Chitosan Nanoparticles for Intranasal Drug Delivery

Abstract

Introduction

Chitosan has been extensively explored in the field of materials science for its utility in nanostructured intranasal drug delivery systems, where researchers focus on manipulating its chemical and physical properties to enhance delivery mechanisms. Chitosan, a natural polysaccharide derived from chitin, offers several unique advantages that make it an ideal candidate for nanoparticle formulation. Its biocompatibility, biodegradability, and non-toxic nature are essential for medical applications, especially for intranasal delivery. Moreover, chitosan possesses inherent mucoadhesive properties due to its positive charge at physiological pH, which allows it to adhere to the negatively charged mucosal surfaces, enhancing the residence time and absorption of the encapsulated drugs. These attributes set chitosan apart from other polymeric nanoparticles, making it particularly suitable for targeted drug delivery and biomedical applications [1,2,3,4].

Nanoparticle Formulation and Surface Modification: Chitosan’s primary amine groups have been used to formulate nanoparticles with various drugs, providing a base for further chemical modifications. For example, chitosan-decorated PLGA nanoparticles have been designed to create a hybrid system that combines the biodegradability and encapsulation efficiency of PLGA with the mucoadhesive properties of chitosan [5]. Similarly, surface modification techniques involve conjugating chitosan with other molecules such as lactoferrin to target specific receptors within the nasal cavity, as seen with N-trimethylated chitosan-modified PLGA nanoparticles [6].

Thiolation of Chitosan: The introduction of thiol groups into chitosan molecules leads to the formation of thiolated chitosan, which shows enhanced mucoadhesiveness due to the formation of disulfide bonds with cysteine-rich subdomains of mucus glycoproteins. This modification has been utilized to develop nanoparticles for drugs like selegiline hydrochloride, aiming to improve the residence time of the formulation within the nasal cavity [7].
Hybrid and Composite Nanoparticles: Research has also focused on creating composite materials that combine chitosan with other biopolymers like alginate [8] or natural phospholipids such as lecithin [9]. These composites are tailored to exploit the synergistic properties of both components, such as improved encapsulation efficiency and tailored degradation rates, which are crucial for sustained release profiles.

Coating and Layering Techniques: Coating nanoparticles with chitosan not only provides a mucoadhesive surface but also protects the core material from premature degradation. For instance, chitosan-coated nanostructured lipid carriers [10] and chitosan-coated PLGA nanoparticles [11] demonstrate how chitosan can be used as a coating material to enhance the stability and delivery efficiency of the nanocarriers.

Chemical Cross-linking: To further stabilize the nanostructures and control the release of loaded agents, chitosan nanoparticles can be cross-linked using various agents. For example, the use of tripolyphosphate for ionic cross-linking of chitosan nanoparticles is a common approach to enhance their stability under physiological conditions [12].
Water-Soluble Derivatives of Chitosan: The native chitosan is soluble only in an acidic environment, and many pharmaceutical and biomedical application of chitosan requires the polymer to have aqueous solubility at biological pHs. N-trimethyl chitosan (TMC) enhances solubility and permeation properties across mucosal barriers, used in nanoparticles for enhanced nasal delivery [6,13,14]. Carboxymethyl chitosan (CMC), soluble and biocompatible, is used for delivering hydrophobic drugs like carbamazepine in nanoparticle form [15]. Chitosan oligosaccharides (COS), low molecular weight and highly soluble, are suitable for nasal sprays, enhancing absorption and reducing viscosity.
Functionalization for Targeted Delivery: Functionalization of chitosan nanoparticles with targeting ligands is another material-focused initiative. Mannose-modified chitosan nanoparticles [16], for instance, target specific receptors on nasal epithelial cells, improving the uptake and bioavailability of the encapsulated drugs.

Dry Powder Formulations: Addressing the challenge of delivering nanoparticles in a dry powder form for nasal administration, chitosan has been formulated into nanospheres that can be administered as dry powders, enhancing the ease of use and stability of the formulation [17].

The investigation of nanostructured chitosan for intranasal delivery is motivated by numerous challenges across various therapeutic areas, with the goal of enhancing drug delivery efficiency, increasing bioavailability, and reducing adverse effects. In the context of neurodegenerative diseases like Alzheimer’s and Parkinson’s, the primary issues are the poor bioavailability and the difficulty for therapeutic agents to cross the blood–brain barrier. Research involving chitosan nanoparticles focuses on improving the delivery to the brain of drugs such as curcumin, piperine, galantamine, huperzine A, and sitagliptin, which are typically constrained by low solubility and significant first-pass metabolism [5,6,8,18,19]. For Parkinson’s disease, studies are also examining the use of these nanoparticles to enhance the solubility and brain absorption of medications including ropinirole, bromocriptine, piribedil, and phenytoin [9,11,20,21,22].

In psychiatric care, the enhancement of central nervous system penetration and the improvement of oral bioavailability are key. Intranasal chitosan delivery systems are being developed for crucial psychiatric medications such as selegiline, risperidone, lurasidone, and olanzapine, addressing conditions like depression, schizophrenia, and bipolar disorder [7,23,24,25]. Pain management also utilizes the targeted central nervous system (CNS) delivery capabilities of nanostructured chitosan, focusing on increasing the brain delivery of pain relievers such as cyclobenzaprine and tapentadol, which aims to reduce systemic side effects [26,27].
Another major area of research is the development of nasal vaccines using chitosan nanoparticles, which seeks to boost immunogenicity and mucosal immunity against pathogens such as influenza, hepatitis, respiratory syncytial virus, pertussis, and SARS-CoV-2 [13,14,17,28,29,30,31,32,33,34,35,36,37]. These initiatives reflect the ongoing need for effective vaccination strategies that generate strong immune responses without the need for traditional injection methods.

In diabetes treatment, the exploration of intranasal chitosan delivery systems for insulin aims to enhance systemic absorption and effectiveness [38,39,40,41,42]. This method could offer a less invasive alternative to traditional subcutaneous injections, potentially improving patient adherence and overall quality of life. Moreover, the adaptability of chitosan nanoparticles is being explored in managing allergies, asthma, and nasal congestion, with formulations designed to address issues such as drug hydrophobicity, nasal irritation, and poor mucosal absorption [43,44,45].
Together, these research efforts reflect a significant and widespread interest in leveraging nanostructured chitosan for intranasal delivery as a strategy to overcome numerous challenges in drug delivery, with the ultimate goal of improving therapeutic outcomes for a variety of medical conditions.

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Omidian, H.; Gill, E.J.; Dey Chowdhury, S.; Cubeddu, L.X. Chitosan Nanoparticles for Intranasal Drug Delivery. Pharmaceutics 2024, 16, 746. https://doi.org/10.3390/pharmaceutics16060746

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Read also our introduction article on Chitosan here: