School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.
Jiangsu Hengrui Pharmaceuticals Co., Ltd., Lianyungang, 222000, People's Republic of China.
Pharm Res. 2022 Aug;39(8):1891-1906. doi: 10.1007/s11095-022-03265-3. Epub 2022 Jun 13.
Semaglutide is the only oral GLP-1 RA in the market, but oral bioavailability is generally limited in range of 0.4-1%. In this study, a new GLP-1RA named SHR-2042 was developed to gain higher oral bioavailability than semaglutide.
Self-association of SHR-2042, semaglutide and liraglutide were assessed using SEC-MALS. The intestinal perfusion test in SD rats was used to select permeation enhancers (PEs) including SNAC, C10 and LCC. ITC, CD and DLS were used to explore the interaction between SHR-2042 and SNAC. Gastric administrated test in SD rats was used to screen SHR-2042 granules with different SHR-2042/SNAC ratios. The oral bioavailability of SHR-2042 was studied in rats and monkeys.
The designed GLP-1RA, SHR-2042, gives a better solubility and lipophilicity than semaglutide. While it forms a similar oligomer with that of semaglutide. During the selection of PEs, SNAC shows better exposure than the other competing PEs including C10 and LCC. SHR-2042 and SNAC bind quickly and exhibit hydrophobic interaction. SNAC could promote monomerization of SHR-2042 and form micelles to trap the monomerized SHR-2042. The oral bioavailability of SHR-2042 paired with SNAC is 0.041% (1:0, w/w), 0.083% (1:10, w/w), 0.32% (1:30, w/w) and 2.83% (1:60, w/w) in rats. And the oral bioavailability of SHR-2042 matched with SNAC is 3.39% (1:30, w/w) in monkeys, which is over 10 times higher than that of semaglutide.
We believe that the design and development of oral SHR-2042 will provide a new way to design more and more GLP-1RAs with high oral bioavailability in the future.
司美格鲁肽是市场上唯一的口服 GLP-1RA，但口服生物利用度通常在 0.4-1%范围内。在这项研究中，开发了一种新的 GLP-1RA 名为 SHR-2042，以获得比司美格鲁肽更高的口服生物利用度。
使用 SEC-MALS 评估 SHR-2042、司美格鲁肽和利拉鲁肽的自缔合。使用 SD 大鼠肠灌注试验选择渗透增强剂 (PE)，包括 SNAC、C10 和 LCC。使用 ITC、CD 和 DLS 研究 SHR-2042 与 SNAC 之间的相互作用。使用 SD 大鼠胃给药试验筛选不同 SHR-2042/SNAC 比例的 SHR-2042 颗粒。在大鼠和猴子中研究 SHR-2042 的口服生物利用度。
设计的 GLP-1RA，SHR-2042，比司美格鲁肽具有更好的溶解度和亲脂性。而它与司美格鲁肽形成类似的寡聚物。在选择 PE 时，SNAC 显示出比其他竞争 PE（包括 C10 和 LCC）更好的暴露度。SHR-2042 和 SNAC 快速结合并表现出疏水相互作用。SNAC 可以促进 SHR-2042 的单体化并形成胶束以捕获单体化的 SHR-2042。与 SNAC 配对的 SHR-2042 的口服生物利用度在大鼠中分别为 0.041%（1:0，w/w）、0.083%（1:10，w/w）、0.32%（1:30，w/w）和 0.32%（1:60，w/w）。与 SNAC 匹配的 SHR-2042 的口服生物利用度在猴子中为 3.39%（1:30，w/w），是司美格鲁肽的 10 倍以上。
我们相信，口服 SHR-2042 的设计和开发将为未来设计更多具有高口服生物利用度的 GLP-1RA 提供新途径。
