Fabrication and Characterization of Clozapine Nanoemulsion Sol-Gel for Intranasal Administration.

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.

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

(1) Background: Clozapine is the most effective antipsychotic. It is, however, associated with many adverse drug reactions. Nose-to-brain (N2B) delivery offers a promising approach. This study aims to develop clozapine-encapsulated thermosensitive sol-gels for N2B delivery. (2) Methods: Poloxamer 407 and hydroxypropyl methylcellulose were mixed and hydrated with water. Glycerin and carbopol solutions were added to the mixture and stirred overnight at 2-8 °C. Clozapine 0.1% w/w was stirred with polysorbate 20 (PS20) or polysorbate 80 (PS80) at RT (25 °C) before being added to the polymer solution. The final formulation was made to 10 g with water, stirred overnight at 2-8 °C and then adjusted to pH 5.5. (3) Results: Formulations F3 (3% PS20) and F4 (3% PS80) were selected for further evaluation, as their gelation temperatures were near 28 °C. The hydrodynamic particle diameter of clozapine was 18.7 ± 0.2 nm in F3 and 20.0 ± 0.4 nm in F4. The results show a crystallinity change in clozapine to amorphous. Drug release studies showed a 59.1 ± 3.0% (F3) and 53.1 ± 2.7% (F4) clozapine release after 72 h. Clozapine permeated after 8 h was 20.8 ± 3.0% (F3) and 17.8 ± 3.1% (F4). The drug deposition was higher with F4 (144.8 ± 1.4 µg/g) than F3 (110.7 ± 2.7 µg/g). Both sol-gels showed no phase separation after 3 months. (4) Conclusions: Binary PS80-P407 mixed micelles were more thermodynamically stable and rigid due to the higher synergism of both surfactants. However, binary mixed PS20-P407 micelles showed better drug permeation across the nasal mucosa tissue and may be a preferable carrier system for the intranasal administration of clozapine.

A systematic review and meta-analysis of the association between clozapine and norclozapine serum levels and peripheral adverse drug reactions.

RATIONALE: Clozapine is the most effective antipsychotic for treatment-refractory schizophrenia for reducing positive psychotic symptoms. It is associated with a reduction in hospitalisation and overall mortality. In spite of this, clozapine remains underutilised due to its complex adverse drug reaction (ADR) profile. OBJECTIVE: This systematic review aims to investigate the association of clozapine and norclozapine serum levels, and peripheral ADRs. METHODS: Studies were searched from four electronic databases (PubMed, EMBASE, PsycINFO and CINAHL) from inception to 12 June 2020. Studies were included if they had adult patients, provided data on steady-state trough clozapine or norclozapine levels and reported on clozapine-associated ADRs. Pregnant women, case reports and series were excluded. RESULTS: A statistically significant correlation was found for clozapine serum levels and triglycerides (n = 70; r = 0.303, 95% CI 0.0119-0.546, p = 0.042), heart rate (n = 137; r = 0.269, 95% CI 0.0918-0.486, p = 0.035), and overall combined ADRs (n = 160; r = 0.264, 95% CI 0.110-0.405, p = 0.001), but not for absolute neutrophil count (n = 223; r = - 0.164, 95% CI - 0.529-0.253, p = 0.444) or total white cell count (n = 18; r = 0.0176, 95% CI - 0.203-0.237, p = 0.878). Interestingly, norclozapine serum levels were found to be statistically correlated to triglycerides (n = 120; r = 0.211, 95% CI 0.0305-0.378, p = 0.022), total cholesterol (n = 120; r = 0.272, 95% CI 0.0948-0.432, p = 0.003) and weight gain (n = 118; r = 0.208, 95% CI 0.0261-0.377, p = 0.025). CONCLUSIONS: Heart rate, triglycerides and combined ADRs are significantly correlated with clozapine levels, and triglycerides, total cholesterol and weight gain with norclozapine levels. Future prospective, randomised controlled studies are needed to identify the cause-effect relationship between clozapine levels and peripheral ADRs.

Nose-to-brain delivery of antipsychotics using nanotechnology: a review.

INTRODUCTION: Orally-administered antipsychotics are effective in the management of psychosis-related disorders although generation-specific adverse drug reactions (ADRs) significantly hinder clinical outcomes, driven by issues such as patient non-compliance. Direct nose-to-brain (N2B) delivery of antipsychotics via the olfactory epithelium could avert peripheral ADRs by maximizing cerebral drug concentrations, and reducing drug levels in the periphery. However, there exist physicochemical challenges related to psychotropic drugs, alongside biochemical barriers associated with targeting the olfactory region. Nanotechnological approaches present a viable strategy for the development of intranasal antipsychotic formulations where drug stability, mucosal absorption and cerebrospinal fluid (CSF)-bioavailability can be optimized. AREAS COVERED: This review explores the unique anatomical features of the nasal cavity as a pathway for antipsychotic drug delivery to the brain. Nanocarrier-based approaches to encapsulate antipsychotics, and enhance stability, absorption and bioavailability are explored. The aim of this review is to determine current knowledge gaps for direct N2B psychotropic drug delivery, and identify clinically acceptable strategies to overcome them. EXPERT OPINION: The olfactory epithelium may be the most effective and direct administration route for antipsychotic delivery to the central nervous system (CNS). This research is novel and has the potential to revolutionize the mode of delivery of neurological medicines to the CNS in the future.

Preparation of albendazole-loaded liposomes by supercritical carbon dioxide processing.

Supercritical fluid (SCF) technology offers a potential green alternative to organic solvent-based methods for drug formulation. Albendazole (ABZ) has promising anticancer activity when formulated to increase its cellular uptake. Herein, a static volume method was used to determine the solubility of ABZ in supercritical carbon dioxide (scCO2) for the future development of such ABZ formulations. The solubility of ABZ in scCO2 (250 bar, 37 °C) was approximately 12 mg/100 mL. The extent of dissolution was measured at various time points to determine when saturation solubility occurred, which was demonstrated from 9 h. In order to determine if scCO2 processing induced ABZ polymorphism, DSC/TGA, FTIR and XRD were used, which demonstrated no change in its solid state. Following this, ABZ loaded liposomes were manufactured using SCF technology. The liposomes diameter was 167.2 ± 5.3 nm as determined by Zetasizer, and confirmed by cryo-transmission electron microscopy. In conclusion, scCO2 was used successfully to solubilize ABZ, and to manufacture liposomes of nano-sized range. This study provides insight into use of green technology for future ABZ liposomal formulation without the need for organic solvents.