整理 | GLP1减重宝典内容团队 在医药领域，口服给药因其便捷性和患者依从性高而备受青睐。但对于多肽类药物，如GLP-1受体激动剂司美格鲁肽，实现口服给药一 直是个技术挑战。多肽分子在胃酸和消化酶的作用下容易降解，且难以被肠道吸收。然而，司美格鲁肽口服制剂的成功上市，标志着这 一难题已被攻克。 司美格鲁肽口服制剂的开发克服了多重障碍，包括胃酸和消化酶导致的不稳定性、多肽分子的大分子尺寸带来的吸收难题，以及个体差 异对疗效的影响。这一成就得益于其创新的分子结构和辅助成分SNAC（一种修饰的辛酸钠）的运用。 脂肪酸酰化修饰技术提升了多肽的脂溶性，促进了肠道吸收，并延长了药物的半衰期。SNAC通过调整胃内微环境，不仅促进了多肽的 吸收，还保护了多肽不被胃酸和酶降解。药代动力学和药效学研究确定了最佳给药方法和剂量，确保了与300 mg SNAC结合的司美格鲁 肽片剂能够实现最优的生物利用度。 此外，司美格鲁肽片剂的崩解和吸收过程迅速，大约1小时后即可观察到药物吸收，随即发挥其长效GLP-1RA的药效。临床研究也证实 了司美格鲁肽片剂的滴定方法和临床疗效，从低剂量开始逐步递增至有效剂量，以实现最佳临床效果。研究显示， ...

Core Viewpoint - The successful development of oral semaglutide marks a significant breakthrough in the administration of peptide drugs, overcoming challenges related to stability, absorption, and individual variability in efficacy [4][6][9]. Group 1: Development and Mechanism - Oral semaglutide has successfully addressed multiple barriers, including instability due to gastric acid and digestive enzymes, large molecular size affecting absorption, and individual differences in therapeutic response [4]. - The use of SNAC (sodium N-(8-[2-hydroxybenzoyl] amino) caprylate) enhances the solubility and absorption of the peptide, while also protecting it from degradation [6]. - Pharmacokinetic and pharmacodynamic studies have established optimal dosing methods, ensuring that the semaglutide tablet combined with 300 mg of SNAC achieves maximum bioavailability [6]. Group 2: Clinical Efficacy - Clinical studies have demonstrated that a 14 mg oral semaglutide tablet can significantly reduce HbA1c levels by approximately 2% and promote weight loss [9]. - In the OASIS 1 study, participants with an average baseline weight of 105.4 kg experienced an average weight reduction of 17.4% (18.34 kg) with the 50 mg oral semaglutide group, indicating a more pronounced weight loss effect compared to previous studies [9]. Group 3: Mechanism of Action - Semaglutide acts as a "satiety manager" by directly suppressing appetite through central nervous system activation, particularly in the hypothalamus and brainstem [10]. - It slows gastric emptying, prolonging the feeling of fullness, and stabilizes blood sugar levels, indirectly reducing appetite fluctuations [11][12]. - The drug activates three key pathways: central nervous system pathways that enhance satiety signals, gastrointestinal-vagal pathways that slow gastric emptying, and pancreatic-metabolic pathways that smooth blood sugar levels [13].