Design and Optimization of Thermo-reversible Nasal in situ Gel of Atomoxetine Hydrochloride Using Taguchi Orthogonal Array Design

Abstract

The present investigation was aimed to develop a thermo-reversible nasal in situ gel of atomoxetine
hydrochloride (AH) with reduced nasal muco-ciliary clearance in order to improve residence time and targeting the
brain through nasal mucosa for the treatment of attention-deficit hyperactivity disorder (ADHD). In situ gel
formulations were prepared using different concentrations of the thermo-gelling poloxamer 407 and mucoadhesive
polymers. Temperature-triggered ionic gelation is the mechanism involved. Taguchi L9 OA experimental design was
employed for the optimization of the effect of independent variables (Poloxamer 407 and Carbopol 934P) on the
response (gelation temperature). In situ gel formulation F4 having 20% poloxamer 407 and 0.3% carbopol 934P and
formulation F6 having 20% poloxamer 407 and 0.2% HPMC K100 were optimized based on evaluation parameters.
The gelation temperature of F4 and F6 was found to be 37°C ± 0.4 and 37°C ± 0.2, drug content 98.34 and 98.33% and
drug release was 83.18, 82.4% in 4 hrs with a flux of 436.9 and 428.1 μg.cm2/hr, respectively. The release pattern of
drug followed first-order kinetics with Higuchi release mechanism. The value of ‘n’ from Korsemeyer equation
indicated the anomalous diffusional drug release. This study concluded that in situ gel enhanced the nasal residence
time and thus may improve the bioavailability of the drug through nasal route by avoiding first pass metabolism.