Katakam M, Banga A K
Department of Pharmacal Sciences, School of Pharmacy, Auburn University, Alabama 36849-5503, USA.
PDA J Pharm Sci Technol. 1995 Jul-Aug;49(4):160-5.
Aggregation of peptide/protein drugs is of concern as it may lead to reduced bioactivity, immunogenic reactions, blockage of infusion pumps or unacceptable physical appearance. Aggregation of insulin and its prevention by carbohydrate excipients was investigated in this study. Aggregation was induced in solid-state by incubating with moisture at 37 degrees C, or in solution by lyophilization, shaking or multiple passage through a needle. Moisture-induced aggregation in solid state with bovine and human insulin resulted in soluble aggregates which were analyzed by light scattering technique. They were found to be noncovalent by size exclusion chromatography. Three of the four carbohydrate excipients used, i.e., dextrose, Emdex and hydroxypropyl beta-cyclodextrin minimized the moisture-induced aggregation of bovine insulin, with dextrose and Emdex being somewhat more effective. In lyophilization studies, bovine insulin was found to aggregate more than human insulin. In syringe/needle study, aggregation increased as a function of the number of times the solution was passed through the needle. Aggregation induced by shaking insulin solutions resulted in insoluble aggregation, which could also be minimized by carbohydrate excipients.
肽/蛋白质药物的聚集令人担忧，因为它可能导致生物活性降低、免疫反应、输液泵堵塞或外观不可接受。本研究调查了胰岛素的聚集情况以及碳水化合物辅料对其的预防作用。通过在37℃下与水分孵育在固态中诱导聚集，或通过冻干、振荡或多次通过针头在溶液中诱导聚集。固态中水分诱导的牛胰岛素和人胰岛素聚集产生了可溶性聚集体，通过光散射技术进行分析。通过尺寸排阻色谱法发现它们是非共价的。所使用的四种碳水化合物辅料中的三种，即葡萄糖、Emdex和羟丙基-β-环糊精，使牛胰岛素的水分诱导聚集最小化，葡萄糖和Emdex的效果稍好一些。在冻干研究中，发现牛胰岛素比人胰岛素更容易聚集。在注射器/针头研究中，聚集随着溶液通过针头次数的增加而增加。振荡胰岛素溶液诱导的聚集导致不溶性聚集，碳水化合物辅料也可以使其最小化。
