Ferraro F, Sonnleitner L M, Neut C, Mahieux S, Verin J, Siepmann J, Siepmann F
Univ. Lille, Inserm, CHU Lille, U1008, F-59000 Lille, France.
Univ. Lille, Inserm, CHU Lille, U1286, F-59000 Lille, France.
Int J Pharm X. 2024 Feb 8;7:100233. doi: 10.1016/j.ijpx.2024.100233. eCollection 2024 Jun.
Polysaccharides were identified, which allow for colon targeting in human Inflammatory Bowel Disease (IBD) patients, as well as in rats and dogs (which are frequently used as animals in preclinical studies). The polysaccharides are degraded by colonic enzymes (secreted by bacteria), triggering the onset of drug release at the target site. It has to be pointed out that the microbiota in rats, dogs and humans substantially differ. Thus, the performance of this type of colon targeting system observed in animals might not be predictive for patients. The aim of this study was to limit this risk. Different polysaccharides were exposed to culture medium inoculated with fecal samples from IBD patients, healthy dogs and "IBD rats" (in which colonic inflammation was induced). Dynamic changes in the pH of the culture medium were used as an indicator for the proliferation of the bacteria and, thus, the potential of the polysaccharides to serve as their substrate. Fundamental differences were observed with respect to the extent of the pH variations as well as their species-dependency. The most promising polysaccharides were used to prepare polymeric film coatings surrounding 5-aminosaliciylic acid (5-ASA)-loaded starter cores. To limit premature polysaccharide dissolution/swelling in the upper gastro intestinal tract, ethylcellulose was also included in the film coatings. Drug release was monitored upon exposure to culture medium inoculated with fecal samples from IBD patients, healthy dogs and "IBD rats". For reasons of comparison, also 5-ASA release in pure culture medium was measured. Most film coatings showed highly species-dependent drug release kinetics or limited colon targeting capacity. Interestingly, extracts from aloe vera and reishi (a mushroom) showed a promising potential for colon targeting in species.
已鉴定出多种多糖，这些多糖可实现对人类炎症性肠病（IBD）患者以及大鼠和狗（临床前研究中常用的动物）的结肠靶向。这些多糖会被结肠酶（由细菌分泌）降解，从而在靶位点引发药物释放。必须指出的是，大鼠、狗和人类的微生物群存在很大差异。因此，在动物身上观察到的这种结肠靶向系统的性能可能无法预测患者的情况。本研究的目的是降低这种风险。将不同的多糖暴露于接种了IBD患者、健康狗和“患IBD大鼠”（诱导了结肠炎症）粪便样本的培养基中。培养基pH值的动态变化被用作细菌增殖的指标，进而作为多糖作为其底物的潜力指标。在pH值变化程度及其物种依赖性方面观察到了根本差异。最有前景的多糖被用于制备包裹负载5-氨基水杨酸（5-ASA）的起始核心的聚合物薄膜包衣。为了限制多糖在上消化道中过早溶解/膨胀，薄膜包衣中还加入了乙基纤维素。将包衣制剂暴露于接种了IBD患者、健康狗和“患IBD大鼠”粪便样本的培养基中后监测药物释放。作为对照，还测量了5-ASA在纯培养基中的释放情况。大多数薄膜包衣显示出高度依赖物种的药物释放动力学或有限的结肠靶向能力。有趣的是，芦荟和灵芝（一种蘑菇）的提取物在各物种中显示出有前景的结肠靶向潜力。
