Abstract：
The purpose of our research is to develop functional additives that enhance mucosal absorption of biologics, such as peptide/protein and antibody drugs, to provide their non-to-poor invasive dosage forms self-managed by patients. Our previous in vivo and in vitro studies demonstrated that the intranasal absorption of biologics in mice was significantly improved when coadministered with oligoarginines anchored chemically to hyaluronic acid via a glycine spacer, presumably through syndecan-4-mediated macropinocytosis under activation by oligoarginines. The present mouse experiments first revealed that diglycine-L-tetraarginine-linked hyaluronic acid significantly enhanced the intranasal absorption of sulpiride, which is a poor-absorptive organic compound with a low molecular weight. However, similar enhancement was not observed for levofloxacin, which has a similarly low molecular weight but is a well-absorptive organic compound, probably because its absorption was mostly dominated by passive diffusion. The subsequent monkey experiments revealed that there was no species difference in the absorption-enhancing ability of diglycine-L-tetraarginine-linked hyaluronic acid for not only organic compounds but also biologics. This was presumably because the expression levels of endocytosis-associated membrane proteins on the nasal mucosa in monkeys were almost equivalent to those in mice, and poorly membrane-permeable/membrane-impermeable drugs were mainly absorbed via syndecan-4-mediated macropinocytosis, regardless of animal species. Drug concentrations in the brain assessed in mice and monkeys and those in the cerebral spinal fluids (CSFs) assessed in monkeys indicated that drugs would be delivered from the systemic circulation to the central nervous system by crossing the blood-brain and the blood-CSF barriers under coadministration with the hyaluronic acid derivative. In line with our original hypothesis, this new set of data supported that our oligoarginine-linked hyaluronic acid would locally perform on the mucosal surface and enhance the membrane permeation of drugs under its colocalization.
摘要：
我们研究的目的是开发能增强生物制品粘膜吸收的功能性添加剂，如肽/蛋白质和抗体药物，提供患者自我管理的非不良侵入性剂型。我们先前的体内和体外研究表明，当通过甘氨酸间隔基与化学锚定透明质酸的寡精氨酸共同给药时，小鼠中生物制剂的鼻内吸收显着改善。推测是通过寡核苷酸精氨酸激活下的syndecan-4介导的巨细胞增多作用。本小鼠实验首次揭示二甘氨酸-L-四精氨酸连接的透明质酸显著增强舒必利的鼻内吸收,这是一种低分子量的低吸收性有机化合物。然而,左氧氟沙星没有观察到类似的增强，它具有类似的低分子量，但是一种吸收良好的有机化合物，可能是因为它的吸收主要由被动扩散主导。随后的猴子实验表明，二甘氨酸-L-四精氨酸连接的透明质酸不仅对有机化合物而且对生物制剂的吸收增强能力没有物种差异。据推测，这是因为猴子鼻粘膜内吞作用相关膜蛋白的表达水平几乎与小鼠相当，膜通透性差/膜不透性差的药物主要通过syndecan-4介导的大胞吞作用吸收，无论动物种类。在小鼠和猴子中评估的脑中的药物浓度以及在猴子中评估的脑脊髓液(CSF)中的药物浓度表明,在与透明质酸衍生物共同施用的情况下,药物将通过穿过血脑和血CSF屏障而从全身循环递送至中枢神经系统。根据我们最初的假设，这组新的数据支持我们的寡精氨酸连接的透明质酸将在粘膜表面局部发挥作用,并在其共定位下增强药物的膜渗透.
