Spray-Dried Formulation of Epicertin, a Recombinant Cholera Toxin B Subunit Variant That Induces Mucosal Healing.
Spray-Dried Formulation of Epicertin, a Recombinant Cholera Toxin B Subunit Variant That Induces Mucosal Healing.
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DOI：
10.3390/pharmaceutics13040576
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发表时间：
2021-04-18
期刊：
影响因子：
5.4
通讯作者：
Hamorsky KT
中科院分区：
文献类型：
--
作者：
Reeves MA;Royal JM;Morris DA;Jurkiewicz JM;Matoba N;Hamorsky KT
表没食子素(EPT)是霍乱毒素B亚单位的重组变异体，经C端KDEL内质网滞留基序修饰。EPT在溃疡性结肠炎的治疗中具有潜在的治疗潜力。此前，口服EPT在葡聚糖硫酸钠(DSS)诱导的小鼠急性和慢性结肠炎中显示出结肠上皮修复活性。然而，口服给药需要用碳酸氢钠进行繁琐的预处理，以便在胃内转运时保存这种不耐酸的药物物质，从而阻碍了其在慢性病治疗中的轻松应用。在这里，我们开发了EPT的固体口服配方，它绕过了胃酸的降解。EPT被喷雾干燥并包装成肠溶胶囊，以允许在结肠中依赖于pH的释放。GM1捕获KDEL检测、ELISA法和大小排除高效液相色谱法表明，EPT粉末的活性和结构稳定性可保持长达9个月。胶囊崩解试验表明，EPT在pH为1的条件下仍保持包封性，但在pH为6.8的条件下释放超过180分钟，约为近端结肠的pH。一项急性DSS结肠炎研究证实，与赋形剂处理的小鼠相比，口服未经胃酸中和预处理的胶囊EPT对C57BL/6小鼠的治疗效果(p<；0.05)。这些结果为喷雾干燥EPT的肠溶口服制剂提供了基础。
Epicertin (EPT) is a recombinant variant of the cholera toxin B subunit, modified with a C-terminal KDEL endoplasmic reticulum retention motif. EPT has therapeutic potential for ulcerative colitis treatment. Previously, orally administered EPT demonstrated colon epithelial repair activity in dextran sodium sulfate (DSS)-induced acute and chronic colitis in mice. However, the oral dosing requires cumbersome pretreatment with sodium bicarbonate to conserve the acid-labile drug substance while transit through the stomach, hampering its facile application in chronic disease treatment. Here, we developed a solid oral formulation of EPT that circumvents degradation in gastric acid. EPT was spray-dried and packed into enteric-coated capsules to allow for pH-dependent release in the colon. A GM1-capture KDEL-detection ELISA and size-exclusion HPLC indicated that EPT powder maintains activity and structural stability for up to 9 months. Capsule disintegration tests showed that EPT remained encapsulated at pH 1 but was released over 180 min at pH 6.8, the approximate pH of the proximal colon. An acute DSS colitis study confirmed the therapeutic efficacy of encapsulated EPT in C57BL/6 mice upon oral administration without gastric acid neutralization pretreatment compared to vehicle-treated mice (p < 0.05). These results provide a foundation for an enteric-coated oral formulation of spray-dried EPT.
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DOI：
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发表时间：
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期刊：
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影响因子：
--
作者：
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