*4.2.1 Chitosan NP by ionic gelation*

*Chitin and Chitosan - Physicochemical Properties and Industrial Applications*

quaternization of chitosan reinforces its impact on the tight junctions of the GIT epithelium whilst grafting carboxylated chitosan with poly(methyl methacrylate) imparts increased pH sensitivity [81]. Physical modification through blending with other polymers may be used to enhance desirable physical properties. For example, blending of chitosan with polyethylene glycol (PEG) and polyvinyl alcohol (PVA) ameliorate the hydrophilic property of chitosan, while blending of chitosan with

*Chemical structure of chitosan, comprising N-acetyl-D-glucosamine (right) and D-glucosamine (left) units.*

Some of the key desirable features in orally administered dosage forms is delayed GI transit in the duodenum and ability to traverse the epithelium effectively. In this regard, chitosan-based NP have been shown to possess these attributes. Mucoadhesion refers to the adhesion between two materials, one of which is mucosal [83]. It can be utilised to prolong the GI transit of dosage forms in the duodenum, thereby improving bioavailability. Delayed transit results from interactions of positively charged moieties in chitosan with negatively charged moieties in sialic acid within mucin [81]. Chitosan is also capable of physically penetrating the mucous network. Prolonged GI residence results in higher net drug flux across the GIT membrane. Drug flux is a combination of passive diffusion and uptake of whole NP by Peyer's patches [84]. Moreover, chitosan offers controlled drug release capabilities via diffusion from the matrix. Yin et al. prepared thiolated trimethyl chitosan NP for the oral delivery of insulin, where increase in the mucoadhesion resulted in increased insulin transport through rat intestine and uptake by Peyer's patches compared to controls. They attributed these results to the disulfide bond formation between the NP and mucin [85]. Overall, to achieve the desired properties of interest such as particle size, particle size distribution and area of application, the mode of preparation of chitosan NP

The preparation of chitosan NP is principally divided into two approaches. The first approach is based on a two-step procedure, where an emulsification system is carried out to generate nanodroplets in which organic compounds (polymer, monomer, and lipid) are solubilized, followed by precipitation or polymerisation into NP [61]. The second approach involves a one-step procedure where the NP are directly generated via different mechanisms such as nanoprecipitation or ionic gelation [86]. An example of each of the two general approaches is summarized in

cellulose improves its antibacterial properties [82].

**4.1 Mucoadhesion from chitosan**

**Figure 4.**

plays an essential role.

**4.2 Fabrication methods for chitosan NP**

**36**

the following.

Ionic gelation, also known as ionotropic gelation or polyelectrolyte complexation involves the gradual addition of a cross-linking agent (tripolyphosphate, glutardehyde etc.) into an aqueous solution of chitosan under continuous stirring to form hydrogels [87]. The polyanions from the cross-linker forms a meshwork of structures by interacting with the polyvalent cations within chitosan, leading to gelation [88]. APIs can be loaded into these hydrogels during the production where it becomes encapsulated or added to the formed NP, where it can be adsorbed into the matrix. The choice of the cross-linker should be matched to the desired physical characteristics of the NP, such as mechanical strength, as well as safety profiles. For example, glutardehyde reported to be toxic when used in high concentrations and results in NP with low mechanical strength. This has been attributed to its double bond (–C=N–) association with the amine group in chitosan [89]. Genipin is a natural cross-linker obtained from iridoid glucoside (geniposide) and present in gardenia fruits that can be cross-linked with chitosan. It displays slower degradation rate than glutaraldehyde and possess higher biocompatibility. Sodium tripolyphosphate (STPP) displays better crosslinker characteristics than each of the above because of its inorganic nature and consequently, results in production of chitosan NP with better mechanical stability. The size dimension derived from STPP gelled chitosan NP is of lower order as well. Another attractive feature of STPP is that it is nontoxic, relatively inexpensive, multivalent, has quick gelling property and thus, widely utilised as a crosslinker in chitosan-based NP [90–92].
