Oral delivery of peptides requires formulations with high concentrations of permeation enhancer (PE) to promote absorption, and often necessitates fasting time between dosing and food ingestion. Improved formulations promoting a more rapid absorption would increase convenience of use but requires a faster onset of action. We have developed a salcaprozate-based ionic liquid (IL) formulation, namely choline salcaprozate (CHONAC), for oral delivery of a glucagon-like peptide-1 (GLP-1) analogue via gastric absorption. In vitro studies confirmed the higher amount of PE accommodated in the same volume of dosage form as well as faster release of the active pharmaceutical ingredient (API) and PE compared to the tablet reference. Storage stability of the CHONAC formulation was demonstrated for up to 3 weeks at 4 °C. The peptide absorption efficacy of the IL formulation was first evaluated in vivo in rats and anesthetized dogs, showing a faster absorption compared to the reference formulations. In awake dogs, while the CHONAC formulation still enabled earlier API absorption, its overall exposure was inferior to the tablet reference. This was attributed mostly to the gastric physiology, causing formulation dilution in the presence of additional fluid as well as fast transit of liquids into the duodenum, where peptides liable to proteolytic degradation such as the one used in this study showed a negligible absorption, potentially also due to a lower permeation-enhancing capability of CHONAC in the duodenal region. Exploring these issues, an in vivo study in anesthetized dogs involving repeated dosing of a liquid salcaprozate-based formulation in the stomach revealed the potential to sustain peptide absorption throughout the dosing period with a constant absorption rate. In conclusion, combining the advantages of high PE amounts and fast onset of action provided by the IL formulation, and ensuring a prolonged interaction of peptide and PE at a relevant concentration with the stomach epithelium, are necessary to enhance oral peptide bioavailability via gastric delivery.

中文翻译：

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用于 GLP-1 胃输送的基于沙卡百氮酯的离子液体：体内性能的机制理解


口服肽需要具有高浓度渗透增强剂 （PE） 的制剂以促进吸收，并且通常需要在给药和食物摄入之间禁食。促进更快吸收的改进配方将增加使用的便利性，但需要更快的起效。我们开发了一种基于沙丙酸盐的离子液体 （IL） 制剂，即沙丙酸盐胆碱 （CHONAC），用于通过胃吸收口服胰高血糖素样肽-1 （GLP-1） 类似物。体外研究证实，与片剂参考相比，相同体积的剂型可容纳的 PE 量更高，活性药物成分 （API） 和 PE 的释放速度更快。CHONAC 制剂在 4 °C 下可储存长达 3 周。 IL 制剂的肽吸收功效首先在大鼠和麻醉狗体内进行评估，与参考制剂相比，吸收更快。在清醒的狗中，虽然 CHONAC 制剂仍然能够早期 API 吸收，但其总体暴露量不如片剂参考。这主要归因于胃生理学，在存在额外液体的情况下导致制剂稀释以及液体快速转运到十二指肠，其中易发生蛋白水解降解的肽（例如本研究中使用的肽）显示出可忽略不计的吸收，也可能是由于 CHONAC 在十二指肠区域的渗透增强能力较低。探讨这些问题，一项在麻醉狗中进行的体内研究涉及在胃中重复服用基于沙卡百氮酸盐的液体制剂，揭示了在整个给药期间以恒定吸收速率维持肽吸收的潜力。 总之，结合 IL 制剂提供的高 PE 量和快速起效的优势，并确保相关浓度的肽和 PE 与胃上皮细胞长时间相互作用，对于通过胃输送提高口服肽的生物利用度是必要的。