El-Setouhy Doaa Ahmed, Ibrahim A B, Amin Maha M, Khowessah Omneya M, Elzanfaly Eman S
Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt.
Labeled Compounds Department, Hot Labs Center, Atomic Energy Authority, P.O. Box 13759, Cairo, Egypt.
Eur J Pharm Sci. 2016 Sep 20;92:244-54. doi: 10.1016/j.ejps.2016.05.002. Epub 2016 May 3.
Haloperidol is a commonly prescribed antipsychotic drug currently administered as oral and injectable preparations. This study aimed to prepare haloperidol intranasal miniemulsion helpful for psychiatric emergencies and exhibiting lower systemic exposure and side effects associated with non-target site delivery. Haloperidol miniemulsions were successfully prepared by spontaneous emulsification adopting 2(3) factorial design. The effect of three independent variables at two levels each namely; oil type (Capmul®-Capryol™90), lipophilic emulsifier type (Span 20-Span 80) and HLB value (12-14) on globule size, PDI and percent locomotor activity inhibition in mice was evaluated. The optimized formula (F4, Capmul®, Tween 80/Span 20, HLB 14) showed globule size of 209.5±0.98nm, PDI of 0.402±0.03 and locomotor inhibition of 83.89±9.15% with desirability of 0.907. Biodistribution study following intranasal and intravenous administration of the radiolabeled (99m)Tc mucoadhesive F4 revealed that intranasal administration achieved 1.72-fold higher and 6 times faster peak brain levels compared with intravenous administration. Drug targeting efficiency percent and brain/blood exposure ratios remained above 100% and 1 respectively after intranasal instillation compared to a maximum brain/blood exposure ratio of 0.8 post intravenous route. Results suggested the CNS delivery of major fraction of haloperidol via direct transnasal to brain pathway that can be a promising alternative to oral and parenteral routes in chronic and acute situations. Haloperidol concentration of 275.6ng/g brain 8h post intranasal instillation, higher than therapeutic concentration range of haloperidol (0.8 to 5.15ng/ml), suggests possible sustained delivery of the drug through nasal route.
氟哌啶醇是一种常用的抗精神病药物，目前有口服和注射制剂。本研究旨在制备有助于治疗精神科急症的氟哌啶醇鼻内微乳剂，该微乳剂具有较低的全身暴露量以及与非靶部位给药相关的副作用。采用2(3)析因设计通过自发乳化成功制备了氟哌啶醇微乳剂。评估了三个自变量（每个自变量有两个水平），即油相类型（Capmul®-Capryol™90）、亲脂性乳化剂类型（司盘20-司盘80）和HLB值（12-14）对小鼠体内微球大小、多分散指数（PDI）和运动活性抑制百分比的影响。优化配方（F4，Capmul®，吐温80/司盘20，HLB 14）的微球大小为209.5±0.98nm，PDI为0.402±0.03，运动抑制率为83.89±9.15%，可取性为0.907。对放射性标记的（99m）Tc黏膜黏附性F4进行鼻内和静脉给药后的生物分布研究表明，与静脉给药相比，鼻内给药的脑内峰值水平高1.72倍且快6倍。与静脉给药后最大脑/血暴露比0.8相比，鼻内滴注后药物靶向效率百分比和脑/血暴露比分别保持在100%以上和1以上。结果表明，氟哌啶醇的主要部分通过直接经鼻至脑途径递送至中枢神经系统，这在慢性和急性情况下可能是口服和胃肠外给药途径的一个有前景的替代方法。鼻内滴注8小时后，脑内氟哌啶醇浓度为275.6ng/g，高于氟哌啶醇的治疗浓度范围（0.8至5.15ng/ml），表明该药物可能通过鼻腔途径持续给药。
