Development and Characterization of Citalopram-Loaded Thermosensitive Polymeric Micelles for Nasal Administration.

The intranasal (IN) route of administration is a promising non-invasive approach for brain targeting, bypassing the blood-brain barrier and enhancing bioavailability. Citalopram hydrobromide (CT), a widely prescribed sparingly water-soluble selective serotonin reuptake inhibitor (SSRI), faces challenges with oral and intravenous administration, including delayed onset, adverse effects, and patient compliance issues. This study aimed to develop a novel thermoresponsive polymeric micelle (PM) system based on Pluronic copolymers (Pluronic F127 and Poloxamer 188) improving CT's solubility, stability, and nasal permeability for enhanced antidepressant efficacy. A preliminary study was conducted to select the optimized formulation. The preparation process involved using the thin-film hydration method, followed by freeze-drying. Comprehensive evaluations of optimized formulation characteristics included Z-average, polydispersity index (PdI), thermal behavior (lower critical solution temperature, LCST), encapsulation efficiency, X-ray powder diffraction (XRPD), thermodynamic solubility, and biological stability. Additionally, in vitro CT release and CT permeability in nasal conditions were studied. Stability under storage was also evaluated. The optimized CT-PM formulation showed nanoscale micelle size (Z-average of 31.41 ± 0.99 nm), narrow size distribution (polydispersity index = 0.241), and a suitable thermal behavior for intranasal delivery (lower critical solution temperature (LCST) ~31 °C). Encapsulation efficiency reached approximately 90%, with an amorphous structure confirmed via XRPD, leading to a 95-fold increase in CT solubility. The formulation demonstrated appropriate biological and physical stability. In vitro studies showed a 25-fold faster CT release from optimized formulation compared to the initial CT, while CT-PM permeability in nasal conditions increased four-fold. This novel nanoscale thermosensitive formulation is a value-added strategy for nasal drug delivery systems, offering enhanced drug solubility, rapid drug release, stability, and improved permeability. This smart nanosystem represents a promising platform to overcome the limitations of conventional CT administration, improving therapeutic outcomes and patient compliance in depression management.