Chitosan and Its Use for Drug Delivery

Chitosan is a polysaccharide found in shellfish, fungi, annelids, mollusks, and insects. It is the second most outspread natural polysaccharide on Earth, after cellulose. Commercially, it is produced from chitin, being a poly β (1 → 4) -2-amino-2-deoxy-β-D-glucan deacetylated chitin. It has a strong affinity for polyanions, contains reactive NH<sup>3</sup> <sup>+</sup> and OH<sup>−</sup> groups, and is soluble in acidic aqueous solutions. It is nontoxic, odorless, bio-compatible, and biodegradable. Due to its antibacterial properties, chitosan is used for microencapsulation, in particular for cells that require a cationic environment. Numerous applications in drug delivery include drug targeting systems for oral, nasal, ocular, and transdermal routes [102]. For this purpose, chitosan has been used in the development of gels, films, oral tablets, beads, and microspheres [103].

The capacity of chitosan as an encapsulating agent is greatly influenced by its molecular weight, degree of deacetylation and crystallinity, and extent of ionization/the free amino group. Thus, when the amino group at the 2-position of glucosamine units of chitosan is the main site for the immobilization of thiol groups, it results in thiolated chitosan. The thiolated chitosan derivatives are chitosan-cysteine, chitosan-thiolactic acid, chitosan-thioglycolicacid, chitosan-homocystenine, chitosan-N-acetylcysteine, and chitosan-glutathione. The thiolated chitosan has been used for anticancer drugs because it offers efficient mucoadhesivity, membrane permeation, and an enhancing capability and improved inhibition for P-glycoprotein [104]. Phosphorylated chitosan and its derivatives have different features such as high hidrosolubility and a metal chelating tendency, used in tissue regeneration, drug delivery intermediates, fuel cells, and in the food industry [105].

Structurally, chitosan is composed of free amine groups in media with a pH over 7.5 and protonated amines are formed in media with a lower pH. These pH-sensitive characteristics make chitosan-based compounds suitable in controlled-release technologies. Under well-established conditions, chitosan microcapsules containing the drug as an active ingredient permits its slow release at the target site [106]. For example, when encapsulated in chitosan, lipophilic drugs were effectively released into the intestinal tract [107]. When used as a vehicle to encapsulate vaccines, it allowed for their controlled release and delivery to targeted sites [108].

There are a number of advantages in using chitosan in the pharmaceutical industry for drug delivery, such as: (i) the controlled release of encapsulated substances; (ii) the elimination of toxic agents in the development process (due to dissolution in aqueous solution); (iii) crosslinking readily available free amino groups; and (iv) improved membrane absorption by mixing cationic chitosan with an anionic material [109]. When used as a coating agent for nanoparticles for the treatment of brain disease, chitosan protects against enzyme degradation, controls release, and improves bioavailability. In addition, it enhances drug permeability across the blood–brain barrier by affecting tight junctions [110]. Equally important are its hemostatic, bacteriostatic, anticholesterol, anticarcinogenic, and fungal characteristics.

In addition, chitosan has good bioadhesive properties and slows down the drug release in the nasal cavity, thus increasing bioavailability and the transfer of drugs from the nasal cavity to the brain [111]. When chitosan was used in membrane development, it increased permeability to acidic drugs. It is insoluble at a pH greater than 6.5 and prevents the burst effect of the release in the first segments of the gastrointestinal tract [112]. It has also been used successfully for antiviral and antibiotic encapsulation, as seen from Table 3.


#### **Table 3.** Chitosan use for drug delivery.

Chitosan has been extensively used as a matrix for extended drug release, especially due to the simple obtaining procedure, low cost, and biocompatibility. The biocompatibility of chitosan also derives from the fact that it is already part of the human food chain due to its presence in numerous fungi [123]. Chitosan increases the solubility of insoluble drugs when used in mixtures with inorganic nanoparticles, forming a stable complex with safe delivery to the specific site. It was effective when encapsulated hemoglobin, astaxanthin, quercetin, vaccines, or vitamins. Besides its applicability in drug delivery, chitosan is also used in wound dressing, tissue engineering, bioimaging, biosensors, and packaging, among other uses [124].
