## 5 Chitosan Nanocarriers in Brain Targeting
### In Situ Gel
The cell proliferation showed that neural stem cells proliferated significantly on the chitosan-alginate hydrogel [91]. The inclusion of microsphere into pre-formed chitosan/alginate hydrogel provided the most effective delivery system, arising from the ability of the system to entrap the drug strongly, resulting in a sustained drug delivery by diffusion [92]. Thermo-sensitive injectable gels with good stability and thermosensitivity were developed from chitosan. The absence of adverse effects in vivo after the administration of the formulation was significant [93; 94]. [PERSON] et al. developed dopamine-based and polydopamine crosslinked injectable hydrogels under physiological conditions. The abundant amino groups on quaternized chitosan backbone influenced its crosslinking with polydopamine to form a stable hydrogel. The hydrogel prepared from quaternized chitosan and polydopamine was characterized by a low polymer concentration, resulting in a pore size which was large and useful for rapid drug release. The introduction of gelatin into the aforementioned hydrogel increased the biocompatibility, polymer concentration, and mechanical properties of the hydrogel. The hydrogels exhibited stable mechanical properties and good degradability. The release profile of the injectable hydrogels was sustained, revealing their capability to exhibit a long-term drug release. The release of dopamine from the hydrogels was controlled for more than 20 days, and it was influenced by the amount of the drug in the hydrogels [95]. In situ gel loaded with rivastigmine tartarate for administration via intranasal route was reported by [PERSON] et al. [96]. The gels were prepared from HPMC (hydroxypropyl methylcellulose), Carbopol 934, NaCMC (sodium salt of carboxymethylcellulose), Chitosan, and pluronic F127. Chitosan and NaCMC increased the \(T_{sol-gel}\) of the prepared gel. The low viscosity of the gel-containing chitosan is attributed to the amino group from the chitosan which reduced water channel formation around the triblock of pluronic, thereby lowering its gelation capability. The transnasal permeation of the formulation was high, resulting in 0.54% ID/g distribution to the brain when compared to the drug solution, which was 0.16% ID/g. Ex vivo permeation of the drug through the nasal membrane was 84% drug release and it was 28% drug release from the pure drug solution over a period of 6 h. The steady-state flux of the optimized gel was 259 \(\upmu\)g/cm\({}^{2}\)/hr when compared to the drug solution which was 86.2 \(\upmu\)g/cm\({}^{2}\)/hr. The apparent permeability coefficient of the formulation was \(1.67\times 10^{-4}\) cm/h and the drug solution was \(0.56\times 10^{-4}\) cm/h. The drug concentration in the brain after the administration of the formulation intranasally was higher than the drug solution administered either intranasally or intravenously. The brain/blood ratios of the in situ gel was 1.16 when compared to the drug intranasal solution and intravenous solution which was 0.31 and 0.025, respectively, indicating the direct nose-to-brain transport of the drug from the in situ gel. This could be due to the high drug permeation from the in situ gel observed in the ex vivo permeation study. The drug distribution in the vital organs, such as the liver and the kidney, was high after the administration of the drug solution indicating that the in situ gel has the capability to reduce the systemic drug distribution to vital organs resulting in drug targeting to the brain and hence, reduced side effects [96]. An intranasal thermosensitive gel loaded with rasagilinemesylate (RM), a drug used for the treatment of Parkinson's disease, was developed from poloxamer 407, carbopol 934 P, poloxamer 188, and chitosan. In vivo, pharmacokinetic studies in rabbits indicated a significant (\(p<0.05\)) enhancement in drug bioavailability from intranasal gels when compared to the oral drug solution. Further biological studies in Wistar rats indicated that the intranasal gels were not toxic and non-irritant to the rat nasal mucosa.