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.

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.

Nanocrystals, defined as crystalline particles with dimensions in the nanometer range (<1000 nm), exhibit unique properties that enhance the efficacy of poorly soluble active compounds. This review explores the fundamental aspects of nanocrystals, including their characteristics and various preparation methods, while addressing critical factors that influence their stability and incorporation into final products. A key focus of the review is the advantages offered by nanocrystals in dermal applications. It also highlights their ability to enhance passive diffusion into the skin and facilitate penetration via particle-assisted dermal penetration. Additionally, the review discusses their capacity to penetrate into hair follicles, enabling targeted drug delivery, and their synergistic potential when combined with microneedles, which further enhance the dermal absorption of active compounds. The review also addresses several commercial products that successfully employ nanocrystal technology, showcasing its practical applications. Summary: Nanocrystals with their special properties are an emerging trend for dermal applications, particularly the development of plantCrystals—natural nanocrystals sourced from plant materials—which represent a promising path for future research and formulation strategies. These advancements could lead to more sustainable and effective dermal products.

Background/Objectives: PlantCrystals (PCs) are submicron particles derived from plants or parts of plants that can be produced by bead milling and/or high-pressure homogenization. Previous studies suggested improved dermal drug delivery of lipophilic active ingredients (API), which was explained by the formation of extracellular vesicles (EVs) during the production of PCs. The aim of this study was to investigate the suitability of PCs for enhancing the dermal penetration efficacy of different types of APIs. Methods: For this purpose, hydrophilic, lipophilic, and poorly water-soluble API-surrogates were loaded into PCs, and the dermal penetration efficacy, as well as the skin hydrating properties, were determined with an ex vivo porcine ear model. The penetration efficacy of the API surrogates from the PCs was compared to other formulation principles, e.g., simple API solutions, API loaded into classical EVs, and API added to the PCs after preparation. Silymarin-PCs—unloaded and loaded with API—were obtained by milling milk thistle seeds using small-scale bead milling. The PCs were characterized by size, size distribution, and zeta potential. Results: Milling of milk thistle seeds resulted in the formation of submicron particles with sizes of about 300 nm. Loaded PCs had a slightly larger size. Loading API into PCs resulted in improved dermal penetration when compared to the other formulation principles. The effect was most pronounced for the lipophilic API-surrogate (+90%, p < 0.001) and least pronounced for the hydrophilic API-surrogate (+2%, p > 0.05). The improved penetration of API from PCs can be explained by the formation of EVs during the production of the PCs in which the API is encapsulated. The encapsulation seemed to be highly efficient for the lipophilic API-surrogate, moderate for the poorly soluble API-surrogate, and very limited for the hydrophilic API-surrogate. All formulations increased the skin hydration significantly by about 30–40%. Conclusions: Milk thistle seeds are suitable for the production of PCs. These PCs improve skin hydration and enhance the dermal penetration of poorly water soluble and lipophilic APIs. However, they have limited effects on the dermal penetration efficacy of hydrophilic APIs.