*4.4.2 Anti-bacterial agent delivery*

*Chitin and Chitosan - Physicochemical Properties and Industrial Applications*

**4.4 Chitosan as an oral delivery vehicle for therapeutics**

antibacterial agents, polyphenolic compounds and protein drugs.

absorption of Dox and thus improved oral bioavailability [106].

As mentioned in sections 4.1 and 4.2, extensive research presented the potential of chitosan as an oral absorption enhancer owing to its mucoadhesive properties and ability to loosen tight junctions within the GI epithelia, hence permitting the passage of macromolecular therapeutics across a "well-organised" epithelia [100]. Moreover, due to various characteristics; i.e. non-toxic, biodegradable, biocompatible, antimicrobial property etc. [104], chitosan NP hold promise as a suitable oral delivery vehicle for a wide spectrum of therapeutics including, anti-cancer drugs,

Chemotherapeutic APIs usually exhibit low bioavailability following oral administration. Several studies have investigated chitosan-based NP as a possible delivery system to address this issue. For example, doxorubicin (Dox), broadly employed to treat breast, bladder and other cancers, is typically delivered intravenously. The oral bioavailability of Dox is low due to efflux transporter P-glycoprotein, which identifies Dox as a substrate, restraining its cellular uptake [105]. In 2013, Feng et al. developed chitosan/o-carboxymethyl chitosan (CS/CMCS) NP as a pH responsive carrier for the oral delivery of Dox. They investigated the bioavailability of orally administered Dox-CS/CMCS NP and free Dox drug on Sprague–Dawley rats. Negligible Dox was detected in plasma after the oral dosage of free Dox, representing its poor absorption. On the other hand, 2.3-folds increase in plasma concentration of Dox was registered after an oral dose of Dox-CS/CMCS NP. Moreover, accumulation of Dox in the liver, spleen and lungs were demonstrated in rats treated with oral Dox- CS/CMCS NP, as opposed to DoX solution which was more concentrated in the kidneys. They concluded that the NP matrix improved the intestinal

and may act as an effective barrier to drug diffusion. The extent of drug diffusion through this gelled matrix depends on the diffusivity of the drug [99]. In alkaline media, the polymer matrix does not swell and drug release is controlled mainly by passive diffusion into the medium and the polymer plays an insignificant role in the drug release profile. If the drug is weakly bound to the surface of the NP, an initial burst release occurs [97]. In vitro drug release from chitosan NP usually show a two-step pattern with an initial rapid release followed by sustained release [101]. Patel et al. observed that rifampicin- chitosan NP presents a burst effect in the early stages followed by slow sustained drug release in which 90% of rifampicin was released in the range of 28–34 h. A good correlation fit was obtained between the cumulative drug released and square root of time, signifying that the drug release from the NP is diffusion-controlled as described by the Higuchi model. They concluded that rifampicin release from chitosan NP is pH dependent, i.e., faster at a lower pH than around neutral pH [102]. Similarly, Avadi et al. observed that insulin-loaded gum arabic/chitosan NP present a burst effect release in acidic medium, relating it to high solubility of both chitosan and insulin. No burst release was observed at higher pH values of 6.5 and 7.2. They concluded that the release followed a non-Fickian transport, governed by diffusion and/or swelling of the chitosan chains [103]. The performance of chitosan NP in the GIT depends on its response to the external milieu as discussed above. Equally important is how the GIT responds to the presence of NP. The following section describes the consequence of NP deployment in the GIT in the management of selected diseases and

**38**

expected responses.

*4.4.1 Anti-cancer drug delivery*

Chitosan impedes the growth of bacteria, fungi, and yeast [109]. It exhibits potential antimicrobial properties at pH below 6.0 because of the positively charged – NH3 + at the C-2 position within the glucosamine. Low molecular weight chitosan derived NP integrate with bacterial DNA, impeding mRNA synthesis. Conversely, the NH3 + in high molecular chitosan derived NP interact with the negatively-charged cell wall in microorganisms and subsequently amend cell permeability [110]. Alqahtani et al. formulated chitosan NP from high and low molecular weight variants to encapsulate the non-antibiotic diclofenac sodium (DIC). The antibacterial properties of NP from low and high molecular weight of chitosan on *Staphylococcus aureus* and *Bacillus subtilis* was significantly higher than from DIC alone. The antibacterial activity of chitosan was higher from the high molecular weight chitosan at pH = 5.5 [111]. In another *in vitro* study, Qi et al., investigated the antibacterial activity of chitosan NP and copper-loaded chitosan NP against various microorganisms (*E. coli, S. choleraesuis, S. typhimurium and S. aureus*). The antibacterial activity of chitosan NP and copper-loaded chitosan NP were significantly higher than from chitosan and doxycycline alone. Furthermore, copper-loaded NP indicated higher antibacterial activity against microorganism compared to chitosan NP void of copper. They concluded that this is due to the higher surface charge density of copper-loaded NP that improves the affinity of the cargo with the negatively charged bacteria membrane. Clearly, the antimicrobial property of chitosan is demonstrable and may augment the antibacterial effects of therapeutic antimicrobial when administered orally.
