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.

The effective dermal penetration of active ingredients (AI) is a major task in the formulation of topical products. Besides the vehicle, the mechanical skin treatments are also considered to impact the penetration efficacy of AI. In particular, professional skin treatments, i.e., professional cosmetic skin treatments, are considered to be optimal for the dermal delivery of AI. However, a systematic study that proves these theories is not yet available and was therefore performed in this study while utilizing an ex vivo porcine ear model with subsequent digital image analysis. Hydrophilic and lipophilic fluorescent dyes were used as AI surrogates and were applied onto the skin without and with professional skin treatments. The skin hydration and the penetration efficacy were determined, respectively. Results showed that professional skin treatments with massage were able to increase the skin hydration, whereas a professional skin treatment without massage could not increase the skin hydration when compared to skin without professional skin treatment. Regarding the penetration efficacy, it was found that all parameters tested, i.e., type of professional skin treatment, lipophilicity of the AI, and the time point at which the AI are applied onto the skin, can have a tremendous impact on the penetration efficacy of the AI. The most effective penetration and the most effective skin hydration is achieved with a professional skin treatment that includes a professional skin massage. This kind of skin treatment can therefore be used to improve dermal drug delivery.

The limited water solubility of active compounds remains a significant challenge for efficient dermal drug delivery, particularly for BCS class IV drugs such as curcumin. This study aimed to enhance curcumin’s dermal penetration using two strategies: extracellular vesicles (EVs) and plantCrystals derived from soybeans. EVs were isolated using classical methods. However, plantCrystals containing extracellular vesicles (PCEVs) were formed during the preparation of plantCrystals through bead milling. Curcumin was either added after PCEVs were formed, resulting in curcumin-added PCEVs, or added to the soybean dispersion before bead milling, forming curcumin-loaded PCEVs. The formulations were characterized for their physicochemical properties and assessed for dermal penetration efficacy using quantitative dermatokinetic and semi-quantitative ex vivo porcine ear models. The results indicated that curcumin-loaded PCEVs achieved higher penetration efficacy compared to curcumin-added PCEVs and curcumin-loaded EVs, with approximately 1.5-fold and 2.7-fold increases in penetration efficacy, respectively. Additionally, curcumin-loaded PCEVs showed superior penetration depth, while curcumin from the curcumin-loaded EVs remained in the stratum corneum. These findings suggest that the plantCrystals strategy via bead milling offers a more effective approach than the classical EVs strategy for improving the topical delivery of class IV drugs like curcumin.

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.

Background/Objective: This study provided a comparison of the influence of each component of the microemulsion formulation and investigated the impact of varying concentrations of the microemulsion components on curcumin’s ability to penetrate the skin using an ex vivo porcine ear model. Methods: Curcumin microemulsions with different compositions were prepared and analyzed for their physicochemical properties. The dermal penetration efficacy of curcumin was evaluated from the different formulations and compared with non-microemulsion formulations. Results: Findings proved that microemulsion formulations improve the dermal penetration efficacy for curcumin when compared with non-microemulsion formulations. The composition of the microemulsion affects the penetration efficacy of curcumin and increases with decreasing oil content and increasing surfactant and water content. The best penetration for curcumin is achieved with a microemulsion that contained 7.7 g of medium-chain triglycerides as the oil phase, 6.92 g of Tween^® 80 and 62.28 g of ethanol as the surfactant mixture, and 23.1 g water. Conclusions: The present study provides a foundational basis for further development of different microemulsion formulations for enhancing the dermal penetration of poorly water-soluble active compounds.

Dermal drug delivery presents a significant challenge for poorly soluble active compounds like curcumin, which often struggle to penetrate the skin barrier effectively. In this study, the dermal penetration efficacy of curcumin nanocrystals and bulk suspensions when applied to skin using microneedles of varying lengths—0.25 mm, 0.5 mm, and 1.0 mm—was investigated in an ex vivo porcine ear model. The findings revealed that all formulations, in conjunction with microneedle application, facilitated transepidermal penetration; however, the combination of microneedles and curcumin nanocrystals demonstrated the highest efficacy. Notably, the 1.0 mm microneedle length provided optimal penetration, significantly enhancing curcumin delivery compared with bulk suspensions alone. Additionally, even the use of 0.25 mm microneedles resulted in a high level of efficiency, indicating that shorter microneedles can still effectively facilitate drug delivery. Overall, this study underscores the potential of microneedle technology in improving the transepidermal absorption of poorly soluble actives like curcumin, suggesting that the integration of nanocrystals with microneedles could enhance the therapeutic effects of topical curcumin applications.