Bernkop-Schnürch A
Institute of Pharmaceutical Technology, Center of Pharmacy, University of Vienna, Austria.
J Control Release. 1998 Mar 2;52(1-2):1-16. doi: 10.1016/s0168-3659(97)00204-6.
The peroral administration of peptide drugs is a major challenge to pharmaceutical science. In order to provide a sufficient bioavailability of these therapeutic agents after oral dosing, several barriers encountered with the gastrointestinal (GI) tract have to be overcome by a suitable galenic. One of these barriers is caused by proteolytic enzymes, leading to a severe presystemic degradation in the GI tract. Besides some other strategies to overcome the so-called enzymatic barrier, the use of inhibitory agents has gained considerable scientific interest, as various in vivo studies could demonstrate a significantly improved bioavailability of therapeutic peptides and proteins, due to the co-administration of such excipients. In vitro techniques to evaluate the actual potential of inhibitory agents incubation with pure proteases, freshly collected gastric or intestinal fluids, mucosal homogenates, brush border vesicles and freshly excised mucosa. In situ techniques are based on single-pass perfusion studies cannulating different intestinal segments and determining the amount of undegraded model drug in perfusion solutions or blood. For in vivo studies, insulin is mostly used as a model drug, offering the advantage of a well-established method to evaluate the biological response after oral dosing by determining the decrease in blood glucose level. Generally, inhibitory agents can be divided into: inhibitors which are not based on amino acids (I), such as p-aminobenzamidine, FK-448 and camostat mesilate; amino acids and modified amino acids (II), such acid derivatives; peptides and modified peptides (III), e.g. bacitracin, antipain, chymostatin and amastatin; and polypeptide protease inhibitors (IV), e.g. aprotinin, Bowman-Birk inhibitor and soybean trypsin inhibitor. Furthermore, complexing agents and some mucoadhesive polymers also display enzyme inhibitory activity. Drawbacks of inhibitory agents, such the risk of toxic side effects or high production costs, might be excluded by the development of advanced drug delivery systems. Initial steps in this direction can be seen in the development of delivery system containing mucoadhesive polymers providing an intimate contact to the mucosa, thereby reducing the drug degradation between delivery system and absorbing membrane, controlled release systems which provide a simultaneous release of drug and inhibitor and in the immobilisation of enzyme inhibitors on delivery systems.
肽类药物的口服给药是药学领域的一项重大挑战。为了使这些治疗药物在口服给药后具有足够的生物利用度，合适的药剂学方法必须克服胃肠道（GI）遇到的几个障碍。其中一个障碍是由蛋白水解酶引起的，导致胃肠道内严重的首过降解。除了一些克服所谓酶屏障的其他策略外，抑制剂的使用引起了相当大的科学兴趣，因为各种体内研究表明，由于此类辅料的共同给药，治疗性肽和蛋白质的生物利用度有显著提高。体外技术用于评估抑制剂与纯蛋白酶、新鲜采集的胃液或肠液、粘膜匀浆、刷状缘小泡和新鲜切除的粘膜一起孵育的实际潜力。原位技术基于单通道灌注研究，通过插管不同的肠段并测定灌注溶液或血液中未降解的模型药物量。在体内研究中，胰岛素大多用作模型药物，其优点是有一个成熟的方法，通过测定血糖水平的降低来评估口服给药后的生物学反应。一般来说，抑制剂可分为：非基于氨基酸的抑制剂（I），如对氨基苯甲脒、FK - 448和甲磺酸卡莫司他；氨基酸和修饰氨基酸（II），如氨基酸衍生物；肽和修饰肽（III），例如杆菌肽、抗痛素、抑糜酶素和氨肽酶抑制剂；以及多肽蛋白酶抑制剂（IV），例如抑肽酶、鲍曼 - 伯克抑制剂和大豆胰蛋白酶抑制剂。此外，络合剂和一些粘膜粘附聚合物也表现出酶抑制活性。抑制剂的缺点，如有毒副作用的风险或高生产成本，可能会通过先进药物递送系统的开发而被排除。在这个方向上的初步步骤可以在含有粘膜粘附聚合物的递送系统的开发中看到，该系统与粘膜紧密接触，从而减少递送系统和吸收膜之间的药物降解，控释系统可同时释放药物和抑制剂，以及将酶抑制剂固定在递送系统上。
