*3.6. Permeation Parameters of Fluconazole from Optimized HA-FS-NTF by Ex Vivo Permeation Studies*

The cumulative permeation of fluconazole through the sheep buccal mucosa was found to be 400 <sup>±</sup> 57, 294 <sup>±</sup> 34, and 122 <sup>±</sup> <sup>18</sup> <sup>µ</sup>g/cm<sup>2</sup> (Table 9) after 3 h of an experimental period from the 0.5% HA-FS-NTF optimized hydrogel, marketed 0.5% fluconazole gel, and aqueous 0.5% fluconazole suspension, respectively. With respect to the examined formulations, the optimized HA-FS-NTF hydrogel had maximum fluconazole permeation across the oral mucosa, and this is statistically significant (*p* < 0.05) when compared with the other two formulations. Our ex vivo permeation results of the tested formulations could be correlated with the in vitro release profile of the respective formulations, where the highest in vitro release from the HA-FS-NTF is reflected by the highest ex vivo permeability from the same formulation (400 µg/cm<sup>2</sup> ). The D, EF, Pc, and Jss of the optimized HA-FS-NTF were found to be superior when compared with those of the marketed gel and aqueous suspension (Table 9).

**Table 9.** Parameters of permeation for fluconazole across the buccal mucosa for different formulations.


The maximum permeation of fluconazole through the buccal mucosa could be explained by the fact that the presence of nanosized vesicles containing the drug provided a platform for rapid skin permeation, which could be through transcellular and paracellular pathways [28,38]. Additionally, the presence of an edge activator in the HA-FS-NTF formulation (i.e., a surfactant, Tween 20®) might also act as a penetration enhancer that might aid in drug transport across the skin [39]. The presence of the edge activator in the HA-FS-NTF interchange with keratin-based filaments with a disruption is advantageous for drug transport. Oral thrush is not just a superficial manifestation, but the fungal growth also affects deeper skin layers. Therefore, permeation of fluconazole into deeper layers is of the utmost importance.
