College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 08826 Seoul, Republic of Korea.
Korea Institute of Geoscience and Mineral Resources, Daejeon, Republic of Korea.
Int J Pharm. 2020 Mar 30;578:119103. doi: 10.1016/j.ijpharm.2020.119103. Epub 2020 Feb 7.
Vactosertib is a novel inhibitor of transforming growth factor-β signaling. Clinical applications of vactosertib have been challenging since conventional oral formulations such as immediate-release tablets demonstrate a rapid rise and fast decline in plasma concentrations. In this study, a novel bentonite-based, modified-release, freeze-dried powder of vactosertib was developed and evaluated to determine its potential in the treatment of ulcerative colitis. The formulation released vactosertib slowly and steadily in an in vitro drug release test. The extent of vactosertib released from the formulation was markedly low (18.0%) at pH 1.2 but considerably high (95.6%) at pH 7.4. Compared with vactosertib oral solution, the formulation demonstrated a 52.5% lower mean maximum concentration of vactosertib and three times longer median time to maximum concentration without a significant change in the extent of vactosertib absorption in a rodent colitis model. Furthermore, colitis mice administered with this formulation showed a significant reduction in the total histopathological score by 30% compared with those administered with the positive control, whereas the administration of vactosertib oral solution resulted in only a 10% reduction. Collectively, this novel formulation resolved the pharmacokinetic drawbacks of vactosertib and is expected to enhance its therapeutic effect by delivering vactosertib to the colitis lesions in the lower gastrointestinal tract.
伏卡替尼是一种新型转化生长因子-β信号抑制剂。由于传统的口服制剂，如速释片剂，在血浆浓度上表现出快速上升和快速下降，因此伏卡替尼的临床应用一直具有挑战性。在这项研究中，开发并评估了一种新型基于膨润土的、改良释放的、冷冻干燥的伏卡替尼粉末，以确定其在溃疡性结肠炎治疗中的潜力。该制剂在体外药物释放试验中缓慢而稳定地释放伏卡替尼。在 pH 值为 1.2 时，该制剂释放的伏卡替尼量明显较低（18.0%），而在 pH 值为 7.4 时，释放量则相当高（95.6%）。与伏卡替尼口服溶液相比，该制剂在溃疡性结肠炎模型中显示出 52.5%的伏卡替尼平均最大浓度降低和三倍的达峰时间延长，而伏卡替尼吸收程度没有明显变化。此外，与给予阳性对照的结肠炎小鼠相比，给予该制剂的结肠炎小鼠的总组织病理学评分降低了 30%，而给予伏卡替尼口服溶液的小鼠仅降低了 10%。总的来说，这种新型制剂解决了伏卡替尼的药代动力学缺陷，有望通过将伏卡替尼递送到下消化道的结肠炎病变部位来增强其治疗效果。
