Biotechnology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA.
Synthetic Molecule Design and Development, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA.
Pharm Res. 2022 Oct;39(10):2555-2567. doi: 10.1007/s11095-022-03372-1. Epub 2022 Sep 1.
Oral delivery of therapeutic peptides has been challenging due to multiple physiological factors and physicochemical properties of peptides. We report a systematic approach to identify formulation compositions combining a permeation enhancer and a peptidase inhibitor that minimize proteolytic degradation and increase absorption of a peptide across the small intestine.
An acylated glucagon-like peptide-1/glucagon co-agonist peptide (4.5 kDa) was selected as a model peptide. Proteolytic stability of the peptide was investigated in rat and pig SIF. Effective PEs and multiple component formulations were identified in rats. Relative bioavailability of the peptide was determined in minipigs via intraduodenal administration (ID) of enteric capsules.
The peptide degraded rapidly in the rat and pig SIF. Citric acid, SBTI, and SBTCI inhibited the enzymatic degradation. The peptide self-associated into trimers in solution, however, addition of PEs monomerized the peptide. C10 was the most effective PE among tested PEs (DPC, LC, rhamnolipid, C12-maltosides, and SNAC) to improve intestinal absorption of the peptide in the rat IJ-closed loop model. A combination of C10 and SBTI or SBTCI increased the peptide exposure 5-tenfold compared to the exposure with the PE alone in the rat IJ-cannulated model, and achieved 1.06 ± 0.76% bioavailability in minipigs relative to subcutaneous via ID administration using enteric capsules.
We identified SBTI and C10 as an effective peptidase inhibitor and PE for intestinal absorption of the peptide. The combination of SBTI and C10 addressed the peptide physiochemical properties and provides a formulation strategy to achieve intestinal delivery of this peptide.
由于多种生理因素和肽的物理化学性质，治疗性肽的口服递送一直具有挑战性。我们报告了一种系统的方法来确定制剂成分，将渗透增强剂和肽酶抑制剂结合在一起，最大限度地减少肽的蛋白水解降解并增加肽在小肠中的吸收。
选择酰化胰高血糖素样肽-1/胰高血糖素共激动肽（4.5 kDa）作为模型肽。在大鼠和猪 SIF 中研究了肽的蛋白水解稳定性。在大鼠中确定了有效的 PE 和多种成分制剂。通过十二指肠内给药（ID）肠溶胶囊在小型猪中确定了肽的相对生物利用度。
肽在大鼠和猪 SIF 中迅速降解。柠檬酸、SBTI 和 SBTCI 抑制了酶促降解。肽在溶液中自缔合形成三聚体，然而，PE 的添加使肽单体化。在测试的 PE 中（DPC、LC、鼠李糖脂、C12-麦芽糖和 SNAC），C10 是最有效的 PE，可提高肽在大鼠 IJ 闭环模型中的肠道吸收。与 PE 单独使用相比，C10 与 SBTI 或 SBTCI 的组合使肽暴露增加了 5 到 10 倍，并且在使用肠溶胶囊通过 ID 给药时，相对于皮下给药，在小型猪中实现了 1.06±0.76%的生物利用度。
我们确定 SBTI 和 C10 是有效的肽酶抑制剂和 PE，可促进肽的肠道吸收。SBTI 和 C10 的组合解决了肽的物理化学性质，并提供了一种制剂策略，以实现该肽的肠道递送。
