Tamie Kurihara-Bergstrom

Percutaneous Absorption Enhancement of an Ionic Molecule by Ethanol–Water Systems in Human Skin

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.

Enhanced transdermal delivery of estradiol in vitro using binary vehicles of isopropyl myristate and short-chain alkanols

Abstract The effect of binary vehicles of isopropyl myristate (IPM) and short-chain alkanols on the enhancement of skin permeation of estradiol (E 2 ) was studied in vitro using human epidermal membrane. The steady-state fluxes of E 2 and solvents across the skin were determined from saturated solutions of neat and binary solvents of IPM and ethanol (EtOH), n -propanol ( n -PrOH), n -octanol ( n -OcOH), or isopropanol (i-PrOH). While the neat solvents modestly increased the E 2 flux, addition of IPM to the alkanols resulted in a synergistic enhancement of the E 2 flux. Among the (1:1) binary cosolvents evaluated, i-PrOH produced the highest E 2 flux (1.1 μg/cm 2 per h), which was 35-fold greater than from water and over 15-fold greater than from the neat solvents. This combination was also the best in terms of relative compositions of the IPM/i-PrOH cosolvents. A strong correlation between E 2 and i-PrOH fluxes suggested the enhancement for both permeants. While i-PrOH traversed the skin, IPM was retained in the stratum corneum. The uptake of both IPM and E 2 in the stratum corneum was largely increased by adding i-PrOH (up to 50%) to IPM.

COTRANSPORT OF ESTRADIOL AND ETHANOL THROUGH HUMAN SKIN IN VITRO : UNDERSTANDING THE PERMEANT/ENHANCER FLUX RELATIONSHIP

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 (<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.

Quantitative Evaluation of Ethanol Effects on Diffusion and Metabolism of β-Estradiol in Hairless Mouse Skin

The influence of low levels of ethanol on the simultaneous diffusion and metabolism of β-estradiol (E2β) in hairless mouse skin was quantitatively evaluated. A wide range of diffusion/metabolism experiments was conducted with full-thickness skin, stripped skin, and dermis at the various ethanol levels. The experiments were carried out in a two-chamber diffusion-cell system where ethanol was present in both the donor and the receiver chambers at equal concentrations. Analysis of the experimental data with several enzyme distribution models further showed that the best model was that for which the enzyme activity resided totally in the epidermis and near the basal layer of the epidermis. The ethanol effects were separated and quantified in terms of the diffusion and metabolism parameters. Aqueous ethanol, even at low concentrations (≤25%), was found to have two important effects on E2β transport: ethanol functions as an inhibitor of the enzymatic conversion of E2β to estrone (E1) in the viable epidermis, and ethanol is able to enhance the transport of permeants across the lipoidal pathway of the stratum corneum.

Variation of human skin permeation in vitro: Ionic vs neutral compounds

Abstract The variation of skin permeation data has been investigated for ionic vs neutral permeants through human cadaver skin. In contrast to neutral ones, ionic permeants produced highly variable flux data with a positively skewed asymmetrical distribution. This permeant-dependent flux variation may suggest that different mechanisms are involved in the in vitro skin transport for ionic and neutral compounds.

Flow-Through System Effects on in Vitro Analysis of Transdermal Systems

The development of transdermal therapeutic systems (TTS) often involves in vitro evaluation of formulations and prototypes using flow-through diffusion cells. The apparent flux obtained from such methodologies does not accurately represent the actual (intrinsic) permeation of the compound through the skin. Flow-through system parameters, i.e., fraction collector tube volume, receiver cell volume, flow rate, and sampling interval, modify the flux yielding an apparent flux. Both finite-dose flux profiles and infinite-dose diffusional lag times are modified by these parameters. In this study, a transfer function is derived which describes the effect of these parameters. The intrinsic flux is calculated from apparent flux data using the transfer function and experimental flow-through system parameters. This allows the calculation of permeant flux profiles devoid of modification by the experimental methodology.

Quantitation of simultaneous diffusion and metabolism of β-estradiol in hairless mouse skin: Enzyme distribution and intrinsic diffusion/metabolism parameters

Abstract This paper describes a systematic experimental and theoretical study of the simultaneous diffusion and metabolism of β-estradiol (E 2β ) in hairless mouse skin (in vitro). The strategy involved (a) considering a general three-layer skin model (stratum corneum, epidermis, and dermis), (b) considering three possible enzyme distributions (Model A: homogeneous enzyme distribution across both epidermis and dermis; Model B: homogeneous enzyme distribution in the epidermis; and Model C: homogeneous enzyme distribution in the ‘basal cell layer’ only of the epidermis), and (c) carrying out a wide range of independent diffusion experiments so that a ‘best’ model may be deduced in which all of the experimental data are consistent with the model and a single set of transport and metabolism parameters. The various diffusion/metabolism experiments included using three skin membranes (dermis, stripped skin, and full-thickness skin), two membrane configurations (transport of permeants in the direction: stratum corneum → epidermis → dermis, and in the reverse direction), two permeants (E 2β and estrone, E 1 , the principal metabolite), and measuring three fluxes (forward fluxes of E 2β and E 1 and the back flux of E 1 ). Analysis of all of the experimental data demonstrated that Model C was superior to Models B and A; within the uncertainties of the experiments and model fitting, Model C agreed well with the data in all instances while the predictions of Models B and A exhibited significant deviations from the experimental data.

Pharmacokinetic evaluation of transdermal buprenorphine in man

Abstract Transdermal delivery of the synthetic opiate analgesic, buprenorphine, was studied in healthy volunteers. Pharmacokinetic, safety and tolerability data were obtained in a group of 12 healthy subjects following administration of a short intravenous infusion and the application of both aqueous- and ethanol-based fillable transdermal therapeutic systems (FTTS), containing 8 and 37.5 mg of drug, respectively. The total amount delivered by the 10 cm 2 aqueous reservoir system ranged from 0.11 to 0.67 mg over the 24 h application period and the steady state in vivo flux rates were 0.56–1.91 μg/cm 2 /h. The total amount delivered by the 5 cm 2 ethanol-based FTTS ranged from 0.33 to 0.96 mg and the steady state in vivo flux values were 2.14–5.62 μg/cm 2 /h. The results of the feasibility investigation demonstrated that transdermal delivery of buprenorphine produced sustained plasma levels of drug within the range observed after intravenous dosing and that an ethanolic formulation produced approximately a four-fold increase in transdermal flux. The in vivo investigation suggests that transdermal delivery could provide appropriate plasma levels of buprenorphine for sustained analgesic effect.

Skin compatibility of transdermal drug delivery systems

Abstract This article discusses factors affecting the results of contact allergic dermatitis (CAD) with respect to transdermal dosage form development, reviewing our experience in the development of TTS-arecoline for the treatment of Alzheimers disease. A significant improvement in responses of CAD was demonstrated in a in vivo guinea pig model by altering physical chemical properties of the transdermal dosage forms. An immunologic response to a new transdermal candidate compound may selectively be manipulated to prevent CAD.

Assessing the influence of ethanol on simultaneous diffusion and metabolism of ß-estradiol in hairless mouse skin for the ‘asymmetric’ situation in vitro

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 s-estradiol (E2s) 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 E2s 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.