**4. Conclusions**

In summary, an optimal FS-NTF formulation was successfully developed by using the Design Experiment model, where the developed nanotransfersome was embedded into the hyaluronic acid hydrogel matrix. The in vitro drug release pattern and ex vivo permeation study through the sheep buccal mucosa of HA-FS-NTF showed a rapid release of the entrapped drug with significantly increased permeation parameters. These findings are positive indicators for local application in the oral cavity. The rheological properties of the HA-FS-NTF also support the localized application of the developed formulation. An in vitro antifungal assay and in vivo assessment of the ulcer index suggest a beneficial role for the developed formulation against oral candidiasis. The improved antifungal efficacy in our HA-FS-NTF might be due to the synergistic effect of hyaluronic acid, sesame oil, and fluconazole. Therefore, it can be summarized that fluconazole can effectively be delivered for the treatment of oral candidiasis when it is entrapped in a nanotransfersome carrier and embedded into cross-linked hyaluronic acid hydrogel.

**Author Contributions:** Conceptualization and methodology, H.M.A.; software and validation, K.M.H.; formal analysis, investigation, resources, and data curation, K.M.H.; writing—original draft preparation, W.Y.R.; writing—review and editing, K.M.H.; visualization, W.Y.R.; supervision and project administration, K.M.H. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research work was funded by Institutional Fund Projects under grant no. (IFPHI-063- 166-2020).

**Institutional Review Board Statement:** The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Animal Ethics Committee of the Beni-Suef Clinical Laboratory (Approval No.15-08-2020, at August 2020).

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Acknowledgments:** This research work was funded by Institutional Fund Projects under grant no. (IFPHI-063-166-2020). Therefore, authors gratefully acknowledge technical and financial support from the Ministry of Education and King Abdulaziz University, DSR, Jeddah, Saudi Arabia.

**Conflicts of Interest:** The authors declare no conflict of interest.
