Dataset Information

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

ABSTRACT: BACKGROUND: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). OBJECTIVES: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. METHODS: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 14 days. RESULTS: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?±?10.44 nm & 330.2?±?12.90 nm and zeta potential of -21.7?±?1.39 mV and?-?18.26?±?1.64 mV 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. CONCLUSION: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.

SUBMITTER: Pailla SR

PROVIDER: S-EPMC6895326 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Pailla Sravanthi Reddy SR Talluri Sreekanth S Rangaraj Nagarjun N Ramavath Ramdas R Challa Veerabhadra Swamy VS Doijad Nandkumar N Sampathi Sunitha S

Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences 20190629 2

<h4>Background</h4>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).<h4>Objectives</h4>Since ZTP displays dose dependent side effects, purpose of the contemporary study is to develop zotepine loaded nanosuspension (ZTP-NS) for increased brain targetin ...[more]

PMID: 31256410

Similar Datasets

Project description:We previously reported that intranasal insulin protects substantia nigra dopaminergic neurons against 6-hydroxydopamine neurotoxicity in rats. This study aimed to assess insulin pharmacokinetics in the rat brain following intranasal application. Recombinant human insulin (rh-Ins) or phosphate buffer solution was administered to both nostrils of rats. Animals were sacrificed at 15 minutes, 1, 2, and 6 hours to determine insulin levels in different brain regions by an ultrasensitive, human-specific enzyme-linked immunosorbent assay kit. For fluorescence tracing study, rats were administered with intranasal florescence-tagged insulin (Alex546-Ins), and brains were fixed at 10 and 30 minutes to prepare sagittal sections. rh-Ins was detected in all brain regions examined except the cerebral cortex. The highest levels were detected in the brainstem, followed by the cerebellum, substantia nigra/ventral tegmental area, olfactory bulb, striatum, hippocampus, and thalamus/hypothalamus. Insulin levels reached a peak at 15 minutes and then declined gradually overtime, but remained significantly higher than baseline levels at 6 hours in most regions. Consistently, widespread Alex546-Ins-binding cells were detected in the brain at 10 and 30 minutes, with the olfactory bulb and brainstem showing the highest while the cerebral cortex showing lowest fluorescence signals. Double-immunostaining showed that Alex546-Ins-bindings were primarily co-localized with neuronal nuclei-positive neurons. In the subtantia nigra, phospho-Akt was found to be activated in a subset of Alex546-Ins and tyrosine hydroxylase double-labeled cells, suggesting activation of the Akt/PI3K pathway in these dopaminergic neurons. Data from this study suggest that intranasal insulin could effectively reach deep brain structures including the nigrostriatal pathways, where it binds to dopaminergic neurons and activates intracellular cell survival signaling. This study was approved by the Institutional Animal Care Committee at the University of Mississippi Medical Center (protocol 1333A) on June 29, 2015.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets