Rajab Fatima, Sipos Bence, Katona Gábor, Csóka Ildikó
Institute of Pharmaceutical Technology and Regulatory Affairs, University of Szeged, Eötvös Street 6, H-6720 Szeged, Hungary.
Pharmaceutics. 2025 Sep 1;17(9):1147. doi: 10.3390/pharmaceutics17091147.
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.
鼻内给药途径是一种很有前景的脑靶向非侵入性方法，可绕过血脑屏障并提高生物利用度。氢溴酸西酞普兰（CT）是一种广泛使用的微溶于水的选择性 5-羟色胺再摄取抑制剂（SSRI），口服和静脉给药面临挑战，包括起效延迟、副作用和患者依从性问题。本研究旨在基于普朗尼克共聚物（普朗尼克 F127 和泊洛沙姆 188）开发一种新型热响应性聚合物胶束（PM）系统，以提高 CT 的溶解度、稳定性和鼻通透性，增强抗抑郁疗效。进行了一项初步研究以选择优化的制剂。制备过程包括采用薄膜水化法，然后进行冷冻干燥。对优化制剂特性的综合评估包括 Z 平均粒径、多分散指数（PdI）、热行为（低临界溶液温度，LCST）、包封率、X 射线粉末衍射（XRPD）、热力学溶解度和生物稳定性。此外，还研究了体外 CT 在鼻腔条件下的释放和 CT 通透性。还评估了储存稳定性。优化后的 CT-PM 制剂显示出纳米级胶束尺寸（Z 平均粒径为 31.41±0.99nm）、窄尺寸分布（多分散指数 = 0.241）以及适合鼻内给药的热行为（低临界溶液温度（LCST）约为 31°C）。包封率达到约 90%，通过 XRPD 确认具有无定形结构，导致 CT 溶解度提高了 95 倍。该制剂表现出适当的生物学和物理稳定性。体外研究表明，与初始 CT 相比，优化制剂中 CT 的释放速度快 25 倍，而 CT-PM 在鼻腔条件下的通透性提高了四倍。这种新型纳米级热敏制剂是鼻内给药系统的一种增值策略，具有增强的药物溶解度、快速的药物释放、稳定性和改善的通透性。这种智能纳米系统是一个有前途的平台，可克服传统 CT 给药的局限性，改善抑郁症治疗的疗效和患者依从性。
