Boosting buccal drug absorption: Mechanistic insights into bilosome-mediated delivery

Oral administration is the most widely used route for drug delivery. Nevertheless, its effectiveness can be hindered by factors such as changing pH and enzymatic degradation throughout the gastrointestinal (GI) tract.(Lou et al., 2023) The buccal route presents a promising alternative enabling drug absorption directly into systemic circulation via the mucosa. The buccal tissue is non-keratinized, maintaining a near-neutral pH of 6.5 and exhibits low enzymatic activity, characteristics that all help protecting drugs from degradation.(Kim and De Jesus, 2025; Malhotra et al., 2025) In the buccal epithelium, primarily desmosomes ensure cell-to-cell adhesion and provide essential mechanical strength, cohesion, and elasticity throughout the tissue, allowing resistance to constant movement and barrier protection.(Perl et al., 2024).

As an administration route, despite bypassing the first-pass effect of the GI-tract, buccal drug administration can still result in low bioavailability due to limited permeability of the stratified mucosa, its complex tissue architecture and rapid drug clearance by saliva.(Shojaei, 1998) Enhancing drug permeability across the buccal mucosa is necessary for improving bioavailability for most drugs; however, this must be achieved without compromising mucosal integrity. Therefore, it is essential to explore delivery systems that temporarily enhance permeability without injuring the mucosa due to their mode of action.

Nanoparticles have emerged as a versatile and effective strategy for enhancing transmucosal drug delivery, due to their ability to encapsulate both hydrophilic and lipophilic drugs and facilitate controlled drug release thereby enhancing drug bioavailability.(Zhang et al., 2024) Nanoparticles have demonstrated to be a promising strategy for buccal drug delivery in various studies.(Sahatsapan et al., 2022),(Kraisit et al., 2021) This includes the work of Morales et al. showing that insulin-coated nanoparticles incorporated into Eudragit®-based buccal films enhanced permeation across a buccal tissue model, highlighting the role of polymer-nanoparticle interactions in optimizing mucosal delivery.(Morales et al., 2014).

For improving drug absorption through the buccal epithelial barrier several permeation enhancers such as surfactants, fatty acids and bile salts are often used, especially for peptide administration.(Macedo et al., 2020) Bile salts are frequently utilized permeation enhancers in the GI tract and have additionally gained attention for their potential to improve drug absorption through the buccal mucosa by interacting with mucosal lipids. The effects of 0.1 M di- and tri-hydroxy bile salts on ex vivo porcine buccal permeability using FITC as a model drug compound showed a 100- to 200-fold increase in permeability. Nevertheless, histological analyses showed notable structural changes in the epithelium after treatment, including cell loss and tissue separation.(Senel et al., 1994) Another recent approach combined mechanical deformation of the buccal mucosa with permeation enhancers (among them, one bile salt) using a suction patch inspired by octopus’ suckers. In dog models, this method led to an increase in bioavailability of the peptide desmopressin by up to two orders of magnitude compared to commercial tablets.(Luo et al., 2023) Despite this encouraging results, the use of bile salts raises key safety concerns, including tissue irritation, cellular damage, and the rate of mucosal recovery.(Şenel and Hıncal, 2001) Moreover, the relationships between the chemical structure of bile salts, their irritation potential and permeation-enhancing efficacy are still not well understood.

This study used the concept of nanoparticles and the effects of bile salts as permeation enhancers to create bilosomes and to investigate their potential in delivering therapeutic compounds through the buccal mucosa. Bilosomes are lipid-based vesicular carriers incorporating bile salts within their phospholipid bilayer structure. They have demonstrated enhanced stability compared to conventional liposomes, owing to bile salts’ capacity to protect the vesicles from enzymatic degradation and harsh pH conditions.(Shukla et al., 2008) Bilosomes have demonstrated the capacity to enhance mucosal permeation, positioning them as promising carriers for targeted mucosal drug delivery in physiological environments that are comparatively less harsh than the gastrointestinal tract. One study demonstrated that elastic (highly deformable) bilosomes prepared with various bile salt derivatives improved insulin transport across TR146 buccal epithelial cell layers.(Bashyal et al., 2018) Bilosomes showed high encapsulation efficiency, enhanced cellular uptake and permeability, with sodium glycodeoxycholate (SDGC)-loaded bilosomes showing the greatest enhancement on insulin.

Although bilosomes have demonstrated potential in buccal drug delivery, their interactions with key biological barrier components, such as mucins and other components of the cell membrane, remain insufficiently explored. Therefore, the present study encompassed in vitro, and ex vivo models to clarify bilosome behavior and interactions at the buccal surface (Fig. 1) and investigated how bilosomes influenced epithelial junctions and modulated permeation pathways across the buccal barrier. Considering the safety concerns linked to free bile salts, it was also examined how their incorporation into bilosomes might mitigate cytotoxic effects while enhancing permeability.