## 5 Chitosan Nanocarriers in Brain Targeting
### Emulsions  
Nanoemulsions are heterogeneous systems that are composed of ultrafine oil-in-water dispersions stabilized by surfactant molecules [102]. They exhibit unique properties such as good solubilization capacity and thermodynamic stability when compared to other carriers [102; 103]. They have been explored in nose-to-brain drug delivery with good drug permeation through the nasal epithelia to the brain. The use of chitosan extended the nasal residence time of nanoemulsions and enhanced a high influx of drugs from the nose to the brain (Table 3) [104; 102]. Chitosan-coated nanoemulsions were loaded with rosmarinic acid for nasal delivery. The Box-Behnken design was used to develop the formulations. The optimized condition used was as follows: 0.1% chitosan final concentration (w/v), 8.5% oil phase (w/v), and 3:10 lecithin to oil phase ratio (w/w). The nanoemulsions mucoadhesive property was high with a sustained drug release profile. The extended permeation time was also significant with a high drug penetration via the porcine nasal mucosa due to an excellent interaction between the formulation and the nasal mucosa. The nanoemulsion did not induce a cytotoxic effect on the MRC-5 cell lines (Medical Research Council cell strain 5) or human lung fibroblast cells. Fibroblasts are present in the nasal mucosa and they are very important in nasal delivery [105]. Ropinirole, an anti-Parkinson drug, was encapsulated into chitosan-coated nanoemulsion. The optimized formulation exhibited good drug release of 72% with a globule size of 58.61, polydispersity (0.201), and viscosity (31.42 MPa). Ex vivo study revealed drug transportation in the different parts of the Wister rat brain indicating that the intranasal \begin{table}
\begin{tabular}{c c c c c} \hline \hline
**Drug** & **Composition** & **Physicochemical Properties** & **Biological Outcome** & **References** \\ \hline Rivastigime & HPMC, Carbopol & 934, NaCMC, Chitosan, Pluronic F127 & Low viscosity and gelation capability & High drug concentration in the brain. & [96] \\ \hline Rasagiline & Poloxamer 407, carbopol 934 P, poloxamer 188, and chitosan & Good mucoadhesive properties & Non-toxic and non-irritant to the rat nasal mucosa. High drug concentration in rat brain tissue. & [97] \\ \hline Levodopa & Chitosan, ketone musk & The optimized thioated chitosan NPs showed 223 nm particle size, 0.296 PDI and +27.91 mV zeta potential. & The concentration of tholated chitosan nanoparticles in the brain was high when compared to the free drug. The addition of musk ketone to the gel enhanced the concentration of the drug uptake in the brain by increasing the sensitivity of the nasal cavity, thereby inhibiting the efflux of levodopa through P-glycoprotein efflux pump in the brain. & [98] \\ \hline Ropinirole & Chitosan, HPMC & Improved drug bioavailability. & A 90\% high brain transport and a drug targeting index greater than 1. & [99] \\ \hline Levodopa & Chitosan, Pluronic PF127 & Good gelation capability. & The release profile followed & \\  & & & & \\  & & & & \\  & & & & \\ \hline Doxepin & Chitosan, PEG & Good gelation and mucoadhesive properties & In vivo studies showed an enhanced increase in activity count and a reduction in the immobility time, indicating good antidepressant activity. & [101] \\ \hline \hline \end{tabular}
\end{table} 
Table 2: Chitosan-based in situ gels developed for intranasal administration. administration of ropinirole nanoemulsion is a potential therapeutic for [PERSON]'s disease [106]. Buspirone hydrochloride microemulsion formulation for intranasal administration was reported to improve the drug uptake in the brain. Chitosan aspartate and hydroxypropyl-\(\beta\)-cyclodextrinrin were added to the microemulsions to enhance the interaction between the formulation and the nasal mucosa and to improve the drug uptake, respectively.