PDF(Pubmed)
Abstract：
Nose-to-brain delivery (NTBD) offering potential benefits for treating Alzheimer\'s disease. In previous research, insulin dry powder (IDP) formulation for NTBD was developed, exhibiting favorable stability. This study aims to conduct in vitro and ex vivo assessment of release, permeation, mucoadhesion and histopathology, as well as an in vivo biodistribution study to produce IDP for NTBD and evaluate brain biodistribution. Spray-freeze-dried IDP formulations with varying weight ratios of trehalose-to-inulin were produced and analyzed. The release study was carried out in PBS with a pH of 5.8 stirred at 50 rpm and maintained at 37 °C ± 0.5 °C. Goat nasal mucosa was used for ex vivo permeation and mucoadhesion testing under similar conditions. An ex vivo histopathological examination and an in vivo study using enzyme-linked immunosorbent assay, were also performed. The IDP dissolution study demonstrated complete release of all IDPs within 120 min. The permeation study indicated that steady-state conditions were observed between 30 and 240 min. The mucoadhesion study unveiled that IDP F5 exhibited the fastest mucoadhesion time and the least force required within the fastest time of 43.60 ± 2.57 s. The histopathological study confirmed that none of the tested IDPs induced irritation in the nasal mucosa. Furthermore, the biodistribution study demonstrated the absence of detectable insulin in the plasma, while IDP F3 exhibited the highest deposited concentration of insulin within both the olfactory bulb and the whole brain. The extensive evaluation of the IDP formulations through in vitro, ex vivo, and in vivo studies implies their strength non-invasive NTBD. IDP F3, with a 1:1 wt ratio of trehalose to inulin, exhibited favorable brain biodistribution outcomes and was recommended for further investigation and development in the context of NTBD.
摘要：
鼻脑给药（NTBD）为治疗阿尔茨海默病提供了潜在的益处。在以前的研究中，开发了用于NTBD的胰岛素干粉（IDP）配方，表现出良好的稳定性。本研究旨在进行体外和离体释放评估，渗透，粘膜粘连和组织病理学，以及体内生物分布研究，以产生NTBD的IDP并评估脑生物分布。制备并分析了具有不同重量比的海藻糖与菊粉的喷雾干燥的IDP制剂。在pH为5.8的PBS中以50rpm搅拌并保持在37°C±0.5°C下进行释放研究。山羊鼻粘膜在类似条件下用于离体渗透和粘膜粘附测试。离体组织病理学检查和使用酶联免疫吸附测定的体内研究，也表演了。IDP溶出研究表明所有IDP在120分钟内完全释放。渗透研究表明，在30至240分钟之间观察到稳态条件。粘膜粘附研究揭示了IDPF5表现出最快的粘膜粘附时间和在43.60±2.57s的最快时间内所需的最小力。组织病理学研究证实，没有测试的IDP在鼻粘膜中引起刺激。此外，生物分布研究表明，血浆中不存在可检测的胰岛素，而IDPF3在嗅球和整个大脑中均表现出最高的胰岛素沉积浓度。通过体外对IDP制剂进行广泛评估，离体,和体内研究暗示他们的强度非侵入性NTBD。IDPF3，海藻糖与菊粉的重量比为1:1，表现出良好的脑生物分布结果，建议在NTBD的背景下进行进一步研究和开发。
