Tunable Intranasal Polymersome Nanocarriers Triggered Olanzapine Brain Delivery and Improved In Vivo Antipsychotic Activity

TL;DR

This study developed a new intranasal delivery system for the antipsychotic drug olanzapine, improving its brain delivery and reducing side effects.

Contribution

A novel intranasal polymersome nanocarrier was developed to enhance brain targeting and safety of olanzapine.

Findings

Optimized PolyOla showed high drug entrapment and sustained release in vitro.

Intranasal PolyOla increased brain drug levels significantly compared to oral administration.

PolyOla improved antipsychotic efficacy and reduced systemic side effects in rats.

Abstract

Background: Olanzapine (Ola) is a second-generation antipsychotic with clinical utility limited by poor brain bioavailability due to blood–brain barrier restriction, hepatic first-pass metabolism, and systemic side effects. This study aimed to develop and optimize a novel intranasal polymersome-based nanocarrier (PolyOla) to enhance brain targeting, therapeutic efficacy, and safety of Ola. Methods: PolyOla was prepared using poloxamer 401 and optimized through a Box–Behnken Design to minimize particle size and maximize entrapment (EE%) and loading efficiency (LE%). The formulation was characterized by size, morphology, drug release, and serum stability. In vivo studies in adult male Sprague-Dawley rats assessed pharmacokinetics (plasma and brain concentrations), pharmacodynamic efficacy in a ketamine-induced schizophrenia model, and systemic safety markers including metabolic, hepatic, and testicular oxidative stress indicators. Results: Optimized PolyOla exhibited a particle size of 78.3 ± 4.5 nm, high EE% (91.36 ± 3.55%), and sustained in vitro drug release. It remained stable in serum for 24 h. Intranasal administration significantly improved brain delivery of Ola, achieving a 2.7-fold increase in Cmax and a 5.7-fold increase in AUC compared to oral dosing. The brain Tmax was 15 min, with high drug-targeting efficiency (DTE% = 365.38%), confirming efficient nose-to-brain transport. PolyOla-treated rats showed superior antipsychotic performance, reduced extrapyramidal symptoms, and improved systemic safety evidenced by mitigated weight gain, glycemic control, normalized liver enzymes, and reduced oxidative stress. Conclusions: PolyOla offers a safe and effective intranasal delivery platform for Ola, enabling targeted brain delivery and improved management of schizophrenia with reduced peripheral toxicity.

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