Intranasal Zotepine Nanosuspension: intended for improved brain distribution in rats.

Abstract

Zotepine (ZTP), an antipsychotic drug is well tolerated and particularly effective for treating negative symptoms of psychosis. But is limited by low oral bioavailability caused by substantial first pass metabolism and thereby less amount of drug reaches the brain due to blood brain barrier (BBB). Since ZTP displays dose dependent side effects, purpose of the contemporary study is to develop zotepine loaded nanosuspension (ZTP-NS) for increased brain targeting in rats at lower doses. ZTP-NS is prepared by two techniques viz., sonoprecipitation (SP) and combination technique (high pressure homogenization preceded by precipitation) by employing various stabilizers. Optimized ZTP-NS was characterized for particle size, solid state, morphology and solubility. In vitro drug release of ZTP and formulations was conducted using Franz diffusion cell. Stability study was performed at different temperature conditions. Pharmacokinetic study was performed in Wistar rats to determine the bioavailability and brain distribution of ZTP after intra-nasal (IN) and intravenous (IV) administration. Histopathology of brain was done after repeated administration of IN ZTP dispersion and NS up to 14days. The optimized ZTP-NS formulated with Pluronic F-127 (0.3%w/v), Hydroxypropyl methyl cellulose E15 (0.3%w/v) and soya lecithin (0.4%w/v) showed particle size of 519.26 ± 10.44nm & 330.2 ± 12.90nm and zeta potential of -21.7 ± 1.39mV and - 18.26 ± 1.64mV with sonoprecipitation and combination technique respectively. In vitro drug release was high (81.79 ± 3.23%) for ZTP-NS prepared by combination technique. Intranasal NS resulted in high brain concentrations of 8.6 fold (sonoprecipitation) and 10.79-fold hike in AUC0-24h in contrast to intravenous ZTP solution. Histopathology results reveal no significant changes in brain microscopic images. ZTP-NS was successfully developed, characterized and found that nanosuspension is a favorable approach for intranasal delivery of zotepine. Graphical abstract Graphical abstract representing zotepine drawbacks, nanosuspension preparation, characterization and pharmacokinetic study in rats.