Silymarin PlantCrystals for Improved Dermal Drug Delivery

<b>Background/Objectives:</b> 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. <b>Methods:</b> 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. <b>Results:</b> 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%, <i>p</i> < 0.001) and least pronounced for the hydrophilic API-surrogate (+2%, <i>p</i> > 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%. <b>Conclusions:</b> 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.