**4.1 Mucoadhesion from chitosan**

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 plays an essential role.

#### **4.2 Fabrication methods for 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 the following.

**37**

*Gastrointestinal Delivery of APIs from Chitosan Nanoparticles*

widely utilised as a crosslinker in chitosan-based NP [90–92].

Polymeric nano-emulsions are formulated whereby organic solvent is added to a solution of chitosan with surfactant and mixed via sonication [93]. Basically, the emulsion droplets are converted into NP suspension as the organic solvent evaporates by continuous magnetic stirring at room temperature. The NP suspensions are then centrifuged, washed with distilled water to remove additives such as surfactants and finally lyophilized [94]. Poovi et al. encapsulated the poorly water-soluble drug, repaglinide, into chitosan NP using the emulsion evaporation for sustained release. They proved that the NP exhibited a controlled release of repaglinide and obtained a high drug loading (11.22% w/w) and encapsulation efficiency (97.0%) [95]. In another study, Lee et al. employed solvent evaporation method to formulate polymeric NP from chitosan derivatives fluorescein isothiocyanate (FITC) - conjugated glycol CSs (FGCs) using diluted chloroform as the solvent. Size range of 150–500 nm were obtained and the NP remained stable in phosphate buffered

*In vitro* drug release studies give us insights on the response of formulated delivery systems to challenges in *in vivo*. The rate and extent of *in vitro* drug release from chitosan-based NP is influenced by a host of factors, notably, shape and size of the of the delivery system, physicochemical properties of the drug and external media [97]. Three primary mechanisms govern the drug release from chitosan NP, which includes desorption (release of drug from surface), diffusion, and erosion/ degradation of the particle matrix [98]. Erosion or degradation of polymers lead to successive physical depletion of the polymer as chains and bonds break [99]. Drug release from the chitosan NP matrix is often pH dependent because of the solubility of chitosan in acidic media [100]. In acidic media, the matrix swells or disentangles

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,

*DOI: http://dx.doi.org/10.5772/intechopen.95363*

*4.2.1 Chitosan NP by ionic gelation*

*4.2.2 Emulsion evaporation*

saline for 20 days at 37°C [96].

**4.3 In vitro drug release from chitosan NP**
