The atopic dermatitis (AD) complex pathogenesis mechanism reveals marked changes of certain signaling factors as well as some morphological alterations in the epidermis. Reduced resilience against environmental factors and oxidative stress often makes the treatment with corticosteroids or tacrolismus ointments indispensable. In view of the correlation between oxidative stress and AD pathological factors, antioxidants can be incorporated into AD management strategies. This study investigates a curly kale, apple and green tea-containing natural extract rich in antioxidants for its effects on signaling inflammatory molecules and skin barrier enhancement in human epidermal keratinocytes- (NHEKs) based cell assays. Furthermore, the skin penetration on porcine ears was measured ex vivo using Raman micro spectroscopy. Finally, in a double-blind half-side, placebo-controlled clinical study, the effects of a formulation containing this extract were analyzed for the influence of lesion severity, epidermal barrier function, and pruritus in mild to moderately AD patients. Summarizing our results: The extract reduces expression of inflammatory cytokines in keratinocytes and increases barrier-related molecules. The verum formulation with a very high antioxidant capacity used in AD patients with mild to moderate lesions reduces itching, local SCORAD, and improves barrier function and the hydration of skin lesions.

The study aimed at comparing the influence of direct and indirect skin hydration as well as massage on the dermal penetration efficacy of active compounds. Nile red was used as a lipophilic drug surrogate and was incorporated into Vaseline (petroleum jelly). The formulation was applied with and without massage onto either dry skin or pre-hydrated, moist skin. It was expected that the occlusive properties of Vaseline in combination with massage and enhanced skin hydration would cause a superposition of penetration-enhancing effects, which should lead to a tremendous increase in the dermal penetration efficacy of the lipophilic drug surrogate. Results obtained were diametral to the expectations, and various reasons were identified for causing the effect observed. Firstly, it was found that Vaseline undergoes syneresis after topical application. The expulsed mineral oil forms a film on top of the skin, and parts of it penetrate into the skin. The lipophilic drug surrogate, which is dissolved in the mineral oil, enters the skin with the mineral oil, i.e., via a solvent drag mechanism. Secondly, it was found that massage squeezes the skin and causes the expulsion of water from deeper layers of the SC. The expulsed water can act as a water barrier that prevents the penetration of lipophilic compounds and promotes the penetration of hydrophilic compounds. Based on the data, it is concluded that dermal penetration is a complex process that cannot only be explained by Fick’s law. It is composed of at least three different mechanisms. The first mechanism is the penetration of active ingredients with their solvents into the skin (convection, solvent drag), the second mechanism is the penetration of the active ingredient via passive diffusion, and the third mechanism can involve local penetration phenomena, e.g., the formation of liquid menisci and particle-associated penetration enhancement, which occur upon the evaporation of water and/or other ingredients from the formulation on top of the skin.

(1) Background: Ethanol is a multifunctional excipient often used as a preservative in topical formulations. Due to its known ability to impair skin barrier function, this study investigated the effect of ethanol (EtOH) as a preservative in creams on the dermal penetration of active compounds. (2) Methods: A hydrophilic and a lipophilic fluorescent dye were used as active ingredient surrogates that were incorporated into creams with and without ethanol. The dermal penetration efficacy was assessed by epifluorescence microscopy on an ex vivo porcine ear model with intact and irritated skin. (3) Results: Ethanol reduced the dermal penetration by about 40% for the hydrophilic and about 20% for the lipophilic surrogates on intact skin, but had minimal impact on irritated skin. The bio-physical skin properties were also altered by the addition of ethanol to the cream. On intact skin, it increased transepidermal water loss (TEWL) and decreased skin hydration, whereas on irritated skin, it decreased TEWL and increased skin hydration. The results indicate that skin impairment can be considered to have different stages, while in an early stage of skin impairment, the formation of a “Pudding skin” is proposed. A “Pudding skin” is the formation of a thin layer of dried skin on top of the skin that “seals” the lower parts of the skin and reduces dermal penetration and water loss from inside the skin and reduces the dermal penetration of chemical compounds from outside the skin. (4) Conclusions: Overall, the findings emphasize the need to carefully consider the use of ethanol in formulations, balancing its preservative benefits with its potential to impair the efficacy of active ingredients, particularly in varying skin conditions.

The influence of size, particle concentration and applied dose (finite vs. infinite dose) on the dermal penetration efficacy of curcumin was investigated in this study. For this, curcumin suspensions with different particle sizes (approx. 20 µm and approx. 250 nm) were produced in different concentrations (0.625–5% (w/w)). The dermal penetration efficacy was determined semi-quantitatively on the ex vivo porcine ear model. The results demonstrated that the presence of particles increases the dermal penetration efficacy of the active compounds being dissolved in the water phase of the formulation. The reason for this is the formation of an aqueous meniscus that develops between particles and skin due to the partial evaporation of water from the vehicle after topical application. The aqueous meniscus contains dissolved active ingredients, and therefore creates a small local spot with a locally high concentration gradient that leads to improved dermal penetration. The increase in penetration efficacy depends on the number of particles in the vehicle, i.e., higher numbers of particles and longer contact times lead to higher penetration efficacy. Therefore, nanocrystals with a high particle concentration were found to be the most suitable formulation principle for efficient and deep dermal penetration of poorly water-soluble active ingredients.

Objective: This study aimed to investigate the feasibility of using the digital image processing technique, developed to semi-quantitatively study dermal penetration, to study corneal penetration in an ex vivo porcine eye model. Here, we investigated various formulation strategies intended to enhance dermal and corneal bioavailability of the model hydrophobic drug, curcumin. Methods: Several formulation principles were explored, including oily solutions, oily suspensions, aqueous nanosuspension, micelles, liposomes and cyclodextrins. The dermal penetration efficacy was tested using an ex vivo porcine ear model previously developed at Philipps-Universität Marburg with subsequent digital image processing. This image analysis method was further applied to study corneal penetration using an ex vivo porcine whole-eye model. Results: For dermal penetration, oily solutions, oily suspensions and nanosuspensions exhibited the least penetration, whereas liposomes and cyclodextrins showed enhanced penetration. Corneal curcumin penetration correlated with dermal penetration, with curcumin loaded into cyclodextrins penetrating the deepest. Conclusions: Overall, our study suggests that the image analysis method previously developed for ex vivo skin penetration can easily be repurposed to study corneal penetration of hydrophobic drugs.

Dermal penetration is considered to mainly occur via passive diffusion. Therefore, a high concentration gradient of dissolved active ingredient between formulation and skin is needed to achieve an effective dermal penetration. The concentration gradient between formulation and skin can be changed by changing the amount of dissolved active ingredient in the formulation. In case of poorly soluble active ingredients this can be achieved by using nanosized drug material instead of larger sized material. The smaller size and the resulting larger surface increase the kinetic solubility and thus increase the concentration gradient of dissolved active ingredient between formulation and skin, which then results in an increased dermal penetration. In this study we demonstrated that the concentration gradient between formulation and skin can also be influenced by the number of particles being present in the formulation and by the dose (volume of formulation) applied to the skin. Particles of undissolved active ingredient are known to act as a reservoir by releasing dissolved molecules in the liquid phase of the formulation. It could now be demonstrated that the particles - once the liquid in which they are dispersed evaporates - can connect to the skin via an aqueous meniscus. The aqueous meniscus contains dissolved active ingredient and therefore creates a small local spot with a locally high concentration gradient and improved dermal penetration. Therefore, the dermal penetration can be increased with formulations that contain high amounts of particles. This can be achieved by applying formulations with high numbers of particles and/or by applying larger volumes of particle containing formulations to the skin.