Hongbo Zhai

Percutaneous Penetration Enhancers: An Overview

Transdermal drug delivery is the controlled release of drugs through the skin to obtain therapeutic levels systematically. Several technological advances have been made in the recent decades to enhance percutaneous drug penetration. This overview focuses on the physical, biochemical, and chemical means of penetration enhancement, as well as the classification and mechanisms of chemical penetration enhancers, their application in transdermal drug delivery, and trends and development in penetration enhancement.

Effects of Skin Occlusion on Percutaneous Absorption: An Overview

Skin occlusion produces profound changes, including hydration status, barrier permeability, epidermal lipids, DNA synthesis, microbial flora, and numerous molecular and cellular processes. It often, but not always, increases percutaneous absorption of applied chemicals. This overview focuses on the effect of skin occlusion on percutaneous absorption.

Clinical microneedle injection of methyl nicotinate: stratum corneum penetration.

Background/purpose: In recent years, microneedles were proposed as a method to painlessly deliver drugs past the stratum corneum. Microneedles have been fabricated in several designs, but limited studies have tested microneedle injections in humans. In this work, we compare microneedle injections with topical application (TA) to investigate if microneedles enhance in vivo drug delivery past the stratum corneum.

Occlusion vs. skin barrier function.

Background/aims: Skin occlusion may increase percutaneous absorption of applied chemicals, with some exceptions. It also obstructs the normal ventilation of the skin surface and increases stratum corneum hydration and hence compromises skin barrier function.

Skin occlusion and irritant and allergic contact dermatitis : an overview

Occlusion, widely used to enhance percutaneous absorption of drugs, also increases penetration of other chemicals and antigens, and hence may exacerbate irritant and allergic contact dermatitis. This overview summarizes the adverse effects of occlusion.

Effect of barrier creams: human skin in vivo

An in vivo method was developed to measure the effectiveness of skin protective creams against 2 dye indicator solutions: methylene blue in water and oil red O in ethanol, representative of model hydrophilic and lipophilic compounds, 3 representative barrier creams commercialized as effective against lipophilic, hydrophilic, or lipophilic and hydrophilic substances were assayed by measurements of the dye in cyanoacrylate strips of protected skin samples after various application limes. The flexural surfaces of the forearms of 6 normal volunteers (3 female and 3 male, mean age 26.8±4.1 years) were treated. The method was as follows: solutions of 5% methylene blue in water and 5% oil red O in ethanol were prepared, and applied to untreated skin and protective‐cream‐pretreated skin with the aid of aluminum occlusive chambers, for 0 h and 4 h, respectively. At the end of the application time, the creams were removed. Consecutive skin surface biopsies (SSB) from 1 to 4 strips were taken. The amount of stain in each strip was determined by colorimetry, and the cumulative amount of stain from 1 to 4 strips in each measurement was calculated. The cumulative amount represents the amount of permeation of each solution at each time point, and the efficacy of skin barrier cream. The results showed one formulation at both 0 h and 4 h reduced the amount of permeation of melhylene blue (p<0.0l) and oil red O (p<0.01) compared with the control group. Another formulation was protective against the permeation of oil red O (p < 0.0l). but not against methylene blue at 0 h and 4 h; it was not significantly different at 0 h versus 4 h. The 3rd formulation produced increased cumulative amounts to oil red O at both 0 h and 4 h (p<0.05); it also increased permeation amounts to methylene blue (p<0.05) after 4 h. This model appears a facile, rapid and objective early screen to evaluate the efficacy of skin barrier creams in vivo, as well as their individual ingredients.

Evaluating skin-protective materials against contact irritants and allergens.: An in vivo screening human model

2 acute irritants and 1 allergen were selected: sodium lauryl sulfate (SLS) representative of irritant household and occupational contact dermatitis, the combination of ammonium hydroxide (NH4OH) and urea to simulate diaper dermatitis, and Rhus to evaluate the effect of model protective materials. The putative protective materials and vehicle were applied to both ventral forearms of 10 subjects in each group, according to a randomized code. Test materials were spread over a marked 2.0 cm2 area, massaged in, allowed to dry for 30 min, and reapplied with another 30 min drying period. The model irritants and allergen were then applied (0.025 ml) to an Al‐test® occlusive patch, which in turn was placed for 24 h over each of the 8 designated sites. Inflammation was scored according to a clinical scale 72 h post‐application. Paraffin wax plus Acetulan® in cetyl alcohol, and beeswax plus Acetulan® in cetyl alcohol, markedly (p < 0.001) suppressed SLS irritation. Paraffin wax plus beeswax in cetyl alcohol, and Acetulan® in cetyl alcohol reduced NH4OH and urea irritation (p < 0.05), paraffin wax in cetyl alcohol significantly (p < 0.01) decreasing Rhus allergic contact dermatitis. This model, provides an easy approach to screening protectants. Its clinical significance requires comparison with an open rather than an occluded challenge.

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.

Long-term repetitive sodium lauryl sulfate-induced irritation of the skin: an in vivo study

Skin may adapt to topical irritants through accommodation. This study focuses on long‐term exposure to irritants and attempts to demonstrate accommodation. Sodium lauryl sulfate (SLS) induced irritant contact dermatitis at 3 concentrations (0.025% to 0.075%). Distilled water, acetone and an empty chamber served as controls. Experimental compounds were applied to forearms of 7 healthy volunteers for 24 hr before replacing by a fresh chamber for 6 non‐consecutive weeks over 103 days. Possible accommodation was quantified by visual scoring (erythema and dryness) and by bioengineering parameters: transepidermal water loss (TEWL), capacitance, chromametry and laser Doppler flowmetry (LDF). Significant erythema, dryness, elevated TEWL, skin colour reflectance and LDF values occurred during the exposure periods. Upon repeat exposure, an immediate and augmented response in erythema, TEWL, skin colour reflectance and LDF developed. However, irritant skin changes were not sustained. Irritation parameters return to baseline after cessation of exposure. There was no evidence of sustained irritation or accommodation after the last exposure. Study findings do not document sustained accommodation or adaptive hyposensitivity after long‐term repetitive irritant exposure under these test conditions. Alternative models should be developed to prove or disprove the accommodation hypothesis.

Hydration vs. skin permeability to nicotinates in man

Background/aims: Prolonged skin occlusion increases stratum corneum water content and often increases skin permeability and irritant dermatitis. As skin wetness from wearing diapers is considered an important factor favouring the onset of diaper dermatitis, optimal diapering might decrease skin hyperhydration and dermatitis. Our aim is to define the quantitative relationship between nicotinate ester (a model penetrant) skin permeability and hydration, as measured by water evaporation rate (WER), decay curves (at individual time points) and WER‐area under the curve (WER‐AUC); and also to determine the level of skin hydration and skin permeability to nicotinates following a diapering simulation.