Glyceryl behenate-based solid lipid nanoparticles as a carrier of haloperidol for nose to brain delivery: formulation development, in-vitro, and in-vivo evaluation

Abstract This study was aimed to develop the haloperidol (HPL) loaded solid lipid nanoparticles (SLNs) for brain targeting through the intranasal route. SLNs were fabricated by the emulsification diffusion technique using glyceryl behenate as lipid and tween 80 as a surfactant. SLNs were evaluated for particle size, zeta potential, structure, entrapment efficiency, solid state characterization by differential scanning calorimetry (DSC), and in-vitro release. In-vivo biological evaluation was performed on albino Wistar rats for the determination of pharmacokinetic as well as brain targeting parameters. Particle size, PDI, zeta potential, and entrapment efficiency of optimized formulation (HPL-SLNs 6) were found to be 103±09 nm, 0.190±0.029, -23.5±1.07 mV, and 79.46±1.97% respectively. In-vitro drug release studies exhibited that 87.21± 3.63% of the entrapped drug was released from the SLNs within 24 h. DSC curves confirmed that during entrapment in SLNs, the drug was solubilized in the lipid matrix and converted into the amorphous form. Enhanced HPL targeting to the brain was observed from HPL-SLNs as compared to HPL-Sol when administered intranasally. The value of AUC 0-∞ in the brain for HPL-SLNs i.n. was found to be nearly 2.7 times higher than that of HPL-Sol i.v., whereas 3.66 times superior to HPL-Sol administered i.n. Stability studies revealed that the formulation remains unchanged when stored at 4±2 °C (refrigerator) and 25±2 °C /60 ±5% RH up to six months. Finally, it could be concluded that SLN is a suitable carrier for HPL with enhanced brain targeting through i.n administration, as compared to the HPL-Sol, administered i.n. and i.v.

摘要 本研究旨在开发经鼻内给药途径实现脑靶向的载氟哌啶醇（haloperidol, HPL）固体脂质纳米粒（solid lipid nanoparticles, SLNs）。采用乳化扩散法制备SLNs，以山嵛酸甘油酯作为脂质载体，吐温80作为表面活性剂。对所制备的SLNs开展多项表征分析：包括粒径、Zeta电位（zeta potential）、微观结构、包封率（entrapment efficiency），采用差示扫描量热法（differential scanning calorimetry, DSC）进行固态表征，以及体外释放（in-vitro release）试验。
以白化Wistar大鼠（albino Wistar rats）为实验对象完成体内生物学评价（in-vivo biological evaluation），以测定药代动力学（pharmacokinetic）参数及脑靶向相关指标。结果显示，优化处方（HPL-SLNs 6）的粒径、多分散性指数（polydispersity index, PDI）、Zeta电位及包封率分别为103±09 nm、0.190±0.029、-23.5±1.07 mV及79.46±1.97%。
体外药物释放研究表明，24小时内SLNs可释放包封药物的87.21±3.63%。差示扫描量热法曲线证实，药物被包封进入SLNs后，可溶解于脂质基质中并转变为无定形态。与鼻内给药（intranasal, i.n.）的氟哌啶醇溶液（HPL-Sol）相比，鼻内给药的HPL-SLNs可实现更优异的脑靶向递送效果。
HPL-SLNs经鼻内给药后，脑内的AUC₀-∞（血药浓度-时间曲线下面积0至无穷大）约为HPL溶液静脉给药（intravenous, i.v.）组的2.7倍，较鼻内给药的HPL溶液组高出3.66倍。稳定性研究结果显示，该处方在4±2 ℃（冷藏）及25±2 ℃/60±5%相对湿度条件下储存6个月，各项性质无明显变化。
综上，相较于经鼻内及静脉给药的HPL溶液，SLNs作为HPL的递送载体，可通过鼻内给药途径实现更优异的脑靶向递送效果，是一种合适的药物载体。