Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia. However, it causes many adverse drug reactions (ADRs), which lead to poor treatment outcomes. Nose-to-brain (N2B) drug delivery offers a promising approach to reduce peripheral ADRs by minimizing systemic drug exposure. The aim of the present study was to develop and characterize clozapine-loaded nanoemulsion sol-gel (CLZ-NESG) for intranasal administration using high energy sonication method. A range of oils, surfactants, and cosurfactants were screened with the highest clozapine solubility selected for the development of nanoemulsion. Pseudoternary phase diagrams were constructed using a low-energy (spontaneous) method to identify the microemulsion regions (i.e., where mixtures were transparent). The final formulation, CLZ-NESG (pH 5.5 ± 0.2), comprising 1% w/w clozapine, 1% w/w oleic acid, 10% w/w polysorbate 80/propylene glycol (3:1), and 20% w/w poloxamer 407 (P407) solution, had an average globule size of ≤30 nm with PDI 0.2 and zeta potential of -39.7 ± 1.5 mV. The in vitro cumulative drug release of clozapine from the nanoemulsion gel at 34 °C (temperature of nasal cavity) after 72 h was 38.9 ± 4.6% compared to 84.2 ± 3.9% with the control solution. The permeation study using sheep nasal mucosa as diffusion barriers confirmed a sustained release of clozapine with 56.2 ± 2.3% cumulative drug permeated after 8 h. Additionally, the histopathological examination found no severe nasal ciliotoxicity on the mucosal tissues. The thermodynamic stability studies showed that the gel strength and viscosity of CLZ-NESG decreased after temperature cycling but was still seen to be in "gel" form at nasal temperature. However, the accelerated storage stability study showed a decrease in drug concentration after 3 months, which can be expected at elevated stress conditions. The formulation developed in this study showed desirable physicochemical properties for intranasal administration, highlighting the potential value of a nanoemulsion gel for improving drug bioavailability of clozapine for N2B delivery.
Keywords: adverse drug reaction; clozapine; intranasal; nanoemulsion; nose-to-brain delivery; poloxamer.