Development and validation of an alternative disturbed skin model by mechanical abrasion to study drug penetration

Abstract

Pharmaceuticals and cosmetics for dermal application are usually tested on healthy skin, although the primary permeation barrier, the stratum corneum, is often impaired by skin diseases or small skin lesions, especially on the hands. These skin conditions can considerably influence the permeation of chemicals and drugs. Furthermore, risk assessment for example of nanoparticles should be performed under various skin conditions to reflect the true circumstances. Therefore, an alternative and reproducible method for a high throughput of skin samples with impaired skin barrier was developed and verified by skin permeation studies (25 h) of caffeine, sorbic acid and testosterone compared to healthy (untreated) and tape-stripped skin. Skin barrier disruption was controlled by TEWL measurement. Skin permeation of the three substances was increased in tape-stripped and abraded skin compared to untreated skin due to the reduced barrier integrity. Enhancement of drug uptake was highest for the most hydrophilic substance, caffeine, followed by sorbic acid and lipophilic testosterone. No significant difference in drug uptake studies was observed between the new abrasion method with an aluminum-coated sponge and the tape-stripping method. The obtained results demonstrate that this abrasion method is an alternative way to achieve a disturbed skin barrier for drug and chemical uptake studies.

Keywords: Abraded skin; Caffeine; Disturbed skin barrier model; Sorbic acid; Tape stripping; Testosterone.

Graphical abstract

Fig. 1

Transepidermal water loss value with respect to the repetition of abrasions using the sponge (Spontex^® Brillant/Twist sponge, upper left inset) (mean±SD, n = 3).

Fig. 2

Histological section of the pig ear: untreated skin (left), abraded skin with a TEWL value within the range of 30±2  g m⁻² h⁻¹ (center), and abraded skin with a TEWL value above 40  g m⁻² h⁻¹ (right); Magnification ×400.

Fig. 3

Cumulative permeation of caffeine across porcine skin over 25 h (mean±SD, n=6); ● untreated skin, ▲ abraded skin, and ■ tape-stripped skin. The upper left inset shows the apparent permeability after 25 h (Box plot with median, minimum, maximum and the 0.25 and 0.75 quartiles (n=6)); applied concentration: 1 mg/mL.

Fig. 4

Cumulative sorbic acid permeation across porcine skin over 25 h (mean±SD, n = 6); ● untreated skin, ▲ abraded skin, and ■ tape-stripped skin. The upper left inset shows the apparent permeability after 25 h (Box plot with median, minimum, maximum and the 0.25 and 0.75 quartiles (n=6)); applied concentration: 1 mg/mL.

Fig. 5

Cumulative permeability of testosterone across porcine skin over 25 h (mean±SD, n=6); ● untreated skin, ▲ abraded skin, and ■ tape-stripped skin. The upper left inset shows the apparent permeability after 25 h (Box plot with median, minimum, maximum and the 0.25 and 0.75 quartiles (n=6)); applied concentration: 200 µg/mL.

Fig. 6

Left: percentage distribution of the applied substances between donor solution (gray bar), acceptor medium (black bar) and skin membrane (white bar); each skin sample is normalized to 100% (MW±SD, n=6). Right: Total drug uptake (amount of drug in the skin and the acceptor medium) after 25 h (Box plot with median, minimum, maximum and the 0.25 and 0.75 quartiles (n=6)).