Recent advances in modified chitosan-based drug delivery systems for transmucosal applications: A comprehensive review

Recently, transmucosal drug delivery systems (TDDSs) have been extensively studied because they protect therapeutic agents from degradation; improve drug residence time at the mucosal membranes; and facilitate sustained drug release for a prolonged period. Chitosan is a well-researched polymeric excipient due to its biocompatibility, non-toxicity, biodegradability, mucoadhesive, antimicrobial, and low immunogenicity. Its limited mucoadhesiveness in the physiological environment necessitated its chemical modification. This review highlights the recent advances in the chemical modification of chitosan with various chemical groups to generate various functionalized chitosan derivatives, such as thiolated, acrylated, methacrylated, boronated, catechol, and maleimide-functionalized chitosans with superior mucoadhesive capabilities compared to the parent chitosan.

Moreover, it presents the different prepared dosage forms, such as tablets, hydrogels, films, micro/nanoparticles, and liposomes/niosomes for drug administration within various mucosal routes including oral, buccal, nasal, ocular, colonic, intravesical, and vaginal routes. The reported data from preclinical studies of these pharmaceutical formulations have revealed the controlled and target-specific delivery of therapeutics because of their formation of covalent bonds with thiol groups on the mucosal surface. All functionalized chitosan derivatives exhibited long drug residence time on mucosal surfaces and sustainable drug release with excellent cellular permeability, drug efficacy, and biocompatibility. These promising data could be translated from the research laboratories to the clinics with consistent and intensive research effort.

Introduction

Transmucosal drug delivery systems (TDDSs) have attracted the attention of pharmaceutical scientists worldwide in recent years owing to the relative permeability of mucosal membranes that increase drug uptake into blood circulation [1]. Mucosal membranes are moist surfaces that cover different body cavities, including the eyes, respiratory, urinary, reproductive, and gastrointestinal tracts [2,3]. The schematic structure of mucosal surfaces covered with the viscoelastic mucus gel layer is shown in Fig. 1.

The mucus layer comprises a large amount of water (about 95 %), mucins (0.5–5 %), mineral salts (0.5 %-1 %), proteins (1 %), and traces of lipids such as phospholipids and nucleic acids [4]. Mucus composition depends on the secretion site, physiological role, and the individual’s health status [5]. Mucins are large biomacromolecules of extracellular glycoproteins with negative charges, whose molecular weight ranges from 0.5 to 50 MDa [4,6]. It comprises a linear protein core and grafted oligosaccharide side chains, representing about 20–80 % of the total mucin content [7,8]. Mucosal membranes play a defensive role by protecting epithelial cells against environmental factors, such as mechanical or chemical damage [[9], [10], [11]].

TDDSs can be administrated through various mucosal routes including, nasal, ocular, buccal/gingival, oral, gastrointestinal, rectal, intravesical, and vaginal. TDDS formulated using mucoadhesive polymers offer improved drug residence time, controlled drug release, targeted drug delivery, and enhanced bioavailability [1,10,12].

The term “mucoadhesion” means the adhesion of a dosage form to the mucosal surface through different mucoadhesive bonds. The mechanism of mucoadhesion is not fully understood yet; however, different mucoadhesion theories, such as electrostatic, wetting, adsorption, diffusion, and fracture theory, have been proposed. These theories state that mucoadhesion may be related to various physical or chemical bonds between mucoadhesive polymer and mucus layer, such as electrostatic (ionic) interactions, covalent bonds, hydrogen bonds, and hydrophobic effects, as well as van der Waals forces [13,14]. For a solid dosage form, these mucoadhesive bonds are formed in three steps: a) swelling and wetting of mucoadhesive polymer, b) penetration of macromolecules into the mucus gel and formation of interpenetrating layer, and c) formation of physical or chemical bonds at the interface between polymer chains and mucus layer [[15], [16], [17]].

Mucoadhesive polymers of natural origin, such as chitosan, alginate, and cellulose have attracted much attention from researchers for developing improved drug delivery systems. These polymers have excellent properties, including biocompatibility, low immunogenicity, non-toxicity, solubility, swellability, easy availability, and biodegradability. In addition, they exhibit good mucoadhesive properties, which is desirable for the formulation of effective TDDSs [[18], [19], [20], [21], [22]]. Several factors affect this property, including molecular weight, cross-linking and charge density, hydrogen bonding capacity, and polymer hydration [23]. Furthermore, nanoparticles prepared using mucoadhesive polymers protect the encapsulated drug against degradation and enhance the loaded drug’s pharmacodynamics and pharmacokinetics, thereby boosting its penetration and uptake into target tissues [19,24].

This review article discusses the recent advances in the strategies that have been used to improve the mucoadhesiveness of chitosan, which is one of the well-researched mucoadhesive materials for transmucosal drug delivery. It presents various functionalized chitosan derivatives using different highly mucoadhesive functional groups, including thiolated, acrylate, methacrylate, boronated, catechol, and maleimide groups. Moreover, it shows their preparation in different developed dosage forms, such as tablets, hydrogels, films, micro/nanoparticles, and liposomes/niosomes for the drug administration through various mucosal routes including, buccal, oral, colonic, nasal, ocular, intravesical, and vaginal administrated routes in the last 10 years. In addition to discussing the mucoadhesive capability of functionalized chitosan derivatives, in this review, we discussed the enhancement in their physicochemical properties, such as the cell permeability, drug efficacy, and tumor targeting potential.

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Mahmoud H. Abu Elella, Oluwadamilola M. Kolawole, Recent advances in modified chitosan-based drug delivery systems for transmucosal applications: A comprehensive review, International Journal of Biological Macromolecules, Volume 277, Part 4, 2024, 134531, ISSN 0141-8130, https://doi.org/10.1016/j.ijbiomac.2024.134531.

Read more here and watch the video of Chitosan below:

Video: Chitosan as a natural excipient