Nanostructured mucoadhesive buccal tablets for apixaban delivery: mechanistic insights into transmucosal transport...

This study developed and evaluated a nanoparticle-in-matrix mucoadhesive buccal delivery system for apixaban (APX) to improve its dissolution and systemic exposure. APX-loaded polymeric nanoparticles were prepared by antisolvent nanoprecipitation and incorporated into thiolated chitosan-Carbopol^® buccal matrices by direct compression. The optimized nanoparticles exhibited a diameter of 195 ± 22 nm and a 6-fold increase in saturated solubility. The optimized tablets showed rapid hydration (55 ± 4 s), strong mucoadhesion, prolonged ex vivo mucosal retention (7.84 ± 0.41 h), and approximately 80% drug release within 10 min. Ex vivo studies demonstrated a mucosal penetration depth of 285 ± 18 μm. In rabbits, the optimized buccal formulation significantly increased Cmax (3950 ± 310 ng/mL) and AUC₀-₂₄ (31,600 ± 2850 ng·h/mL) compared with marketed tablets (420 ± 55 ng/mL and 4120 ± 390 ng·h/mL, respectively), representing approximately 9.4-fold and 7.7-fold higher exposure (p < 0.05). Faster systemic absorption was also observed, with a Tmax of 0.75 ± 0.20 h and Ka of 1.48 ± 0.18 h^-1. Changes in PT and aPTT were observed; however, these conventional assays have limited sensitivity for quantitatively assessing apixaban pharmacodynamic activity. Histopathological examination indicated favorable local tissue compatibility. Overall, the nanoparticle-in-matrix buccal system markedly enhanced and accelerated APX exposure in rabbits, supporting its potential for buccal delivery while emphasizing the need for dose optimization, pharmacodynamic assessment, and dedicated safety evaluation before clinical translation.