Natural Epithelial Barrier Integrity Enhancers—Citrus medica and Origanum dayi Extracts

Buccal drug delivery offers a promising alternative for avoiding gastrointestinal degradation and first-pass metabolism. However, enhancing the buccal epithelial barrier’s permeability remains challenging. This study explores the effects of ethanolic extracts from Citrus medica var. Balady (CM), Citrus medica var. Calabria (CMC), and Origanum dayi (ORD) on buccal epithelium permeability in vitro using a TR146 cell-based model. The cell viability assay revealed that the extracts were non-toxic at the concentration range tested (<0.5% w/v). Surprisingly, none of the tested extracts significantly enhanced the buccal permeability of 40 kDa Fluorescein Isothiocyanate Dextran (FD40). However, the CMC and ORD extracts significantly reduced the epithelial permeability of FD40, mirroring the effects of hyaluronic acid (HA), a known barrier integrity enhancer. The total phenolic content (TPC) analysis suggested a potential link between the phenolic concentration and epithelial barrier reinforcement. The rapid colorimetric response method was applied to assess the interaction of these extracts with biological membranes. The results indicated that HA interacts with cellular membranes via lipid bilayer penetration, whereas the extracts likely influence the barrier integrity through alternative mechanisms, such as ligand–receptor interactions or extracellular matrix modulation. These findings highlight the potential of CMC and ORD extracts as natural agents to enhance buccal epithelial integrity. In conclusion, incorporating these extracts into formulations, such as hydrogels, could offer a cost-effective and biocompatible alternative to HA for improving buccal cavity health.