Synthesis, development and in vitro evaluation of drug delivery systems with protective effect against degradation by pepsin
Synthesis, development and in vitro evaluation of drug delivery systems with protective effect against degradation by pepsin
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DOI：
10.3109/10611869909085492
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发表时间：
1999-01-01
影响因子：
4.5
通讯作者：
Kratzel, M
中科院分区：
文献类型：
--
作者：
Bernkop-Schnürch, A;Kirchmayer, R;Kratzel, M
已经产生了一种（多）肽药物递送系统，该系统提供针对胃蛋白酶降解的保护作用。由此合成了简化的胃酶抑素类似物，其显示位于末端的伯氨基，允许通过形成酰胺键而容易地共价连接至阴离子粘膜粘附聚合物。这种新型抑制剂的 IC50 测定为 6.65 +/- 1.05 x 10(-6) M。通过碳二亚胺介导，它与聚卡波非和羧甲基纤维素钠 (NaCMC) 共价结合。与聚卡波非-抑制剂缀合物相比，NaCMC-抑制剂缀合物对胃蛋白酶表现出高抑制作用。体外评估了含有 NaCMC-胃蛋白酶抑制剂缀合物 (10%)、NaCMC (56.7%)、胰岛素 (3.3%) 和甘露醇 (30%) 的片剂的保护作用。因此，根据欧洲药典，将片剂与模拟胃液一起在 37 摄氏度下孵育 2 小时。以下分析表明，50.8 +/- 8.6%（平均值 +/- SD；n = 3）的胰岛素在溶胀的载体基质内被降解，而胰岛素在没有 NaCMC-胃蛋白酶抑制剂缀合物的片剂中完全代谢。这种针对胃蛋白酶降解的保护作用可能使此类剂型成为将靶向（多）肽递送至胃的有用工具。
A (poly)peptide drug delivery system providing a protective effect against degradation by pepsin has been generated. A simplified pepstatin analogue was thereby synthesised displaying a terminally located primary amino group allowing an easy covalent attachment to anionogenic mucoadhesive polymers by the formation of amide bonds. The IC50 of this novel inhibitor was determined to be 6.65 +/- 1.05 x 10(-6) M. Mediated by a carbodiimide it was covalently bound to polycarbophil and sodium carboxymethyl cellulose (NaCMC). In contrast to polycarbophil-inhibitor conjugates, NaCMC-inhibitor conjugates displayed a high inhibitory effect towards pepsin. The protective effect of tablets containing a NaCMC-pepsin inhibitor conjugate (10%), NaCMC (56.7%), insulin(3.3%), and mannitol (30%) was evaluated in vitro. Tablets were therefore incubated for 2 h at 37 degrees C with simulated gastric fluid according to the Pharmacopoeia Europea. Following analysis demonstrated that 50.8 +/- 8.6% (mean +/- SD; n = 3) of insulin were degraded within the swollen carrier matrix, whereas insulin was completely metabolised in tablets without the NaCMC-pepsin inhibitor conjugate. This protective effect against degradation by pepsin might make such dosage forms useful tools for a targeted (poly)peptide delivery to the stomach.