Xiaoying Hui

Transungual drug delivery: current status.

Topical therapy is highly desirable in treating nail disorders due to its localized effects, which results in minimal adverse systemic events and possibly improved adherence. However, the effectiveness of topical therapies is limited by minimal drug permeability through the nail plate. Current research on nail permeation that focuses on altering the nail plate barrier by means of chemical treatments, penetration enhancers as well as physical and mechanical methods is reviewed. A new method of nail sampling is examined. Finally limitations of current ungual drug permeability studies are briefly discussed.

In vivo bioavailability and metabolism of topical diclofenac lotion in human volunteers

AbstractPurpose. The primary objective of this study was to determine the rate and extent of transdermal absorption for systemic delivery of diclofenac from Pennsaid (Dimethaid Research, Inc.) topical lotion into the systemic circulation after the lotion was applied to human volunteers, in an open treatment, non-blinded, non-vehicle controlled study. In addition, the in vivo metabolism of this topical diclofenac lotion has also been studied. Methods. Human volunteers were dosed with topical [14C]-diclofenac sodium 1.5% lotion on the knee for 24 h. Sequential time blood and urine samples were taken to determine pharmacokinetics, bioavailability and metabolism. Results. Topical absorption was 6.6% of applied dose. Peak plasma 14C occurred at 30 h after dosing, and peak urinary 14C excretion was at 24−48 h. The urinary 14C excretion pattern exhibits more elimination towards 24 h and beyond, as opposed to early urinary 14C excretion. This suggests a continuous delivery of [14C]-diclofenac sodium from the lotion into and through skin which only ceased when the dosing site was washed. Skin surface residue at 24 h was 26 ± 9.5% dose (remainder assumed lost to clothing and bedding). Extraction of metabolites from urine amounted to 7.4−22.7% in untreated urine, suggesting substantial diclofenac metabolism to more water soluble metabolites, probably conjugates, which could not be extracted by the method employed. Two Dimensional TLC analysis of untreated urine showed minimal or no diclofenac, again emphasizing the extensive in vivo metabolism of this drug. Treatment of the same urine samples with the enzymes sulfatase and (β-glucuronidase showed a substantial increase in the extractable material. Three spots were consistently present in each sample run, namely diclofenac, 3′hydroxy diclofenac and an intermediate polar metabolite (probably a hydroxylated metabolite). Therefore, there was significant sulfation and glucuronidation of both diclofenac and numerous hydroxy metabolites of diclofenac, but many of the metabolites/conjugates remain unidentified. Conclusions. There was a continuous delivery of diclofenac sodium from the lotion into and through the skin, which ceased after the dosing site was washed. The majority of the material excreted in the urine were conjugates of hydroxylated metabolites, and not the parent chemical, although further identification is required.

Human in vivo and in vitro hydroquinone topical bioavailability, metabolism, and disposition

Hydroquinone is a ubiquitous chemical readily available as monographed in cosmetic and nonprescription forms for skin lightening, and is an important industrial chemical. The in vivo bioavailability for 24-h application in humans was 45.3+/-11.2% of dose from a 2% cream formulation containing [14C]hydroquinone, with the majority of radioactivity excreted in the first 24 h. Timed skin wash and skin tape-stripping sequences showed a rapid and continuous movement of hydroquinone into the stratum corneum of human volunteers. Plasma levels taken both ipsilateral and contralateral to the topical dosing site contained radioactivity at the first 0.5-h sampling time. Peak plasma radioactivity was at 4 h in the 8-h blood sampling period. In vitro percutaneous absorption with fresh viable human skin gave a bioavailability of 43.3% of dose, and flux was calculated at 2.85 microg/cm2/h. In vitro, some of the skin samples were pretreated with the metabolic inhibitor sodium azide, which had no effect on percutaneous absorption. Receptor fluid accumulations and 24-h skin samples were extracted and the extracts subjected to thin-layer chromatography (TLC). Control [14C]hydroquinone extraction and TLC had one radioactivity peak, hydroquinone. Receptor fluid and skin extraction had a second peak with the same Rf as benzoquinone, which was decreased with azide treatment. No other peaks were found. Ethyl acetate extraction of urine from the in vivo study showed all radioactivity to be only water-soluble, free hydroquinone released following glucuronidase treatment. Risk assessment should not only involve the bioavailability of intact topical hydroquinone, but also consider phase I and phase II metabolism in both humans and any animal for which toxicity potential was assessed.

Measuring transepidermal water loss: a comparative in vivo study of condenser‐chamber, unventilated‐chamber and open‐chamber systems

Background/aims: Two main systems have been utilized for measuring transepidermal water loss (TEWL): open chamber and closed chamber. Yet, further validation and standardization studies may be necessary to reveal the sensitivity, precision, and robustness of these instruments.

Correlation of transepidermal water loss with skin barrier properties in vitro: comparison of three evaporimeters

Aim: This study investigates the relationship between transepidermal water loss (TEWL) and skin permeability to tritiated water as a rapid assessment of the integrity of the barrier properties of skin as part of in vitro skin permeation studies.

In vivo skin decontamination of methylene bisphenyl isocyanate (MDI): soap and water ineffective compared to polypropylene glycol, polyglycol-based cleanser, and corn oil.

In the home and workplace, decontamination of a chemical from skin is traditionally done with a soap-and-water wash, although some workplaces may have emergency showers. It has been assumed that these procedures are effective, yet workplace illness and even death occur from chemical contamination. Water, or soap and water, may not be the most effective means of skin decontamination, particularly for fat-soluble materials. This study was undertaken to help determine whether there are more effective means of removing methylene bisphenyl isocyanate (MDI), a potent contact sensitizer, from the skin. MDI is an industrial chemical for which skin decontamination, using traditional soap and water and nontraditional polypropylene glycol, a polyglycol-based cleanser (PG-C), and corn oil were all tried in vivo on the rhesus monkey, over 8 h. Water, alone and with soap (5% and 50% soap), were partially effective in the first h after exposure, removing 51-69% of the applied dose. However, decontamination fell to 40-52% at 4 h and 29-46% by 8 h. Thus, the majority of MDI was not removed by the traditional soap-and-water wash; skin tape stripping after washing confirmed that MDI was still on the skin. In contrast, polypropylene glycol, PG-C, and corn oil all removed 68-86% of the MDI in the first h, 74-79% at 4 h, and 72-86% at 8 h. Statistically, polypropylene glycol, PG-C, and corn oil were all better (p < 0.05) than soap and water at 4 and 8 h after dose application. These results indicate that a traditional soap-and-water wash and the emergency water shower are relatively ineffective at removing MDI from the skin. More effective decontamination procedures, as shown here, are available. These procedures are consistent with the partial miscibility of MDI in corn oil and polyglycols.

A real-time in-vivo method for studying the percutaneous absorption of volatile chemicals.

Abstract Realistic estimates of percutaneous absorption following exposures to solvents in the workplace, or through contaminated soil and water, are critical to understanding human health risks. A method was developed to determine dermal uptake of solvents under non-steady-state conditions using real-time breath analysis in rats, monkeys, and humans. The exhaled breath was analyzed using an ion-trap mass spectrometer, which can quantitate chemicals in the exhaled breath stream in the 1–5 ppb range. The resulting data were evaluated using physiologically-based pharmacokinetic (PBPK) models to estimate dermal permeability constants (Kp) under various exposure conditions. The effects of exposure matrix (soil versus water), occlusion versus non-occlusion, and species differences on the absorption of methyl chloroform, trichloroethylene, and benzene were compared. Exposure concentrations were analyzed before and at O.5-hour intervals throughout the exposures. The percentage of each chemical absorbed and the corresponding Kp were estimated by optimization of the PBPK model to the medium concentration and the exhaled-breath data. The method was found to be sufficiendy sensitive for animal and human dermal studies at low exposure concentrations over small body surface areas, for short periods, using non-steady-state exposure conditions.

Percutaneous absorption of arsenic from environmental media

Current knowledge of percutaneous absorption of arsenic is based on studies of rhesus monkeys using soluble arsenic in aqueous solution, and soluble arsenic mixed with soil (Wester et al., 1993). These studies produced mean dermal absorption rates in the range of 2.0-6.4% of the applied dose. Subsequently, questions arose as to whether these results represent arsenic absorption from environmental media. Factors such as chemical interactions, the presence of other metals, and the effects of weathering on environmental media all can affect the nature of arsenic and its potential for percutaneous absorption. Therefore, research specific to more relevant matrices is important. The focus of this effort is to outline study design considerations, including particle size, application rates, means of ensuring skin contact and appropriate statistical evaluation of the data. Appropriate reference groups are also important. The potential for background exposure to arsenic in the diet possibly obscuring a signal from a dermally applied dose of arsenic will also be addressed. We conclude that there are likely to be many site-or sample-specific factors that will control the absorption of arsenic, and matrix-specific analyses may be required to understand the degree of percutaneous absorption.

Skin decontamination: principles and perspectives

Skin decontamination is the primary intervention needed in chemical, biological and radiological exposures, involving immediate removal of the contaminant from the skin performed in the most efficient way. The most readily available decontamination system on a practical basis is washing with soap and water or water only. Timely use of flushing with copious amounts of water may physically remove the contaminant. However, this traditional method may not be completely effective, and contaminants left on the skin after traditional washing procedures can have toxic consequences. This article focuses on the principles and practices of skin decontamination.

Transungual delivery of ketoconazole using novel lacquer formulation.

Onychomycosis, a common fungal infection of the nail, can have a substantial impact on quality of life. The success of topical therapy for onychomycosis depends on effective penetration, which can be enhanced using an appropriate delivery method. This study evaluated the effectiveness of a novel topical lacquer on enhancing [(14)C]-ketoconazole penetration by comparing nail absorption, nail distribution, and nail penetration of [(14)C]-ketoconazole dissolved in the novel lacquer versus a commercial ketoconazole cream. Using the in vitro finite dose model, the formulations were applied daily to human nail plates for 7 days. Drug absorption was measured by monitoring rate of appearance in each nail layer and the supporting bed. After the multiple day treatment, cumulative concentrations of ketoconazole formulated in novel lacquer in the deep nail layer and the nail bed were significantly greater than cumulative concentrations of commercial ketoconazole (p<0.05), as well as several orders of magnitude greater than the minimal inhibitory concentration (MIC) deemed necessary to inhibit the growth of causative dermatophytic and yeast species. These results suggest that this novel ketoconazole lacquer has the potential to be an effective topical treatment for onychomycosis.