Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
Inflammatory Bowel Disease Research Group, King Abdulaziz University, Jeddah, Saudi Arabia.
Pharmacology. 2020;105(9-10):541-549. doi: 10.1159/000505101. Epub 2020 Jan 15.
BACKGROUND/AIMS: Inflammatory bowel disease is a chronic or remitting/relapsing intestinal inflammation, which comprises Crohn's disease and ulcerative colitis (UC). Severe UC is a life-threatening condition that requires corticosteroids (CS) as a first-line rescue therapy. Some patients are refractory to CS and may require alternative immunosuppressive therapy. Oral tacrolimus (FK506), an immunosuppressive agent, has been reported to be effective in the management of severe refractory UC, but it can cause serious adverse effects. This work aims to study the effect of tacrolimus delivered by a colon-targeted delivery system (CTDS) in a dextran sulfate sodium (DSS)-induced animal model of colitis.
We developed and evaluated an oral CTDS of tacrolimus (FK506) loaded pH-dependent polymeric microspheres, composed of Eudragit® S100 as a pH-sensitive polymer using the oil-in-water emulsion method. The physicochemical properties and drug release profiles of these microparticles in gastrointestinal tract (GIT) conditions were examined. A DSS-induced colitis rat model was used to evaluate the potential remedial and in vivo distribution of microspheres.
The pH-microspheres prevented a burst drug release in acidic pH conditions and showed sustained release at a colonic pH. The in vivo distribution study in the rat GIT demonstrated that pH-microspheres were successfully delivered to the inflamed colon. Moreover, it also demonstrated a significant decrease of disease activity and expression of proinflammatory cytokines, such as tumor necrosis factor α, interleukin-1β (IL-1β), and IL-6, and minimized the histological and morphometric changes.
The results confirmed the efficacy of tacrolimus (FK506) CTDs in the management of DSS-induced colitis.
背景/目的：炎症性肠病是一种慢性或缓解/复发的肠道炎症，包括克罗恩病和溃疡性结肠炎（UC）。严重的 UC 是一种危及生命的疾病，需要皮质类固醇（CS）作为一线救援治疗。一些患者对 CS 有抗药性，可能需要替代免疫抑制治疗。口服他克莫司（FK506），一种免疫抑制剂，已被报道在严重难治性 UC 的治疗中有效，但它会引起严重的不良反应。本研究旨在研究结肠靶向递送系统（CTDS）递送至他克莫司（FK506）在葡聚糖硫酸钠（DSS）诱导的结肠炎动物模型中的作用。
我们开发并评估了一种口服 CTDS 的他克莫司（FK506）载药 pH 依赖性聚合物微球，由 Eudragit® S100 组成，作为一种 pH 敏感聚合物，采用油包水乳液法制备。考察了这些微球在胃肠道（GIT）条件下的理化性质和药物释放特性。建立 DSS 诱导的结肠炎大鼠模型，评价微球的潜在治疗作用和体内分布。
pH 微球在酸性 pH 条件下防止了药物的爆发性释放，并在结肠 pH 下显示出持续释放。在大鼠 GIT 的体内分布研究中，pH 微球成功递送至发炎的结肠。此外，它还显著降低了疾病活动度和促炎细胞因子（如肿瘤坏死因子-α、白细胞介素-1β（IL-1β）和 IL-6）的表达，并最小化了组织学和形态学变化。
结果证实了他克莫司（FK506）CTDS 在 DSS 诱导的结肠炎治疗中的疗效。
