Aprodu Andreea, Mantaj Julia, Raimi-Abraham Bahijja, Vllasaliu Driton
Faculty of Life Sciences & Medicine, School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 9NH, UK.
Pharmaceutics. 2019 Mar 19;11(3):127. doi: 10.3390/pharmaceutics11030127.
Biologics have changed the management of Inflammatory Bowel Disease (IBD), but there are concerns regarding unexpected systemic toxicity and loss of therapeutic response following administration by injection. Local delivery of biologics directly to the inflamed mucosa via rectal enema administration addresses the problems associated with systemic administration. Hydrogels are potentially useful delivery vehicles enabling rectal administration of biologics. Here, we prepared a hydrogel system based on methylcellulose (MC) and hyaluronic acid (HA), which possesses mucosal healing properties, incorporating a model macromolecular drug, namely (fluorescently-labeled) bovine serum albumin (BSA). The BSA-loaded MCHA hydrogel showed temperature-dependent gelation (liquid-like at 20 °C and gel-like at 37 °C) and shear thinning behavior, with these being important and desirable characteristics for rectal application (enabling easy application and retention). BSA release from the MCHA system at 37 °C was linear, with 50% of the loaded drug released within 2 h. The system demonstrated acceptable toxicity towards intestinal (colon) Caco-2 epithelial cells, even at high concentrations. Importantly, application of the BSA-loaded MCHA hydrogel to polarized Caco-2 monolayers, with or without an exemplar absorption enhancer, resulted in transintestinal permeability of BSA. The study therefore indicates that the MCHA hydrogel shows potential for topical (rectal) delivery of biologics in IBD.
生物制剂已经改变了炎症性肠病（IBD）的治疗方式，但人们担心注射给药后会出现意外的全身毒性和治疗反应丧失。通过直肠灌肠将生物制剂直接递送至炎症黏膜可解决与全身给药相关的问题。水凝胶是用于生物制剂直肠给药的潜在有用载体。在此，我们制备了一种基于甲基纤维素（MC）和透明质酸（HA）的水凝胶系统，其具有黏膜愈合特性，并包载了一种模型大分子药物，即（荧光标记的）牛血清白蛋白（BSA）。载有BSA的MCHA水凝胶表现出温度依赖性凝胶化（20℃时呈液体状，37℃时呈凝胶状）和剪切变稀行为，这些对于直肠应用而言是重要且理想的特性（便于给药和保留）。在37℃下，BSA从MCHA系统中的释放呈线性，50%的载药在2小时内释放。该系统对肠道（结肠）Caco-2上皮细胞显示出可接受的毒性，即使在高浓度下也是如此。重要的是，将载有BSA的MCHA水凝胶应用于极化的Caco-2单层细胞，无论有无典型的吸收增强剂，都会导致BSA的经肠通透性。因此，该研究表明MCHA水凝胶在IBD中用于生物制剂的局部（直肠）给药具有潜力。
