Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Clin Transl Gastroenterol. 2020 Dec;11(12):e00229. doi: 10.14309/ctg.0000000000000229.
Bile acids, such as chenodeoxycholic acid, play an important role in digestion but are also involved in intestinal motility, fluid homeostasis, and humoral activity. Colonic delivery of sodium chenodeoxycholate (CDC) has demonstrated clinical efficacy in treating irritable bowel syndrome with constipation but was associated with a high frequency of abdominal pain. We hypothesized that these adverse effects were triggered by local super-physiological CDC levels caused by an unfavorable pharmacokinetic profile of the delayed release formulation.
We developed novel release matrix systems based on hydroxypropyl methylcellulose (HPMC) for sustained release of CDC. These included standard HPMC formulations as well as bi-layered formulations to account for potential delivery failures due to low colonic fluid in constipated patients. We evaluated CDC release profiles in silico (pharmacokinetic modeling), in vitro and in vivo in swine (pharmacokinetics, rectal manometry).
For the delayed release formulation in vitro release studies demonstrated pH triggered dose dumping which was associated with giant colonic contractions in vivo. Release from the bi-layered HPMC systems provided controlled release of CDC while minimizing the frequency of giant contractions and providing enhanced exposure as compared to standard HPMC formulations in vivo.
Bi-phasic CDC release could help treat constipation while mitigating abdominal pain observed in previous clinical trials. Further studies are necessary to demonstrate the therapeutic potential of these systems in humans.
胆汁酸，如鹅去氧胆酸，在消化过程中起着重要作用，但也参与肠道蠕动、液体平衡和体液活动。将鹅去氧胆酸钠（CDC）递送到结肠已证明在治疗便秘型肠易激综合征方面具有临床疗效，但与腹痛的高频率相关。我们假设这些不良反应是由延迟释放制剂不利的药代动力学特征引起的局部超生理 CDC 水平触发的。
我们开发了基于羟丙基甲基纤维素（HPMC）的新型释放基质系统，用于持续释放 CDC。这些包括标准 HPMC 配方以及双层配方，以应对因便秘患者结肠液低而导致的潜在输送失败。我们在猪体内进行了体内药代动力学、直肠测压法评估 CDC 的释放曲线（药代动力学建模、体外和体内）。
对于延迟释放制剂，体外释放研究表明 pH 触发的剂量突释与体内巨大的结肠收缩有关。从双层 HPMC 系统释放的 CDC 提供了受控的释放，同时最小化了巨大收缩的频率，并与体内的标准 HPMC 制剂相比提供了增强的暴露。
双相 CDC 释放可以帮助治疗便秘，同时减轻以前临床试验中观察到的腹痛。需要进一步的研究来证明这些系统在人类中的治疗潜力。
