摘要

FDA 批准口服 semaglutide 治疗 2 型糖尿病（2019 年）和口服奥曲肽治疗肢端肥大症（2020 年）证明，如果与选定的肠渗透增强剂一起配制，选定的利基肽可以口服给药。

我们评估了口服奥曲肽制剂 MYCAPSSA®（Chiasma Pharmaceuticals，Needham，MA，USA）。提供了当前肢端肥大症护理标准的概述以及口服奥曲肽与长效注射的益处。我们讨论了所使用的瞬时渗透增强剂 (TPE®) 技术，并详细介绍了来自动物模型和临床试验的安全性和有效性数据。

TPE® 是一种油性奥曲肽悬浮液，其中包含许多赋形剂，这些赋形剂可以通过打开由跨细胞扰动引起的肠上皮紧密连接来瞬时改变上皮屏障的完整性。使用 20 mg 奥曲肽胶囊的 I 期研究产生了约 0.7% 的相对口服生物利用度，并且在两项 III 期研究中实现了主要终点。达到这些终点所需的口服奥曲肽剂量是 0.1 mg 速释皮下注射剂的 200 倍以上，这提醒人们难以实现大分子的口服吸收。与每月长效注射相比，许多肢端肥大症患者更喜欢方便的每日两次口服奥曲肽制剂。

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ABSTRACT

The FDA approval of oral semaglutide for type 2 diabetes (2019) and oral octreotide for acromegaly (2020) is evidence that selected niche peptides can be administered orally if formulated with selected intestinal permeation enhancers.

We evaluated the oral octreotide formulation, MYCAPSSA® (Chiasma Pharmaceuticals, Needham, MA, USA). An outline of the current standard of care in acromegaly and the benefits of oral octreotide versus depot injections is provided. We discuss the Transient Permeation Enhancer (TPE®) technology used and detail the safety and efficacy data from animal models and clinical trials.

TPE® is an oily suspension of octreotide that includes a number of excipients that can transiently alter epithelial barrier integrity by opening of intestinal epithelial tight junctions arising from transcellular perturbation. Phase I studies using 20 mg octreotide capsules yielded a relative oral bioavailability of ~0.7% and primary endpoints were achieved in two Phase III studies. The oral octreotide dose required to achieve these endpoints was over 200 times that of the 0.1 mg immediate-release subcutaneous injection, a reminder of the difficulty in achieving oral absorption of macromolecules. Many acromegaly patients will prefer a convenient twice-daily oral formulation of octreotide compared to monthly depot injections.