## 5 Chitosan Nanocarriers in Brain Targeting
### In Situ Gel
The RM concentration in the rat brain tissue was significant, indicating an enhanced uptake of RM from the formulation when compared to the drug solution [97]. The administration of the drug intranasally overcomes the extensive first pass metabolism, a mechanism that is responsible for poor drug bioavailability of therapeutics administered orally. The extended residence time and intimate contact with nasal epithelium resulting from the mucoadhesive behavior of the gels improved the drug uptake from the nasal cavity [97]. Synthesized thiolated chitosan-based in situ gel loaded with levodopa has also been reported [98]. The optimized NPs particle size was 223 nm with an entrapment efficiency of 76%. The release of the drug from the NPs at pH 6.4 revealed non-Fickian diffusion. In vivo pharmacokinetic studies further revealed enhanced bioavailability in the brain. The concentration of thiolated chitosan nanoparticles in the brain and the plasma was approximately 50% 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]. Ropinrole, a dopamine D2 agonist to the brain was incorporated into mucoadhesive in situ gel formulations. The in situ formulations were prepared from hydroxyl propyl methyl cellulose and chitosan [99]. In vivo evaluation in albino rats after intranasal administration of 99 mTc-ropinirole in situ gel indicated an 82% absolute bioavailability of ropinirole. A nose-to-brain transport of the drug from the in situ gel formulation was confirmed by a 90% high brain transport and a drug targeting index which was greater than 1 [99]. The decreased clearance of the formulation was due to the mucoadhesive properties of chitosan. The positively charged amino groups on the chitosan adhere to the negatively charged sialic acid residue of the mucosa. Chitosan in situ gel loaded with levodopa release profile followed Hixson-Crowell model. The addition of chitosan increased the drug uptake of the formulation in the nasal mucosa via the opening of the junctions between the epithelial cells and also delayed mucociliary clearance. In vivo studies on Swiss albino rat models further indicated that the drug uptake into the brain was influenced by the viscosity of the gel [61; 100]. The intranasal administration of the in situ gel formulation resulted in a high percentage of levodopa in the brain when compared to the drug solution in the saline. The aforementioned result indicated that at the nasal temperature, the gel adheres to the nasal cavity thereby reducing the clearance and controlling the drug release. However, results obtained from the gel of Pluronic PF127 incorporated with chitosan nanoparticles loaded with levodopa showed low drug concentration in the brain. Embedding nanoparticles in a highly viscous gel resulted in the non-availability of the drug at the absorption site due to the slow release of the nanoparticles from the gel matrix [100]. [PERSON] and [PERSON] prepared chitosan-based gels for the delivery of doxepin to the brain via nasal route administration. In vivo studies showed an enhanced increase in activity count and a reduction in the immobility time, indicating good antidepressant activity. Side effects such as the mild swelling of the glands was observed in vivo after the administration of the formulation intranasally. Mice administered with the drug solution suffered from the shuffing of the mucosal epithelium. The release profile of the matrix influenced the permeation rate of drug from the formulation [101].