School of Pharmaceutical Sciences, Jaipur National University, Jaipur 302017, Rajasthan, India; Department of Pharmaceutics, STES's Sinhgad Institute of Pharmacy (Affiliated to Savitribai Phule Pune University), Narhe, Pune 411041, Maharashtra, India.
Department of Pharmaceutics, STES's Sinhgad Institute of Pharmacy (Affiliated to Savitribai Phule Pune University), Narhe, Pune 411041, Maharashtra, India.
Int J Pharm. 2020 Aug 30;586:119499. doi: 10.1016/j.ijpharm.2020.119499. Epub 2020 Jun 4.
The tight junctions between capillary endothelial cells of the blood-brain barrier (BBB) restricts the entry of therapeutics into the brain. Potential of the intranasal delivery tool has been explored in administering the therapeutics directly to the brain, thus bypassing BBB. The objective of this study was to develop and optimize an intranasal mucoadhesive nanoemulsion (MNE) of asenapine maleate (ASP) in order to enhance the nasomucosal adhesion and direct brain targetability for improved efficacy and safety. Box-Behnken statistical design was used to recognize the crucial formulation variables influencing droplet size, size distribution and surface charge of ASP-NE. ASP-MNE was obtained by incorporating GRAS mucoadhesive polymer, Carbopol 971 in the optimized NE. Optimized ASP-MNE displayed spherical morphology with a droplet size of 21.2 ± 0.15 nm and 0.355 polydispersity index. Improved ex-vivo permeation was observed in ASP-NE and ASP-MNE, compared to the ASP-solution. Finally, the optimized formulation was found to be safe in ex-vivo ciliotoxicity study on sheep nasal mucosa. The single-dose pharmacokinetic study in male Wistar rats revealed a significant increase in concentration of ASP in the brain upon intranasal administration of ASP-MNE, with a maximum of 284.33 ± 5.5 ng/mL. The time required to reach maximum brain concentration (1 h) was reduced compared to intravenous administration of ASP-NE (3 h). Furthermore, it has been established during the course of present study, that the brain targeting capability of ASP via intranasal administration had enhanced drug-targeting efficiency and drug-targeting potential. In the animal behavioral studies, no extrapyramidal symptoms were observed after intranasal administration of ASP-MNE, while good locomotor activity and hind-limb retraction test established its antipsychotic activity in treated animals. Thus, it can be concluded that the developed intranasal ASP-MNE could be used as an effective and safe tool for brain targeting of ASP in the treatment of psychotic disorders.
血脑屏障（BBB）的毛细血管内皮细胞之间的紧密连接限制了治疗药物进入大脑。鼻内给药工具的潜力已在将治疗药物直接递送到大脑中得到探索，从而绕过 BBB。本研究的目的是开发和优化马来酸阿塞那平的鼻内粘膜粘附纳米乳（MNE），以增强鼻腔粘膜粘附性和直接靶向大脑的能力，从而提高疗效和安全性。Box-Behnken 统计设计用于识别影响 ASP-NE 粒径、粒径分布和表面电荷的关键制剂变量。通过将 GRAS 粘膜粘附聚合物 Carbopol 971 纳入优化的 NE 中，获得了 ASP-MNE。优化的 ASP-MNE 显示出球形形态，粒径为 21.2±0.15nm，多分散指数为 0.355。与 ASP 溶液相比，ASP-NE 和 ASP-MNE 的体外渗透得到了改善。最后，在绵羊鼻黏膜的体外纤毛毒性研究中发现优化的配方是安全的。雄性 Wistar 大鼠的单剂量药代动力学研究表明，ASP-MNE 经鼻给药后，ASP 在大脑中的浓度显著增加，最大浓度为 284.33±5.5ng/mL。与 ASP-NE 静脉给药（3h）相比，达到最大脑浓度（1h）所需的时间减少了。此外，在本研究过程中已经确定，通过鼻内给药，ASP 的脑靶向能力增强了药物靶向效率和药物靶向潜力。在动物行为研究中，经鼻给予 ASP-MNE 后未观察到锥体外系症状，而良好的运动活动和后肢退缩试验确立了其在治疗动物中的抗精神病活性。因此，可以得出结论，开发的鼻内 ASP-MNE 可作为治疗精神障碍时 ASP 脑靶向的有效和安全工具。
