Université Paris-Saclay, CNRS, Institut Galien Paris-Saclay, 92296 Châtenay-Malabry, France.
Drug Product Development, Sanofi Research and Development, Montpellier, France.
Int J Pharm. 2022 Oct 15;626:122131. doi: 10.1016/j.ijpharm.2022.122131. Epub 2022 Aug 24.
A common approach to tackle the poor intestinal membrane permeability of peptides after oral administration is to formulate them with a permeation enhancer (PE). Increased oral bioavailability for oral peptide candidates has been reported from clinical trials when either salcaprozate sodium (SNAC) or sodium caprate (C) is incorporated in the formulation. However, little is known about how they physically interact with peptides in solution. Our objective was to compare the biophysical interactions between the GLP-1 analogue exenatide (Byetta®, Lilly), and C or SNAC using a variety of advanced analytical techniques. First, critical micelle concentration was measured in different buffers for both PEs. Dynamic light scattering (DLS) measurements revealed specific supramolecular structures arising from exenatide-PE association. Surface plasmon resonance (SPR) indicated the formation of exenatide-PE complexes with a high contribution from non-specific interactions and rapid binding kinetics, resulting in overall low affinities. DLS and isothermal titration calorimetry (ITC) were used to examine the supramolecular organization of the PEs, and revealed thermodynamic signatures characterized by unfavourable enthalpic contributions compensated by favourable entropic ones, but with low-affinity estimates in water (K in the 10-100 µM range). With affinity capillary electrophoresis (ACE), weak interactions between exenatide and SNAC or C were confirmed in saline, with a dissociation constant around 10 µM and 30 µM respectively. In biorelevant intestinal media, the bile salts in FaSSIF and FeSSIF further reduced the binding of both agents to exenatide (K ≈ 100 µM), indicating that the interaction between the PEs and exenatide might be inhibited by bile salts in the GI lumen. This study suggests that the interactions of both PEs with exenatide follow a similar non-covalent mechanism and are of low affinity.
一种常见的解决方法是将肽与渗透增强剂（PE）一起配制，以解决其口服后肠道通透性差的问题。临床试验报道，当将 SNAC 或 C 纳入配方中时，口服肽候选物的口服生物利用度会增加。然而，人们对它们在溶液中与肽的物理相互作用知之甚少。我们的目标是使用各种先进的分析技术比较 GLP-1 类似物 exenatide（Byetta®，礼来）与 C 或 SNAC 的生物物理相互作用。首先，在不同的缓冲液中测量了两种 PE 的临界胶束浓度。动态光散射（DLS）测量显示了 exenatide-PE 缔合产生的特定超分子结构。表面等离子体共振（SPR）表明形成了 exenatide-PE 复合物，其中非特异性相互作用的贡献很大，结合动力学很快，导致总体亲和力较低。DLS 和等温热力学滴定（ITC）用于研究 PE 的超分子组织，结果表明热力学特征由不利的焓贡献补偿，但在水中的亲和力较低（K 值在 10-100 µM 范围内）。通过亲和毛细管电泳（ACE），在盐水中证实了 exenatide 与 SNAC 或 C 之间的弱相互作用，解离常数分别约为 10 µM 和 30 µM。在生物相关的肠道介质中，FaSSIF 和 FeSSIF 中的胆汁盐进一步降低了两种试剂与 exenatide 的结合（K ≈ 100 µM），这表明 PE 与 exenatide 之间的相互作用可能被 GI 腔中的胆汁盐抑制。这项研究表明，两种 PE 与 exenatide 的相互作用遵循相似的非共价机制，亲和力较低。
