McCoubrey Laura E, Seegobin Nidhi, Sangfuang Nannapat, Moens Frédéric, Duyvejonck Hans, Declerck Eline, Dierick Arno, Marzorati Massimo, Basit Abdul W
UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK.
ProDigest BV, Technologiepark-Zwijnaarde 82, 9052 Ghent, Belgium.
J Control Release. 2024 May;369:630-641. doi: 10.1016/j.jconrel.2024.04.016. Epub 2024 Apr 11.
Successful treatment of ulcerative colitis (UC) is highly dependent on several parameters, including dosing regimen and the ability to deliver drugs to the disease site. In this study two strategies for delivering mesalazine (5-aminosalicylic acid, 5-ASA) to the colon were compared in an advanced in vitro model of the human gastrointestinal (GI) tract, the SHIME® system. Herein, a prodrug strategy employing bacteria-mediated drug release (sulfasalazine, Azulfidine®) was evaluated alongside a formulation strategy that utilised pH and bacteria-mediated release (5-ASA, Octasa® 1600 mg). SHIME® experiments were performed simulating both the GI physiology and colonic microbiota under healthy and inflammatory bowel disease (IBD) conditions, to study the impact of the disease state and ileal pH variability on colonic 5-ASA delivery. In addition, the effects of the products on the colonic microbiome were investigated by monitoring bacterial growth and metabolites. Results demonstrated that both the prodrug and formulation approaches resulted in a similar percentage of 5-ASA recovery under healthy conditions. On the contrary, during experiments simulating the GI physiology and microbiome of IBD patients (the target population) the formulation strategy resulted in a higher proportion of 5-ASA delivery to the colonic region as compared to the prodrug approach (P < 0.0001). Interestingly, the two products had distinct effects on the synthesis of key bacterial metabolites, such as lactate and short chain fatty acids, which varied according to disease state and ileal pH variability. Further, both 5-ASA and sulfasalazine significantly reduced the growth of the faecal microbiota sourced from six healthy humans. The findings support that the approach selected for colonic drug delivery could significantly influence the effectiveness of UC treatment, and highlight that drugs licensed for UC may differentially impact the growth and functioning of the colonic microbiota.
溃疡性结肠炎（UC）的成功治疗高度依赖于几个参数，包括给药方案以及将药物输送到疾病部位的能力。在本研究中，在先进的人体胃肠道（GI）体外模型SHIME®系统中比较了两种将美沙拉嗪（5-氨基水杨酸，5-ASA）输送至结肠的策略。在此，评估了一种采用细菌介导药物释放的前药策略（柳氮磺胺吡啶，Azulfidine®）以及一种利用pH和细菌介导释放的制剂策略（5-ASA，Octasa®1600 mg）。进行SHIME®实验以模拟健康和炎症性肠病（IBD）条件下的胃肠道生理学和结肠微生物群，以研究疾病状态和回肠pH变异性对结肠5-ASA递送的影响。此外，通过监测细菌生长和代谢产物来研究产品对结肠微生物组的影响。结果表明，在前药和制剂方法在健康条件下均导致相似百分比的5-ASA回收率。相反，在模拟IBD患者（目标人群）的胃肠道生理学和微生物组的实验中，与前药方法相比，制剂策略导致更高比例的5-ASA递送至结肠区域（P < 0.0001）。有趣的是，这两种产品对关键细菌代谢产物如乳酸和短链脂肪酸的合成具有不同的影响，这些代谢产物根据疾病状态和回肠pH变异性而变化。此外，5-ASA和柳氮磺胺吡啶均显著降低了来自六名健康人的粪便微生物群的生长。这些发现支持选择的结肠给药方法可能会显著影响UC治疗的有效性，并强调获批用于UC的药物可能会对结肠微生物群的生长和功能产生不同的影响。
