Poloxamer-407 thickened lipid colloidal system of agomelatine for brain targeting: Characterization, brain pharmacokinetic study and behavioral study on Wistar rats

The current study was designed to enhance the brain bioavailability and to extract maximum therapeutic benefit from a novel antidepressant drug, agomelatine. For this purpose, a thermoresponsive in situ gel was prepared by dissolving 20% w/v of Poloxamer-407 in agomelatine containing nanoemulsion. To impart mucoadhesive property, 0.5% w/v concentration of chitosan was ensured in the final formulation, named as Ago-NE-gel + 0.5% chitosan. The gelling point and mucoadhesive strength of Ago-NE-gel + 0.5%chitosan were found to be 28 +/- 1 degrees C, and 6246.27 dynes/cm(2) respectively. The size of free micelles of Poloxamer-407 was recorded graphically at 18.43 +/- 0.95 nm whereas the size of sterically stabilized Ago-NE was observed at 142.58 +/- 4.21 nm. The viscosity and pH of Ago-NE-gel+0.5%chitosan were found to be 2439 +/- 23 cP (at 35 +/- 1 degrees C temperature) and 5.8 +/- 0.2 respectively. The developed formulation was found safe on nasal mucosa during the toxicity study. CLSM based brain distribution study suggested that Ago-NE-gel + 0.5%chitosan is more competent to deliver the drug into the brain as compared to agomelatine-suspension. After intranasal administration of Ago-NE-gel + 0.5%chitosan in Wistar rats, the AUC(0.8h) in brain and plasma were found to be 1418.591 +/- 71.87 and 473.901 +/- 32.42 ng.h/ml respectively. The hypothesis conceived at the beginning of this research work was delivered as 2.82 folds enhanced bioavailability of agomelatine in the brain. The behavioral studies confirmed that the antidepressant activity of agomelatine can be improved by loading the drug into a mucoadhesive-nanoemulsion-gel system followed by its intranasal administration.