Xu Jinke, Tam Mifong, Samaei Sepideh, Lerouge Sophie, Barralet Jake, Stevenson Mary M, Cerruti Marta
Department of Mining and Materials Engineering, Faculty of Engineering, McGill University, Montreal H3A 0C5, Canada.
Research Institute of the McGill University Health Centre, Montreal H3G 1A4, Canada.
Acta Biomater. 2017 Jan 15;48:247-257. doi: 10.1016/j.actbio.2016.10.026. Epub 2016 Oct 18.
Mucoadhesive drug delivery systems stick to mucosal tissues and prolong the local retention time of drugs. Since the colon is covered by a mucosal layer, mucoadhesive rectal formulations may improve treatment of such diseases as hypertension or colon cancer. Ulcerative colitis (UC) is an inflammatory bowel disease characterized by chronic inflammation of the colonic mucosa. It is commonly treated with sulfasalazine (SSZ), which is metabolized by the intestinal flora into the therapeutic 5-aminosalicylic acid (5-ASA) and a toxic by-product sulfapyridine (SP). SSZ can be administered orally or rectally. The latter route avoids unintended absorption of the drug or its degradation products in the upper gastrointestinal tract, but often fails due to limited retention time. Here, we propose a mucoadhesive hydrogel to improve the efficacy of rectal SSZ administration. The gel is made of catechol modified-chitosan (Cat-CS) crosslinked by genipin. After loading the gel with SSZ, we evaluated its efficacy in a mouse model of UC. Compared to oral SSZ treatment, rectal SSZ/Cat-CS delivery was more therapeutic, showed equivalent histological scores, and induced a lower plasma concentration of the potentially toxic SP by-product. These results show SSZ/Cat-CS rectal hydrogels are more effective and safer formulations for UC treatment than oral SSZ.
Ulcerative colitis affects the colon by causing chronic inflammation on the mucosa. One of the most common drugs to treat mild to moderate UC is sulfasalazine, which can be administrated both orally and rectally. Rectal formulations are preferable, since their therapeutic effect happens topically, and they prevent side effects related to absorption of the drug in the small intestine. However, the efficacy of rectal sulfasalazine formulations is decreased by their limited colon residence time. Here we propose a chitosan-catechol mucoadhesive gel that allows delivering sulfasalazine more effectively and safely than oral administration. Our results bring new insights into the field of mussel-inspired catechol hydrogels, showing their potential as drug delivery systems to treat a widespread disease such as ulcerative colitis.
粘膜粘附性给药系统可粘附于粘膜组织并延长药物的局部滞留时间。由于结肠被粘膜层覆盖，粘膜粘附性直肠制剂可能改善高血压或结肠癌等疾病的治疗。溃疡性结肠炎（UC）是一种以结肠粘膜慢性炎症为特征的炎症性肠病。它通常用柳氮磺胺吡啶（SSZ）治疗，SSZ被肠道菌群代谢为治疗性的5-氨基水杨酸（5-ASA）和有毒副产物磺胺吡啶（SP）。SSZ可口服或直肠给药。后一种途径可避免药物或其降解产物在上消化道的意外吸收，但由于滞留时间有限，往往效果不佳。在此，我们提出一种粘膜粘附性水凝胶以提高直肠给予SSZ的疗效。该凝胶由经儿茶酚修饰的壳聚糖（Cat-CS）制成，由京尼平交联。在凝胶中加载SSZ后，我们在UC小鼠模型中评估了其疗效。与口服SSZ治疗相比，直肠给予SSZ/Cat-CS更具治疗效果，组织学评分相当，且诱导产生潜在有毒副产物SP的血浆浓度更低。这些结果表明，对于UC治疗，SSZ/Cat-CS直肠水凝胶比口服SSZ是更有效且更安全的制剂。
溃疡性结肠炎通过引起粘膜慢性炎症影响结肠。治疗轻至中度UC最常用的药物之一是柳氮磺胺吡啶，它可口服或直肠给药。直肠制剂更可取，因为其治疗作用是局部的，且可防止与药物在小肠吸收相关的副作用。然而，直肠柳氮磺胺吡啶制剂的疗效因其在结肠的停留时间有限而降低。在此我们提出一种壳聚糖-儿茶酚粘膜粘附性凝胶，它比口服给药能更有效且更安全地递送柳氮磺胺吡啶。我们的结果为受贻贝启发的儿茶酚水凝胶领域带来了新见解，表明它们作为治疗溃疡性结肠炎等广泛疾病的药物递送系统的潜力。
