Intraoral Drug Delivery: Highly Thiolated κ-Carrageenan as Mucoadhesive Excipient

Abstract

Aim: This study aims to design a novel thiolated κ-carrageenan (κ-CA-SH) and evaluate its potential as an excipient for the design of mucoadhesive drug delivery systems. Methods: Native κ-carrageenan (κ-CA) was thiolated with phosphorous pentasulfide in sulfolane and characterized via 1H NMR, FTIR, as well as Ellman’s test. Cytotoxicity was assessed via resazurin assay. In vitro release of the model drug, benzydamine hydrochloride, was determined. Tensile and mucosal residence time studies were performed on buccal and small intestinal mucosa. Mucoadhesive features were investigated via rheological studies with freshly isolated porcine mucus. Results: Thiolated κ-CA (κ-CA-SH) with 1213.88 ± 52 µmol/g thiol groups showed no cytotoxicity at a concentration of 1% (m/v) and low cytotoxicity up to 2% (m/v). Benzydamine hydrochloride showed slow release in solution for both polymers. Tensile studies on buccal and intestinal mucosa showed an up to 2.7-fold and 7.7-fold enhancement in the maximum detachment force (MDF) and total work of adhesion (TWA) of κ-CA-SH vs. κ-CA, respectively. The κ-CA-SH exhibited an up to 4.4-fold improved dynamic viscosity with mucus and significantly prolonged residence time on mucosa compared to native κ-CA. Conclusion: Since highly thiolated κ-CA shows a slow release of positively charged active pharmaceutical ingredients and enhanced mucoadhesive properties, it might be a promising excipient for local drug delivery in the oral cavity.

Challenges in Optimizing Nanoplatforms Used for Local and Systemic Delivery in the Oral Cavity

“…Pharmaceutics 2024, 16, 626 3 of 22 in periodontal regeneration [26], and in oral cancer [27][28][29]. The third type of reporting on the transdermal and transmucosal systems used in oral pathology are particularly focused on the various possibilities of improving absorption, whether we refer to it as a question of excipients with an amplifying effect [15,28,30] or to that of physical amplifiers (microneedles, iontophoresis, sonophoresis, and electrophoresis) [31][32][33][34]. Unlike the previously mentioned works, our work presents a more complex approach, considering a varied oral pathology as well as various types of controlled release systems that address these pathologies.…”

“…The oral mucosa, by its large surface area, is an excellent interface for mucoadhesive systems (tablets, patches, films, gels, wafers, gums) that can be applied either on the oral mucosa, the sublingual mucosa, or even on the gum. The most commonly used form refers to adhesive tablets (e.g., intraoral metronidazole tablets) [30,68,69].…”

Biopolymer Drug Delivery Systems for Oromucosal Application: Recent Trends in Pharmaceutical R&D

“…In general, thiolated biopolymers provide higher mucoadhesion and drug residence time compared to native polymers, thereby increasing drug bioavailability. Thiolated biopolymers also inhibit some enzymes, thereby increasing drug stability, as well as providing controlled drug release and increasing cell permeability [145,146]. The most commonly used thiolating agents are thioglycolic acid, thiourea, 4-aminothiophenol, L-cysteine and Trout's reagent (2-iminothiolane).…”

Recent Advances in Micro- and Nano-Drug Delivery Systems Based on Natural and Synthetic Biomaterials

“…At the molecular level, the chemical structures of already-existing mucoadhesive polymers could be improved. Kali et al [209] suggested the incorporation of thiol groups into polymers in order to enhance mucoadhesion. As a result of the formation of disulfide bonds with cysteine-rich regions in mucins, polycarbophil-cysteine conjugates exhibit a great deal of mucoadhesion.…”