**5. Challenges in oral vaccine delivery system**

Viral protein requires the right structural conformation to attach to the host cell and replicate. Highly acidic in the stomach and extreme temperature changes will cause protein denaturation. The denaturation of the virus will alter the conformation of its structure [58]. The high temperature will break the phosphodiester bond. However, at low temperature, the degradation of the nucleic acid will also lead to viral inactivation [78].

Furthermore, to transport vaccines orally, it should be able to overcome the biological barrier of the intestinal epithelial cell such as tight junction and mucus. The hydrophilic antigen cannot cross the phospholipid bilayer to enter systemic circulation due to the function of tight junction in controlling the permeability of the membranes. Therefore, the uptake of the antigen to mucosal tissue is limited with a short time of exposure [78].

The GIT contains normal flora or microbiota which help in maintaining the structure of the gut mucosal barrier [55]. Those microbiotas not only aid nutrient metabolism, but they also possess an action to protect against invading pathogens [79, 80]. Well-balance microbiota is needed to induce the effectiveness of vaccines through oral administration. The delivery of the vaccine will be interrupted in patients with microbiota dysbiosis, leading to blunted vaccine response [80].

The induction of danger signals appropriately by the vaccine is essential to trigger an immune response [81]. Due to these limitations, there is a problem in inducing an adequate immune response against administered pathogens [3]. Consequently, a higher and repetitive dose is required. Nevertheless, the administration of high antigen doses repetitively may develop systemic oral tolerance towards vaccines [3, 78].

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*Chitosan-Based Oral Drug Delivery System for Peptide, Protein and Vaccine Delivery*

**6. Strategies to improve oral vaccine delivery system using chitosan**

The smaller size of pathogens is readily taken up by dendritic cells [75]. The same goes for peptide, encapsulation of pathogens in nanoparticles is a good approach to improve the effectiveness of vaccines in stimulating the immune system [75].

Small particle size is required to penetrate the mucus. The formulation will be excluded out from the layer of mucus if particle size greater than normal mucus pore size (100–500 nm). This leads to the interruption in the bioavailability of antigen to targeted antigen-presenting cell (APC). Therefore, the development of nanoparticulate systems is required to provide a smaller size (20 – 40 nm) of

Medium molecular weight chitosan (MMWC) with the degree of deacetylation

The antigen should be transported to the intestine and directly to the M-cell of the Peyer's patches [6]. Chitosan develops well-protected mucoadhesion by prolonging the residence time at mucosal surfaces. The uptake of antigen by epithelial cells of the intestine will be improved by chitosan. An increase in the activity of

Chitosan-based drug formulation has gained attention for their ability to serve as a carrier and an enhancer for oral delivery of peptides and vaccines. Although oral delivery is the most convenient and preferred route of administration, however, it has limitations due to the presence of the proteolytic enzyme, pH of GIT and the intestinal barrier to drug absorption. In recent years, there has been considerable research interest in the application of chitosan as an enzyme inhibitor, mucoadhesive agent and efflux pump inhibitor. Interaction of positively-charged amino groups of chitosan with negatively-charged sialic acid groups that exist in mucin prolongs the residence time between drugs and membranes, therefore enhancing the bioavailability of the drugs. Other formulation strategies include encapsulation of proteins, peptides and vaccines into a nanoparticulate delivery system. By encapsulating peptide into a nanocarrier system, the enzymolysis and peptides aggregation can be avoided thus enhances the absorption of peptide drugs in the intestinal epithelium. Similarly, encapsulation of pathogens in nanoparticles is a good approach to improve

The authors acknowledge Faculty of Pharmacy, Universiti Teknologi MARA and

macrophages will improve the secretion of mucosal IgA and IgG [76].

the effectiveness of vaccines in stimulating the immune system.

internal grant (DUCS) 2.0, 600-UiTMSEL (PI. 5/4) (016/2020).

of 85% has been shown to improve the delivery of ovalbumin antigen with the presence of alginate and calcium phosphate (CaP). CaP has adjuvant properties by activating the surface expression of B-cell. CaP can be coated with mucosal penetrating polymers, such as chitosan and alginate to avoid biodegradation by enzymes present in the GIT [82]. In the stomach, the alginate-chitosan-coated CaP nanoparticle delays the release of ovalbumin antigen. The antigen then will be released in the intestine and colon with a sustained-release mechanism. This nanocarrier has successfully encapsulated ovalbumin antigen with small size (< 50 nm) [82].

The uptake of antigen by immune cells depends on the particle size of the antigen.

*DOI: http://dx.doi.org/10.5772/intechopen.95771*

formulation [82].

**7. Conclusions**

**Acknowledgements**

*Chitosan-Based Oral Drug Delivery System for Peptide, Protein and Vaccine Delivery DOI: http://dx.doi.org/10.5772/intechopen.95771*
