A poly(vinyl alcohol)-based dissolvable bilayer film for buccal and sublingual delivery of FITC-dextran 4000 as a model macromolecule.

Oromucosal administration of peptides remains challenging due to the limited permeability of the buccal and sublingual mucosa to hydrophilic macromolecules. This study evaluated the permeation-enhancing performance of the bile salt, sodium glycodeoxycholate (GDC), by investigating its incorporation into a semi-dissolvable bilayer film platform using fluorescein isothiocyanate-labelled dextran 4000 (FD4) as a model macromolecule. In human TR-146 buccal epithelial monolayers, GDC increased FD4 permeability in a concentration-dependent manner, with 1 mM identified as the highest non-cytotoxic concentration. In ex vivo porcine buccal mucosae, 20 mM GDC enhanced FD4 permeation to 6.9% after 3 h (Papp = 6.1 × 10-6 cm/s) while histology was maintained. Ventral lingual mucosae consistently exhibited greater permeability than buccal mucosae, with 20 mM GDC increasing FD4 permeation to 11.4% after 3 h (Papp = 12.6 × 10-6 cm/s). A poly(vinyl alcohol) (PVA)/sodium carboxymethyl cellulose (Na-CMC)-based mucoadhesive layer with an ethyl cellulose backing was selected as the prototype bilayer film based on physicochemical properties and in vitro release characteristics. Incorporation of an equivalent GDC amount into bilayer films entrapping FD4 resulted in permeation of 0.7% and 3.5% across buccal and ventral lingual mucosae after 3 h, respectively. Histological and confocal fluorescence analyses confirmed enhanced tissue penetration and modulation of epithelial barrier structures following GDC exposure. While GDC presented in solution produced higher FD4 permeation than from films, the latter is a dosage form that can be translated to patients. These findings show that mucosal site is an important consideration in the development of GDC-loaded bilayer films and support further evaluation of the ventral lingual/sublingual region for peptide and other macromolecule delivery.