McConnell Emma L, Short Michael D, Basit Abdul W
Department of Pharmaceutics, The School of Pharmacy, University of London, 29/39 Brunswick Square, London WC1N1AX, UK.
J Control Release. 2008 Sep 10;130(2):154-60. doi: 10.1016/j.jconrel.2008.05.022. Epub 2008 Jul 18.
Targeting the colon for site-specific oral delivery can exploit one of two main physiological triggers; the intestinal pH changes or the increase in bacterial numbers in the distal gut. This study aimed to assess how these triggers compared in vivo to determine which concept provides better colon-specific release. Pellets were prepared using theophylline (model drug) and coated with methacrylic acid/methylmethcrylate co-polymer (Eudragit S [a pH-responsive polymer which dissolves above pH 7]) or amylose/ethylcellulose (a polysaccharide/polymeric mixture which is partially digested by colonic bacteria). The immediate release (uncoated) and the two sets of modified release (coated) pellets were administered to eight healthy fasted volunteers in a three-way crossover study. Drug levels were measured in the plasma, and the transit of the modified release pellets was followed by gamma scintigraphy. The immediate release pellets had T(max) values ranging from 0.5-2 h and bioavailability (AUC) ranging from 24.8-50.7 mcg h/ml. The pH-responsive pellets released drug in seven out of eight subjects. In those subjects in whom drug release occurred, the pellets had variable in vivo performance (T(max) ranging from 5-9 h; AUC 8.8-55.0 mcg h/ml) and drug release started in the small intestine for these pellets. The bacterially-triggered pellets (T(max) 8-10 h; AUC 16.5-47.9 mcg h/ml) were colon-specific; drug was detected in the blood only when the pellets reached the colon and release was more sustained than the pH system. The use of the bacterially-triggered delivery concept provided improved colonic delivery over the pH approach.
肠道pH值变化或远端肠道细菌数量增加。本研究旨在评估这些触发因素在体内的比较情况，以确定哪种概念能提供更好的结肠特异性释放。使用茶碱（模型药物）制备微丸，并分别用甲基丙烯酸/甲基丙烯酸甲酯共聚物（尤特奇S[一种在pH值高于7时溶解的pH响应聚合物]）或直链淀粉/乙基纤维素（一种被结肠细菌部分消化的多糖/聚合物混合物）进行包衣。在一项三交叉研究中，将速释（未包衣）和两组缓释（包衣）微丸给予八名健康的空腹志愿者。测量血浆中的药物水平，并通过γ闪烁扫描跟踪缓释微丸的转运。速释微丸的T(max)值范围为0.5 - 2小时，生物利用度（AUC）范围为24.8 - 50.7 mcg h/ml。pH响应性微丸在八名受试者中的七名中释放药物。在那些发生药物释放的受试者中，微丸的体内性能各不相同（T(max)范围为5 - 9小时；AUC为8.8 - 55.0 mcg h/ml），并且这些微丸在小肠中开始释放药物。细菌触发微丸（T(max) 8 - 10小时；AUC 16.5 - 47.9 mcg h/ml）具有结肠特异性；只有当微丸到达结肠时才在血液中检测到药物，并且释放比pH系统更持久。与pH方法相比，使用细菌触发给药概念可改善结肠给药效果。
