Choudhary Ashok J, Mahajan Sakshi S, Majumdar Anuradha S
Department of Pharmacology, Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai, India.
Neurosci Appl. 2024 Mar 27;3:104062. doi: 10.1016/j.nsa.2024.104062. eCollection 2024.
Flurbiprofen, a non-steroidal anti-inflammatory drug (NSAID), has selective amyloid-lowering characteristics and can be utilized for Alzheimer's disease treatment. Oral flurbiprofen has poor brain bioavailability and high dose-related gastrointestinal adverse effects. To overcome these issues, the study aimed to formulate intranasal flurbiprofen solid lipid nanoparticles (SLN) based thermosensitive gel. SLN were formulated by the High-speed homogenization method. A 2 factorial design technique was utilized for optimization, wherein the influence of two independent variables, critical process parameters (X = surfactant concentration, X = D:L ratio) on critical quality attributes (Y = particle size, Y=Percent Drug Loading, Y=Percent Entrapment Efficiency) was ascertained at three distinct levels. The optimized SLN were then prepared into an SLN-based intranasal thermosensitive gel with Poloxamer 188 P (1.2% w/v) and Poloxamer 407 P (18% w/v). The flurbiprofen release study demonstrated a 100% release of flurbiprofen from the SLN-based thermosensitive gel at 6 h. The flurbiprofen release study revealed a complete release of flurbiprofen from the SLN-based thermosensitive gel at 8 h. In the tests, the gel (2 mg/kg) administered intranasally in rats demonstrated nearly three times greater brain bioavailability (C = 490.3 ng/ml) than the oral marketed formulation of flurbiprofen, Ansaid® (10 mg/kg) (C = 145.1 ng/ml). The plasma concentration obtained with intranasal gel (C = 2.5 μg/ml) was lower than the oral marketed formulation (C = 3.4 μg/ml). The time necessary to establish the maximal flurbiprofen concentration (T) in the brain was 2 and 0.5 h for oral and intranasal formulations, respectively. Hence, the intranasal formulation could achieve maximal drug concentration in the brain in less time. Thus, flurbiprofen SLN-based thermosensitive gel can be a potential encouraging safe, non-invasive, and efficacious replacement to oral formulations for achieving direct brain targeting through nose-to-brain drug delivery, thereby treating neuroinflammatory conditions like Alzheimer's disease.
氟比洛芬是一种非甾体抗炎药（NSAID），具有选择性降低淀粉样蛋白的特性，可用于治疗阿尔茨海默病。口服氟比洛芬的脑生物利用度差，且有高剂量相关的胃肠道不良反应。为克服这些问题，本研究旨在制备基于鼻用氟比洛芬固体脂质纳米粒（SLN）的热敏凝胶。SLN采用高速匀化法制备。采用二因素设计技术进行优化，确定了两个独立变量，即关键工艺参数（X1 =表面活性剂浓度，X2 = D:L比）在三个不同水平对关键质量属性（Y1 =粒径，Y2 =载药量百分比，Y3 =包封率百分比）的影响。然后将优化后的SLN与泊洛沙姆188 P（1.2% w/v）和泊洛沙姆407 P（18% w/v）制成基于SLN的鼻用热敏凝胶。氟比洛芬释放研究表明，基于SLN的热敏凝胶在6小时时氟比洛芬释放率为100%。氟比洛芬释放研究显示，基于SLN的热敏凝胶在8小时时氟比洛芬完全释放。在试验中，给大鼠鼻内给药凝胶（2 mg/kg）的脑生物利用度（Cmax = 490.3 ng/ml）比口服市售氟比洛芬制剂安赛德®（10 mg/kg）（Cmax = 145.1 ng/ml）高近三倍。鼻内凝胶的血浆浓度（Cmax = 2.5 μg/ml）低于口服市售制剂（Cmax = 3.4 μg/ml）。口服和鼻内制剂在脑中达到最大氟比洛芬浓度（Tmax）所需时间分别为2小时和0.5小时。因此，鼻内制剂可在更短时间内在脑中达到最大药物浓度。因此，基于氟比洛芬SLN的热敏凝胶可能是一种有潜力的、令人鼓舞的安全、无创且有效的替代口服制剂，通过鼻脑给药实现直接脑靶向，从而治疗如阿尔茨海默病等神经炎症性疾病。
