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Fabrication and Characterization of Clozapine Nanoemulsion SolāGel 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 solāgel (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 Ā±
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 ā¤30 nm with PDI 0.2 and zeta potential
of ā39.7 Ā± 1.5 mV. The in vitro cumulative
drug release of clozapine from the nanoemulsion gel at 34 Ā°C
(temperature of nasal cavity) after 72 h was 38.9 Ā± 4.6% compared
to 84.2 Ā± 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 Ā± 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 āgelā
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