Abstract：
Commonly, most oral non-steroidal anti-inflammatory drugs (NSAIDs) have known gastric adverse reactions due to their long-term and high dose administration. In this study, a novel liquid sustained-release system based on multiple-unit in situ hydrogel beads was designed to address this issue. The system is composed of sodium alginate (SA), gellan gum (GG), zinc oxide (ZnO), and magnesium oxide (MgO). Furthermore, indobufen was loaded into the system to evaluate its gastric mucosal protection effect. This effect can be attributed to the topical antacid, pepsin inhibition, and sustained drug release properties of the system. It was proven that the stored solid gel system could undergo a \"solid to liquid\" transition after shaking. Once swallowed, the liquid gel could disperse well in the stomach as hydrogel beads. Then, the \"liquid to solid\" gelation occurred from the exterior to interior of each multiple-unit gel bead, triggered by the release of Zn2+ and Mg2+ from neutralization reactions. The formed gel demonstrated mild antacid effect that lasted for 3 hours and 66.3% pepsin inhibition in vivo. Moreover, the rats treated with the indobufen gel system showed a drug plasma concentration versus time curve with less fluctuation compared to the rats treated with the marketed preparation (YinDuo®) group. The gel system also exhibited an extended Tmax (6.50 hours) and reduced Cmax (52.87 μg/mL). Additionally, the gastric mucosal protection of the gel system was verified using three types of peptic gastric ulcer models. These findings suggested that this multiple-unit in situ gel could be a potential oral liquid sustained release delivery system for NSAIDs.
摘要：
通常,大多数口服非甾体抗炎药（NSAIDs）由于长期和高剂量给药而存在已知的胃不良反应。在这项研究中,设计了一种基于多单元原位水凝胶珠的新型液体缓释系统来解决这个问题。该系统由海藻酸钠（SA），结冷胶（GG），氧化锌(ZnO),和氧化镁(MgO)。此外，将吲哚布芬加载到系统中以评估其胃粘膜保护作用。这种效果可以归因于局部抗酸剂，胃蛋白酶抑制，和系统的持续药物释放特性。事实证明，储存的固体凝胶系统在摇动后可以经历“固体到液体”的转变。一旦吞下，液体凝胶可以作为水凝胶珠很好地分散在胃中。然后，从每个多单位凝胶珠的外部到内部发生“液体到固体”凝胶化，由中和反应中Zn2+和Mg2+的释放触发。形成的凝胶表现出持续3小时的温和抗酸作用和66.3%的体内胃蛋白酶抑制作用。此外，与用市售制剂(YinDuo®)组治疗的大鼠相比,用吲哚布芬凝胶系统治疗的大鼠显示出具有较小波动的药物血浆浓度对时间的曲线。凝胶系统还表现出延长的Tmax(6.50小时)和降低的Cmax(52.87μg/mL)。此外,使用三种类型的消化性胃溃疡模型验证了凝胶系统的胃粘膜保护作用。这些发现表明，这种多单元原位凝胶可能是一种潜在的NSAID口服液持续释放系统。
