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 AUC 0-24h 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.

Osthole‐Loaded Nanoemulsion Enhances Brain Target in the Treatment of Alzheimer’s Disease via Intranasal Administration

“…The DTP% was greater than 50% by IN administration of OST-NE, indicating that half of the OST in the brain tissue entered the brain directly from the nasal cavity. It is known that drug absorption from the nasal cavity to the brain usually occurs through two pathways: (1) systemic pathway: a certain amount of the drug directly enters the systemic circulation and reaches the brain through the BBB; and (2) olfactory pathway: the drug enters the cerebrospinal fluid or brain directly from the nasal cavity [ 51 ]. DTE% and DTP% correspond to the percentage of drugs that are transported directly to the brain via the olfactory pathway.…”

Development of reverse phase high-performance liquid chromatographic method for the estimation of HIV non-nucleoside reverse transcriptase inhibitor drug efavirenz in the rat brain

“…After oral administration, a very small fraction of the drug reaches the brain due to physiological barriers, and hence, sensitive methods are required for the estimation of the quantities present from micro-to nanogram per milliliter. A low-dose EFV gives virologic failure, and high doses can cause CNS toxicity [14]. Thus, the developed method will help researchers in the evaluation of novel drug delivery systems to estimate the CNS EFV level.…”

“…To the homogenized brain sample, EFV was added linearly in different concentrations for the calibration plot with the six points of 0.4 ppm, 0.8 ppm, 2.4 ppm, 4.8 ppm, 6.4 ppm, and 8 ppm in six different isolated homogenized brain samples. This homogenized brain sample with the addition of the EFV was sonicated for 10 min [12][13][14][15][16][17]. Deproteinization of the sample was carried out by adding 5 mL of ethyl acetate which can be done by the addition of any non-polar solvent.…”

Advanced modification of drug nanocrystals by using novel fabrication and downstream approaches for tailor-made drug delivery

“…Drug nanosuspensions can be further converted to not only tablets (Mori et al., 2016; Anup et al., 2018), capsules (Bonhoeffer et al., 2018), creams (Lai et al., 2015), injectables (Lu et al., 2016; Yang et al., 2017; Sigfridsson et al., 2019) or other traditional formulations (Pailla et al., 2019), but it can be also loaded in carrier such as human erythrocytes (Staedtke et al., 2010) or be combined with fluorescent dyes (Zhao et al., 2011) with the development of modern pharmaceutical technologies. This review would mainly focus on recently developed novel approaches because the traditional methods have been summarized in many related literature (Van Eerdenbrugh et al., 2008; Malamatari et al., 2016).…”