Brain targeting efficiency of intranasal clozapine-loaded mixed micelles following radio labeling with Technetium-99m

Abstract

The research objective is to design intranasal (IN) brain targeted CLZ-loaded polymeric nanomicellar systems (PNMS) aiming to improve central systemic CLZ bioavailability. Direct equilibrium method was used to prepare CLZ-PNMS using two hydrophobic poloxamines; Tetronic V R 904 (T904) and Tetronic V R 701 (T701) and one hydrophilic poloxamer; Synperonic V R PE/F127 (F127). Optimization is based on higher percent transmittance, solubilizing efficiency, and in vitro release after 24 h with smaller particle size was achieved using Design-Expert V R software. The optimized formula was further evaluated via TEM, ex vivo nasal permeation in addition to in vivo biodistribution using radiolabeling technique of the optimized formula by Technetium-99m ( 99m Tc). The optimized formula M5 has small size (217 nm) with relative high percentage of transmittance (97.72%) and high solubilization efficacy of 60.15-fold following 92.79% of CLZ released after 24 h. Ex vivo nasal permeation showed higher flux of 36.62 lg/ cm 2 .h compared to 7.324 lg/cm 2 .h for CLZ suspension with no histological irritation. In vivo biodistribution results showed higher values of radioactivity percentage of the labeled optimized formula ( 99m Tc-M5) in brain and brain/blood ratio following IN administration of 99m Tc-M5 complex which were greater than their corresponding values following intravenous route. It is obvious that nasal delivery of CLZ-PNMS could be a promising way to improve central systemic CLZ bioavailability.

Clozapine-Encapsulated Binary Mixed Micelles in Thermosensitive Sol–Gels for Intranasal Administration

“…These findings demonstrate that PS80 increased the rigidity of the formulation, leading to a lower amount of the drug and a slower rate of drug release from the polymer gel matrix at 34 °C. The increased residence time between clozapine and the nasal mucosa is desirable to prevent drug degradation via mucociliary clearance and the rapid turnover of mucus in the nasal cavity [ 28 ].…”

Self-Assembling Lecithin-Based Mixed Polymeric Micelles for Nose to Brain Delivery of Clozapine: In-vivo Assessment of Drug Efficacy via Radiobiological Evaluation

“…Morphological examination was carried out by TEM (JEOL, Tokyo, Japan). 14,31 In-vitro Release Study The release of CLZ from the optimized formula was examined via dialysis bag technique. Two mL (containing 2mg CLZ) of the optimum CLZ-LbPM formula were transferred into a cellulose dialysis bag (molecular weight cut off 12,000-14,000 Da) in 50 mL phosphate buffer saline PBS (pH 7.4) as a release medium in amber glass bottles.…”

“…13 Another approach for intranasal CLZ appeared in the formulation of polymeric nanomixed micelles using Tetronic® 904/Synperonic® PE/F127, the optimized formula was radiolabeled by 99m Tc to ensure the direct delivery of CLZ from nose to brain and high bioavailability of the drug in the central nervous system (CNS). 14 In recent years, a considerable attention has been directed towards the use of intranasal (I.N.) route for CNS drug delivery.…”

Hyaluronic Acid Scaffolds for Loco-Regional Therapy in Nervous System Related Disorders

“…Hydrogels may function as a reservoir for a prolonged release of APIs in the nasal route towards the CNS [ 62 ] ( Figure 2 B-4). In other works, the development of nanobodies have been recently explored for the intranasal delivery of vaccines encapsulated in a nanogel [ 63 ], temozolomide administration for glioblastoma treatment [ 64 ], poorly soluble drugs such as simvastatin [ 65 ], and intranasal clozapine-loaded Technetium-99m-labeled mixed micelles for the treatment of schizophrenia [ 66 ]. Overall, although under investigation, this route may offer a non-invasive approach to the delivery of APIs in combination with an appropriate encapsulation in nanoparticles, including nanogels.…”