol is approximately 1 hour irrespective of the route of administration and the metabolic plasma clearance rate is between 650 and 900 L/day/m2.
Therapeutic Use
The efficacy of transdermal estradiol as estrogen replacement therapy in peri- or postmenopausal women has been evaluated in noncomparative, placebo-controlled and comparative clinical trials. Dosages ranging from 0.025 to 0.2mg daily have been used. In studies of ⩾ 2 months duration, treatment has generally been cyclical (3 weeks on, 1 week off) and sequential progestagen therapy has usually been administered for 5 to 12 days per cycle to patients with an intact uterus, in order to minimise endometrial proliferation. Climacteric symptoms — hot flushes, sweating, sleep disturbance, vaginal discomfort, poor concentration and irritability — have been eliminated or significantly improved during transdermal estradiol replacement therapy. In comparative studies transdermal estradiol has demonstrated efficacy in the control of climacteric symptoms at least equivalent to those of oral estradiol preparations, ethinylestradiol and conjugated estrogens, and subcutaneous estradiol implants or estradiol/prasterone depot injections. Data from preliminary studies suggest that transdermal estradiol, usually with sequential progestagen, is also effective in other indications for which estrogen therapy is prescribed, such as contraception and as hormone replacement therapy in patients with premature ovarian failure or bilateral oophorectomy participating in fertility programmes. Although transdermal estradiol inhibits bone resorption, few data are currently available regarding its effect on the incidence of osteoporosis and fractures in treated menopausal women.
Analysis of patient acceptability of the transdermal route for estrogen replacement in several studies indicated that > 70% of patients preferred transdermal estradiol over oral or injectable therapies.
Adverse Effects
A significant proportion of patients experience dermatological reactions to the transdermal delivery device. Although these mostly consist of transient erythema/itching at the site of application, which can be minimised by rotation of patch application sites, severe irritation leading to discontinuation of therapy occurs in about 2.5 to 7% of patients overall.
Otherwise, transdermal estradiol therapy is generally well tolerated, the most common systemic adverse symptoms being typical estrogenic effects, such as breast tenderness and spotting/bleeding and general effects such as fatigue, abdominal bloating and nausea, which result in discontinuation of treatment in < 4% of patients. Estrogenic stimulation of the endometrium occurs with transdermal estradiol therapy and coadministration of a sequential progestagen (which may also produce a more acceptable bleeding pattern) is therefore recommended for patients with an intact uterus in order to minimise endometrial proliferation.
Unlike oral estrogens, transdermal estradiol does not stimulate hepatic metabolism and consequently plasma concentrations of renin substrate, sex hormone-, thyroxine- and cortisol-binding globulins and clotting factors are not elevated.
It has been suggested that transdermal estradiol might be associated with a lower incidence of adverse effects than oral estrogen replacement therapies because of the lower circulating estrogen concentrations involved and the lack of untoward effects on liver metabolism. However, this has not been confirmed in comparative studies to date; generally, adverse effects have been comparable in patients receiving transdermal estradiol and those receiving oral or injectable estrogens.
Dosage and Administration
The recommended initial dosage of transdermal estradiol for the treatment of menopausal symptoms is 0.05mg daily, which may be increased in cases of inadequate response after 2 to 3 weeks’ treatment, or decreased if breast discomfort or breakthrough bleeding occur. For maintenance therapy the lowest effective dose should be used. Treatment may be continuous or may be given in 4-week cycles (3 weeks on/1 off). Sequential progestagen treatment should be administered for 10 to 12 days per month to patients with an intact uterus.
The transdermal estradiol delivery system should be changed twice weekly. Contraindications to the use of estradiol include carcinoma of the breast or endometrium, leiomyoma of the uterus, endometriosis, vaginal bleeding of unknown origin, severe renal, hepatic, or cardiac disease and active or previous thromboembolic disease.
The permeation enhancing property of 5% oleic acid in ethanol on -estradiol was investigated in vitro and in vivo using symmetrical and asymmetrical side-by-side diffusion cells and the human skin sandwich flap, respectively. -Estradiol permeability in vitro and in vivo was similar in 75% ethanol (ETOH). Oleic acid (5%) did not alter -estradiol permeability in vivo but increased permeability sixfold in vitro in symmetrical diffusion cells. -Estradiol permeability in oleic acid was not different from that in ETOH, however, using asymmetrical diffusion cells. Stratum corneum-to-vehicle partition coefficients of -estradiol in the vehicles were similar, yet fourfold more steroid was detected in skin biopsies from the in vitro symmetrical diffusion cells. Thus, oleic acid increased -estradiol permeability in vitro only when skin was equilibrated with fatty acid. Attention to in vitro diffusion cell design and its relevance in vivo is critical to defining the mechanisms of enhanced solute permeation.
The influence of ethanol on the transport behavior of β-estradiol and other permeants in hairless mouse skin was investigated over a 0–100% ethanol/saline concentration range. At high ethanol levels (> 50%), there were significant increases in new pore formation in the stratum corneum component of the skin. With pure ethanol, pore pathway transport dominated the permeation for all solutes, irrespective of polarity. At low ethanol levels (<25%), ethanol had little or no effect on the pore pathway. However, the transport of β-estradiol and hydrocortisone via the lipid pathway of the stratum corneum was greatly enhanced. The enhancement factor, E, for β-estradiol and for hydrocortison was calculated from the experimental permeation data by correcting for the dermis /epidermis permeability coefficient, the stratum corneum pore pathway permeability coefficient, and by using solubility data to correct for chemical potential changes with solvent composition. The E-values for β-estradiol and for hydrocortisone were found to be of the same magnitude (7 to 9 at 25% ethanol and of the order of 100 at 50% ethanol). It is proposed that the ethanol enhancement effects at low ethanol levels may be interpreted in terms of fluidity increases in the transport rate-limiting lipid domains.
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.
A novel theoretical model/method has been developed to predict permeant transport across skin for the ‘asymmetric’ case, i.e., for situations in which there is significant cotransport of an enhancer solvent along with the principal permeant. The method has successfully predicted effects of the simultaneous transport of ethanol on the simultaneous diffusion and metabolism of ß-estradiol (E2ß) at steady state in hairless mouse skin using parameter values deduced from experiments conducted under symmetric conditions (i.e., the same ethanol concentration on both sides of the skin membrane). The studies have involved the determination of (a) effective ethanol concentration gradients and (b) skin position-depedent permeability coefficients and partition coefficients, concentration (activity) gradients, and fluxes for E2ß and its transdermal metabolite, estrone (E1), with stripped skin and with full thickness skin. As this approach is quite general and as the asymmetric situation is the practical situation in vivo, it is believed that the outcomes of this study are important in transdermal/dermal formulations research.
Ethanol–water systems enhance permeation of ionic solutes through human stratum corneum. Optimum enhancement of salicylate ion permeation has been observed with ethanol volume fractions near 0.63. The mechanism of action of ethanol–water systems enhancing skin permeation was investigated by in vitro skin permeation studies combined with Fourier transform infrared spectroscopy experiments. The increased skin permeation of the ionic permeant by the ethanol–water systems may be associated with alterations involving the polar pathway. Polar pathway alterations may occur in either or both the lipid polar head and proteinaceous regions of the stratum corneum. Ion-pair formation may also contribute to increased permeation. However, the decreased permeation of salicylate ion observed at higher volume fractions of ethanol may be attributed to decreased uptake of permeant into the stratum corneum.
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.
The successful introduction of nitroglycerin transdermal delivery systems for the prophylactic treatment of angina pectoris has spawned an explosion of interest in this route of drug delivery in the field of pharmaceutics. Since that time, we have gained a great deal more knowledge concerning the design of membrane controlled delivery systems. This route of administration has been proposed and investigated in a number of disease states using several drugs. We would like to report our experience in investigating the transdermal route for long term treatment of postmenopausal symptoms using estradiol replacement therapy.The rationale for the development of a transdermal estradiol system is associated with the metabolic and pharmacological effects of orally administered estrogen replacement in post-menopausal women. Because estradiol is metabolized almost completely on first pass through the liver, orally administered estrogens result in nonphysiologic levels of the estrogenic metabolites of the natural ovarian hormone. Transdermal delivery of estradiol successfully by-passes the first pass effect and results in a more normal estrogen blood profile. The results of several biopharmaceutics studies demonstrate the characteristics of the membrane controlled delivery system which was designed around pharmacologic principles. In addition, a number of clinical trials have shown that total required doses of estradiol provided transdermally are only a fraction of those required by the oral route. We will also discuss problems associated with adequately defining total drug input from transdermal devices when working in these very small dosing ranges.
The feasibility of developing a membrane-controlled reservoir-type dual-controlled transdermal delivery system for the simultaneous transdermal delivery of levonorgestrel (LNG) and estradiol (E2) was studied. The skin permeation profiles were observed to follow a zero-order kinetics throughout the course of 72-h permeation studies in the hydrodynamically well-calibrated Valia-Chien permeation cells. The skin permeation rate of LNG from its aqueous saturated solution was extremely low (0.03 μg cm−2 h−1 ), but was enhanced exponentially by the addition of ethanol. The rate of skin permeation was observed to be first enhanced as increasing the volume fraction of ethanol in the donor solution, which reached the maximal rate of 7.69 μg cm−2h−1 at 70% (v/v) of ethanol, and then declined with the further increase in the volume fraction. The peak permeation rate achieved by 70% (v/v) of ethanol was further increased with the addition of skin permeation enhancers, such as azone and oleic acid. The permeation of LNG through the (ethylene/vinyl acetate) copolymer (EVA) membrane-covered hairless rat skin also showed the same zero-order permeation kinetics, with rate increased as increasing the weight fraction of vinyl acetate in the copolymer, but decreased as increasing the thickness of the membrane. Moreover, the permeation rate of LNG across the membrane-covered rat skin increased linearly with the increase of oleic acid concentration. The skin permeation rate of E2 across both hairless rat and human cadaver skin covered with EVA membrane was found to be controlled by variation in the loading dose of E2 in the reservoir formulation without affecting the permeation rate of LNG. The ratio of the permeation rate of LNG over E2 could be modulated by varying the loading doses of E2 and LNG. Thus, it was possible to achieve the dual-controlled delivery of LNG and E2 at a specific ratio of delivery rate, for contraception or treatment of postmenopausal syndromes, by controlling the composition of reservoir formulation, the weight fraction of vinyl acetate in the EVA membrane and its thickness, as well as the loading doses of LNG and E2.
Considerable interest in using the transdermal route for drug administration has strengthened the need for investigations of vehicle effects. The influence of ethanol on the in vitro transport behaviour of saturated oestradiol (OE) solutions through excised human skin and model membranes (silastic, human skin-silastic sandwich and snake skin) was investigated over 0–90% w/w ethanol/water vehicle compositions. Human skin showed a maximum flux of OE (1.45 ± 0.39 μ cm-2 h-1) at ethanol vehicle contents between 40 and 60% w/w. Silastic membranes were used to help elucidate the mechanisms of ethanol as an enhancer. Partition coefficients and uptake of OE by stratum corneum and silastic membranes from the co-solvent systems were determined and the results suggested that the enhanced permeation of OE from vehicles with ethanol concentrations up to 60% w/w was partially related to increased drug solubility in the stratum corneum. The other part was related to ethanol effects on stratum corneum components. The decrease of OE flux from vehicles with higher ethanol concentrations was due to ethanol dehydration effects on the stratum corneum. This was confirmed by measuring the uptake of ethanol and water from different concentrations of ethanol; increasing ethanol concentration in the donor produced a significant decrease in the stratum corneum water content. Also, when the skin hydration was controlled using the skin-silastic sandwich model, the OE flux did not significantly decrease at high ethanol concentration. Ethanol actions were further investigated by measuring the permeation rate of OE through a model animal membrane, shed snake skin. Different results were obtained than for human skin and silastic membrane. The maximum flux of OE through dorsal snake skin appeared at higher ethanol vehicle concentration (80% w/w) when compared with human skin. Ventral snake skin showed increasing OE flux up to 40% w/w ethanol which remained essentially constant up to 90% ethanol. The results obtained with snake skin were attributed to the lower water content of this membrane.
To evaluate the effects of vehicle supplementation on serum estradiol (E2) delivery pharmacokinetics from the Ciba-Geigy (Summit, NJ) 0.1-mg Estraderm Patch.
Postmenopausal women were randomized to a 28-day crossover treatment protocol separated by a 14-day wash out period.
Normal human volunteers were studied in an academic research environment.
The subject pool included eight healthy postmenopausal women between 32 and 60 years of age.
In treatment A, a 0.1-mg Estraderm Patch was worn for 7 days; in treatment B, and identical patch was worn into which 0.6 mL of ethanol was injected on day 3 of use.
Serum E2 levels were measured in both groups.
Although E2 absorption showed characteristic interpatient variability, addition of ethanol significantly extended the mean time for serum E2 levels to return to baseline, without increasing peak absorption. The mean extension was 50 hours.
The addition of ethanol to the Estraderm Patch increased the duration of elevated serum E2 levels measured in menopausal women, thus potentially increasing the effective life span of the transdermal therapeutic system.
The thermodynamic and kinetic limits of ethanol-enhanced estradiol skin transport have been investigated by studying the relationship between estradiol and ethanol steady-state flux in the cotransport of permeant and enhancer in situations in which there exists an enhancer solvent gradient across the skin ("asymmetric" configuration). For aqueous ethanol solution saturated with estradiol, the flux of estradiol across the human epidermal membrane is empirically observed to be linear with the ethanol flux. A physical model approach has been used to determine the basis of this empirical linearity and to predict permeant/enhancer transport across the skin for the asymmetric configuration. Enhancement factors, determined with a balanced ethanol concentration across the skin ("symmetric" configurations), are used to predict fluxes in the asymmetric configurations. The model demonstrates that ethanol enhances the stratum corneum transport of estradiol and of itself by increasing the respective diffusion coefficients at lower concentrations (less than 50%) and by both increasing the diffusion coefficients and decreasing the membrane activity coefficients at moderate concentrations (50 to 75%). The model also demonstrates that the permeant flux, in general, is not linear with the cotransported enhancer flux.
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.
The influence of ethanol on the permeation of 17β-estradiol (estradiol) across viable human skin in vivo was investigated with the human skin sandwich flap model. Maintaining continuous delivery of a constant concentration of the solute in phosphate-buffered saline, pH 7.4 (PBS), or mixtures of ethanol in PBS to the skin surface revealed that steady-state flux of estradiol was achieved within 30–60 min and maintained throughout 4 hr. The 10-fold decrease in in vivo flux and permeability coefficient (K
p) of tracer estradiol solutions in ethanol or ethanol solutions compared with PBS vehicle reflected the 10-fold difference in the apparent partition coefficients (K
m) of estradiol from the respective vehicles into isolated human stratum corneum. Neither the stratum corneum thickness nor the diffusion coefficient of estradiol was significantly different among the vehicles tested. In vivo flux of estradiol in ethanol or ethanol solutions across viable human skin was increased with saturated solutions of estradiol. Further, in vivo flux of estradiol from vehicles such as PBS, ethanol, and ethanol mixtures, which minimally alter the rate-limiting barrier, can be successfully predicted with knowledge of only two physicochemical parameters, the estradiol concentration in the vehicle and the K
m of estradiol from the vehicle into isolated human stratum corneum.
The solution properties of aqueous ethanol donor solutions were characterized for the particular case of an increased flux nitroglycerin transdermal system. Permeation through porous and nonporous polymer membranes was investigated and modelled. While the permeation of ethanol through the porous membranes is adequately described by theory, clogging of pores occurs in the presence of lactose. Permeation through ethylene vinyl acetate membranes reflects interactions of the solute and solvent with the polymer.
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.
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.
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.
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.
The mutual hairless rat skin permeation-enhancing effect of ethanol (EtOH)/water systems and oleic acid (OA) was investigated with model lipophilic (estradiol, progesterone, levonorgestrel) and hydrophilic drugs (zalcitabine, didanosine, zidovudine). The aqueous solubility and hairless rat skin permeation rate of each drug, saturated in various compositions of EtOH/water system (with and without OA), was determined at 37 degrees C. The hairless rat skin permeation rates of ethanol from EtOH/water systems (with and without OA) were also measured to investigate the skin permeation-enhancing mechanism of EtOH/water systems and OA. Both saturated solubility and steady-state permeation rates of each drug in EtOH/water systems increased exponentially as the volume fraction of ethanol increased, reached the maximum value, and then decreased with further increases in the ethanol volume fraction. Moreover, the hairless rat skin permeation rate of each drug had a good linear relationship with that of ethanol up to 70% (v/v) of ethanol in the EtOH/water system. The addition of OA in the EtOH/water system (70:30 and 60:40 for lipophilic and hydrophilic drugs, respectively) further enhanced the skin permeation rate of both ethanol and drugs. However, > 2.0% (v/v) OA was required to achieve the plateau level in the skin permeation rate of lipophilic drugs, whereas only 0.3% (v/v) OA was required for hydrophilic drugs. The skin permeation rate of ethanol also increased with the addition of OA in the EtOH/water systems (70:30 and 60:40), reached the plateau level with < 1.0% (v/v) OA, and did not significantly change with higher OA concentration. These results suggest that the addition of OA in the EtOH/water system is a useful method to enhance the hairless rat skin permeation rate of both hydrophilic and lipophilic drugs, with more enhancement for hydrophilic drugs.
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.
Materials selections for transdermal delivery systems Transdermal drug delivery
- J R W Baker
- Heller
Mechanism of action of ethanol as flux enhancer for drug permeation through human skin
- E S I S Yum
- L Lee
- F Taskovich
- Theeuwes
Physical chemical analysis of percutaneous absorption process from creams and ointments
- T Higuchi