ORIGINAL ARTICLE Mucoadhesive bilayered buccal platform for antifungal drug delivery into the oral cavity Burcum Uzunoğlu 1,2 & Clive G. Wilson 3 & Meral Sağıroğlu 4 & Selin Yüksel 1 & Sevda Şenel 1 # Controlled Release Society 2020 Abstract A drug delivery technology comprising a mucoadhesive bilayered buccally anchored tablet containing natamycin was developed. The concept was to anchor the tablet to the buccal tissue and allow controlled release of the drug through the matrix into the mouth. Carbomer (Carbopol ® 974 P NF) was used to formulate the mucoadhesive layer. Hydroxypropyl methylcellulose (HPMC) (Methocel® K4M) at 10, 15, 20, and 40% w/w was used for the drug-containing layer. Natamycin, an amphoteric macrolide antifungal agent, was incorporated into the formulations. In addition, tablets containing erythrosine as a marker were prepared in order to examine the distribution and retention of the dye in the oral cavity. As expected, the in vitro analysis showed that the concentration of natamycin released decreased with the increasing proportion of HPMC in the formulation. A small volunteer study was conducted using the tablets containing 10% and 20% HPMC to quantitate the patterns of distribution of the drug released into the oral cavity (upper right buccal vestibule, lower right and left buccal vestibules, and sublingual region). The mucoadhesive bilayered buccal tablet formulation provided a unidirectional release of the drug from the tablet into the oral cavity in a prolonged release fashion, maintaining drug concentration above the MIC value (2 μg/mL) for Candida albicans. The amount of the drug in the sublingual region was found to be lowest when compared with other regions, which is due to the higher flow of saliva in this region. Keywords Mucoadhesive buccal tablet . Drug delivery into the oral cavity . Natamycin . Oral candidiasis . In vivo Introduction Candidiasis induced by Candida albicans (C. albicans) is the most common fungal infections of the oral cavity in humans [1, 2]. The organism is present in the oral flora of most healthy individuals, but sometimes, it can colonize extensively and may cause a variety of mycotic infections, most due to pre- existing or associated variations in the host immune system [3]. Oral candida infection generally requires prolonged ther- apy with antifungal agents [4]. Topical application of antifun- gals, which provide high drug levels, is usually preferred for uncomplicated, localized candidiasis in patients with normal immune function. However, one of the major limitations in successful application of the drug into the oral cavity is the dilution and rapid elimination of the drugs from the oral cavity due to the flushing action of saliva and the movement of the tongue [5]. Since most antifungals do not possess the inherent ability to bind to the oral mucosa, the goal of delivery to the fungal infection would best be achieved through improved formulations providing a controlled input of drug into the mouth. Many of these systems are developed with the * Sevda Şenel ssenel@hacettepe.edu.tr Burcum Uzunoğlu burcumuzunoglu@rxkurumsal.com Clive G. Wilson c.g.wilson@strath.ac.uk Meral Sağıroğlu mozalp@hacettepe.edu.tr Selin Yüksel selin.yuksel@hacettepe.edu.tr 1 Department of Pharmaceutical Technology, Hacettepe University, Faculty of Pharmacy, 06100 Ankara, Turkey 2 Present address: Rx Corporate Communications, Mustafa Kemal Mah. Eskişehir yolu 9. km, Mahall Ankara C2 Blok No 10, Çankaya, Ankara, Turkey 3 Strathclyde Institute of Pharmacy & Biomedical Sciences, G4 ONR, Glasgow, Scotland, UK 4 Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Hacettepe University, 06100 Ankara, Turkey Drug Delivery and Translational Research https://doi.org/10.1007/s13346-020-00798-1