The use of chemical permeation enhancers (PEs) is the most widely tested approach to improve oral absorption of low permeability active agents, as represented by peptides. Several hundred PEs increase intestinal permeability in preclinical bioassays, yet few have progressed to clinical testing and, of those, only incremental increases in oral bioavailability (BA) have been observed. Still, average BA values of ~1% were sufficient for two recent FDA approvals of semaglutide and octreotide oral formulations. PEs are typically screened in static in vitro and ex-vivo models where co-presentation of active agent and PE in high concentrations allows the PE to alter barrier integrity with sufficient contact time to promote flux across the intestinal epithelium. The capacity to maintain high concentrations of co-presented agents at the epithelium is not reached by standard oral dosage forms in the upper GI tract in vivo due to dilution, interference from luminal components, fast intestinal transit, and possible absorption of the PE per se. The PE-based formulations that have been assessed in clinical trials in either immediate-release or enteric-coated solid dosage forms produce low and variable oral BA due to these uncontrollable physiological factors. For PEs to appreciably increase intestinal permeability from oral dosage forms in vivo, strategies must facilitate co-presentation of PE and active agent at the epithelium for a sustained period at the required concentrations. Focusing on peptides as examples of a macromolecule class, we review physiological impediments to optimal luminal presentation, discuss the efficacy of current PE-based oral dosage forms, and suggest strategies that might be used to improve them.

使用化学渗透促进剂 (PE) 是最广泛测试的方法，以改善以肽为代表的低渗透活性剂的口服吸收。数百个 PE 在临床前生物测定中增加肠道通透性，但很少有进展到临床测试，其中仅观察到口服生物利用度 (BA) 的增量增加。尽管如此，约 1% 的平均 BA 值足以满足 FDA 最近批准的两项索马鲁肽和奥曲肽口服制剂的要求。PE通常在体外和离体静态筛选在模型中，高浓度的活性剂和 PE 共同存在允许 PE 在足够的接触时间下改变屏障完整性，以促进穿过肠上皮的通量。由于稀释、来自管腔成分的干扰、快速的肠道转运和 PE本身的可能吸收，标准口服剂型在上消化道体内未达到在上皮维持高浓度共呈递药物的能力. 由于这些不可控的生理因素，已在临床试验中评估的速释或肠溶衣固体剂型中基于 PE 的制剂产生低且可变的口服 BA。让 PE 显着增加口服剂型的肠道通透性在体内，策略必须促进 PE 和活性剂在所需浓度的持续时间内在上皮共同呈递。以肽作为大分子类的例子，我们回顾了优化管腔呈现的生理障碍，讨论了当前基于 PE 的口服剂型的功效，并提出了可用于改进它们的策略。