Lynn K. Pershing

Mechanism of ethanol-enhanced estradiol permeation across human skin in vivo.

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 (Kp) of tracer estradiol solutions in ethanol or ethanol solutions compared with PBS vehicle reflected the 10-fold difference in the apparent partition coefficients (Km) 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 Km of estradiol from the vehicle into isolated human stratum corneum.

Feasibility of Measuring the Bioavailability of Topical Betamethasone Dipropionate in Commercial Formulations Using Drug Content in Skin and a Skin Blanching Bioassay

An in vivo technique has been developed which simultaneously compares a skin blanching bioassay with drug content in human stratum corneum following topical application of four 0.05% beta-methasone dipropionate formulations. Bioavailability of drug from commercial cream and ointment formulations was assessed by quantification of drug content in tape-stripped stratum corneum and skin blanching in the treated skin site under occluded conditions. Tape-stripping removed stratum corneum to a varying degree between individuals but was consistent (35%) within an individual with all formulations, day to day. A correlation (r = 0.9935) between the amount of drug in the treated stratum corneum normalized for surface area and the corresponding skin blanching score was observed with four 0.05% betamethasone dipropionate formulations. Increasing the amount of drug in the tape-stripped stratum corneum correlated with an increased skin blanching score. Ointment formulations delivered more drug to the skin and produced greater blanching scores than the cream formulations. Topical corticosteroid content in the treated skin site can therefore be quantified and correlates well with the resulting pharmacodynamic activity.

Variability and correlation of chromameter and tape-stripping methods with the visual skin blanching assay in the quantitative assessment of topical 0.05% betamethasone dipropionate bioavailability in humans

Abstract Bioavailability between five commercial 0.05% betamethasone diproprionate formulations in human skin is demonstrated with three methods; visual skin blanching, tape-stripping and a chromameter. Reproducibility of each method is evaluated for both intra- and inter-subject variability. The variability (coefficient of variation) in the intra-subject studies is consistently less than that in the inter-subject studies for all methods evaluated. The variability in the subjective visual skin blanching assay increases as a function of time. Variability in the tape-stripping technique performed at one time point only ranges from 7 to 30% in the intra-subject study to greater than 70% in the inter-subject study. Variability in the a scale on the chromamater is consistent over time (approx. 24%). The b scale on the chromameter demonstrates an inter-subject variation of about 15%, while the luminosity scale demonstrates a variability of approx. 6%. The rank order of 0.05% betamethasone diproprionate formulation potency is similar between the visual skin blanching assay, tape-stripping and the a scale on the chromameter. Further, the rank correlation between tape-stripping and the a scale on the chromameter with the subjective visual skin blanching assay is moderate to excellent ( r =0.6, and −0.9, respectively). Thus, tape-stripping and the chromameter offer the investigator two objective, standardized and noninvasive methods with which to compare bioequivalence of topical corticosteroids.

Percutaneous Absorption of Benzoic Acid Across Human Skin. I. In Vitro Experiments and Mathematical Modeling

The percutaneous absorption of benzole acid across human skin in vitro was experimentally and mathematically modeled. Skin partition coefficients were measured over a range of benzoic acid concentrations in both saline and distilled water. The permeation of benzoic acid was measured across isolated stratum corneum, stratum corneum and epidermis, and split-thickness skin. These experiments demonstrated that the stratum corneum was the rate-limiting barrier and that the flux is proportional to the concentration of the undissociated species. The permeation data were analyzed with a comprehensive non-steady-state mathematical model of diffusion across skin. Two adjustable parameters, the effective skin thickness and diffusivity, were fit to the permeation data by nonlinear regression.

Principles and criteria in the development and optimization of topical therapeutic products : Sponsored by the American Association of Pharmaceutical Scientists (AAPS) and U.S. Food and Drug Administration (FDA)

Abstract This report derived from the dermatological workshop discusses the problems and issues in the development and optimization of topical therapeutic drug products. It provides a clear understanding and differentiation between transdermal and dermal products. The report also discusses the bioavailability/bioequivalence issues for topical therapeutic products.

Reflectance spectrophotometer: the dermatologists' sphygmomanometer for skin phototyping?

To date, human skin phototype (SPT) has been determined subjectively by self- or trained investigator assessment using sun burning and/or sun tanning responses, ethnicity, hair, and eye color. This study evaluated objective reflectance spectrophotometer (RS) assessment of SPT in 353 males or females (18-72 years old with Fitzpatrick SPT I-VI) using the area-under-the-intensity curve (AUIC) over the 450-615 nm wavelength interval of reflected light (AUIC). Photoprotected constitutive skin color sites produced higher AUIC values than photo-exposed facultative skin color sites. Constitutive skin color at the upper volar arm was equal to the buttocks. Within-site and between-site AUIC reproducibility of constitutive skin color at the upper volar arm was 3 and 5% coefficient of variation (CV), respectively, which was similar to seasonal variability (8% CV). AUIC values decreased proportionately at both constitutive and facultative sites as a function of increasing SPT from I to VI (r=0.8). RS-measured constitutive skin color at the upper volar arm fit a quadratic equation (r(2)=0.94) that differentiated (P<0.05) between each of the six SPTs and agreed +/-1 SPT category with clinician-assessed SPT. Thus, RS assessment of constitutive skin color at the upper volar arm provides a quick, noninvasive, precise, and accurate method to objectively determine SPT.

Disparity of in Vitro and in Vivo Oleic Acid-Enhanced β-Estradiol Percutaneous Absorption Across Human Skin

The permeation enhancing property of 5% oleic acid in ethanol on β-estradiol was investigated in vitro and in vivo using symmetrical and asymmetrical side-by-side diffusion cells and the human skin sandwich flap, respectively. β-Estradiol permeability in vitro and in vivo was similar in 75% ethanol (ETOH). Oleic acid (5%) did not alter β-estradiol permeability in vivo but increased permeability sixfold in vitro in symmetrical diffusion cells. β-Estradiol permeability in oleic acid was not different from that in ETOH, however, using asymmetrical diffusion cells. Stratum corneum-to-vehicle partition coefficients of β-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 β-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.

Development of in vivo bioequivalence methodology for dermatologic corticosteroids based on pharmacodynamic modeling

Dermatologic corticosteroid products produce skin blanching that is related to clinical potency and dose. (For application of the vasoconstrictor assay to bioavailability and bioequivalence assessment, dose is defined in terms of duration of treatment exposure [dose duration], so the terms dose and dose duration have been used interchangeably). The vasoconstrictor assay is the method of choice to assess dermatologic corticosteroid products bioequivalence if dose‐response is validated. This article examines dose‐response validation to meet objectives of US Food and Drug Administration (FDA) bioequivalence guidance for dermatologic corticosteroid products.

A comparative analysis of extracellular fluid volume of several tissues as determined by six different markers

Abstract The uptake and distribution of 6 different extracellular markers were analyzed in ten tissues of the rat. The saccharides, 3 H-mannitol, 3 H-raffinose, 3 H-inulin, and 14 C-inulin, reached a steady-state distribution in all tissues within ≈15 min after intraperitoneal injection; 22 Na and 36 Cl followed similar kinetics in all tissues except the choroid plexuses and the thyroid, which required > 1 hr to obtain a steady-state plateau. In most tissues, the steady-state spaces of 3 H-raffinose, 3 H-inulin, and 14 C-inulin (60 min) were not significantly different; however, the 3 H-mannitol, 22 Na and 36 Cl spaces were on average 45, 54, and 79%, respectively, greater than the 3 H-inulin space.

Current Challenges in Bioequivalence, Quality, and Novel Assessment Technologies for Topical Products

This paper summarises the proceedings of a recent workshop which brought together pharmaceutical scientists and dermatologists from academia, industry and regulatory agencies to discuss current regulatory issues and industry practices for establishing therapeutic bioequivalence (BE) of dermatologic topical products. The methods currently available for assessment of BE were reviewed as well as alternatives and the advantages and disadvantages of each method were considered. Guidance on quality and performance of topical products was reviewed and a framework to categorise existing and alternative methods for evaluation of BE was discussed. The outcome of the workshop emphasized both a need for greater attention to quality, possibly, via a Quality-By-Design (QBD) approach and a need to develop a “whole toolkit” approach towards the problem of determination of rate and extent in the assessment of topical bioavailability. The discussion on the BE and clinical equivalence of topical products revealed considerable concerns about the variability present in the current methodologies utilized by the industry and regulatory agencies. It was proposed that academicians, researchers, the pharmaceutical industry and regulators work together to evaluate and validate alternative methods that are based on both the underlying science and are adapted to the drug product itself instead of single “universal” method.