V Tamizmaran, Mannur V S, Koli Rahul, Biradar Prakash
Department of Pharmaceutical Quality Assurance, KLE College of Pharmacy Belagavi, KLE Academy of Higher Education and Research, Nehru Nagar, 590010 Belagavi, Karnataka, India.
Department of Pharmacology, KLE College of Pharmacy Belagavi, KLE Academy of Higher Education and Research, Nehru Nagar, 590010 Belagavi, Karnataka, India.
Mol Pharm. 2025 Jul 7;22(7):4293-4313. doi: 10.1021/acs.molpharmaceut.5c00584. Epub 2025 Jun 23.
Schizophrenia, a complex neuropsychiatric disorder originating in the central nervous system, poses significant therapeutic challenges primarily due to the restrictive nature of the blood-brain barrier (BBB). In this study, a fisetin-loaded mucoadhesive microemulsion (fisetin-MME) was successfully developed and optimized via Box-Behnken Design (BBD) to enhance the solubility and brain-targeting potential of fisetin following intranasal administration. The optimized formulation exhibited a mean droplet size of 64.0 nm ± 0.05, a polydispersity index (PDI) of <0.5, and high entrapment efficiency (94.9%), alongside favorable thermodynamic stability, rheological characteristics, and mucoadhesive strength (3.24 ± 0.95 g). Physicochemical characterization by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier-transform infrared spectroscopy (FT-IR), and transmission electron microscopy (TEM) confirmed the structural integrity and compatibility of the formulation. A validated reverse-phase high-performance liquid chromatography (RP-HPLC) method consistently quantified fisetin with a retention time of 6.01 ± 0.23 min. The fisetin-MME demonstrated enhanced release (85.2 ± 2.345%) and nasal mucosal permeation (87.6 ± 0.25%), with significantly improved flux (40.23 ± 0.06 μg/cm/h) and permeability coefficient (81.23 × 10 cm/s), indicating efficient transmucosal transport. Pharmacokinetic evaluation revealed a marked improvement in both systemic and brain bioavailability following intranasal administration, with a brain C_max of 261.53 ± 0.14 ng/g and AUC-t of 2564.0 ± 232.0 h·ng/g, surpassing the reference standard (C_max of 228.50 ± 0.36 ng/g; AUC-t of 2257.6 ± 245.9 h·ng/g). Behavioral assessments, including the Forced Swim Test and Balance Beam Test, demonstrated significant amelioration of schizophrenia-like symptoms, including hyperlocomotion, catalepsy, and impaired motor coordination, with fisetin-MME showing superior neuroprotective and antidepressant effects compared to the standard drug by Day 14 ( < 0.001). Histopathological analysis further supported these findings, demonstrating marked neuroprotective effects in the cortical and hippocampal regions, as evidenced by reduced neuronal degeneration and attenuation of neuroinflammatory markers. These results highlight the potential of intranasally delivered fisetin-MME as a promising nanotherapeutic strategy for the management of schizophrenia.
精神分裂症是一种起源于中枢神经系统的复杂神经精神疾病，主要由于血脑屏障（BBB）的限制性，给治疗带来了重大挑战。在本研究中，通过Box-Behnken设计（BBD）成功开发并优化了一种载有非瑟酮的粘膜粘附微乳剂（非瑟酮-MME），以提高非瑟酮经鼻给药后的溶解度和脑靶向潜力。优化后的制剂平均液滴尺寸为64.0 nm±0.05，多分散指数（PDI）<0.5，包封率高（94.9%），同时具有良好的热力学稳定性、流变学特性和粘膜粘附强度（3.24±0.95 g）。通过差示扫描量热法（DSC）、热重分析（TGA）、傅里叶变换红外光谱（FT-IR）和透射电子显微镜（TEM）进行的物理化学表征证实了制剂的结构完整性和相容性。一种经过验证的反相高效液相色谱（RP-HPLC）方法能够持续定量非瑟酮，保留时间为6.01±0.23分钟。非瑟酮-MME表现出增强的释放（85.2±2.345%）和鼻粘膜渗透（87.6±0.25%），通量（40.23±0.06 μg/cm/h）和渗透系数（81.23×10 cm/s）显著提高，表明粘膜转运效率高。药代动力学评估显示，经鼻给药后全身和脑生物利用度均有显著改善，脑C_max为261.53±0.14 ng/g，AUC-t为2564.0±232.0 h·ng/g，超过参考标准（C_max为228.50±0.36 ng/g；AUC-t为2257.6±245.9 h·ng/g）。包括强迫游泳试验和平衡木试验在内的行为评估表明，精神分裂症样症状显著改善，包括活动亢进、僵住和运动协调受损，到第14天，非瑟酮-MME与标准药物相比显示出卓越的神经保护和抗抑郁作用（<0.001）。组织病理学分析进一步支持了这些发现，显示在皮质和海马区域有显著的神经保护作用，神经元变性减少和神经炎症标志物减弱证明了这一点。这些结果突出了经鼻给药的非瑟酮-MME作为一种有前途的纳米治疗策略用于精神分裂症管理的潜力。
