Physical Biochemistry, University of Potsdam, Karl-Liebknecht-Str. 24-25, Golm, D-14476, Potsdam, Germany.
Sanofi-Aventis Deutschland GmbH, Industrial Park Höchst, D-65926, Frankfurt, Germany.
Pharm Res. 2017 Nov;34(11):2270-2286. doi: 10.1007/s11095-017-2233-0. Epub 2017 Jul 31.
Comparison of the dissociation kinetics of rapid-acting insulins lispro, aspart, glulisine and human insulin under physiologically relevant conditions.
Dissociation kinetics after dilution were monitored directly in terms of the average molecular mass using combined static and dynamic light scattering. Changes in tertiary structure were detected by near-UV circular dichroism.
Glulisine forms compact hexamers in formulation even in the absence of Zn. Upon severe dilution, these rapidly dissociate into monomers in less than 10 s. In contrast, in formulations of lispro and aspart, the presence of Zn and phenolic compounds is essential for formation of compact R6 hexamers. These slowly dissociate in times ranging from seconds to one hour depending on the concentration of phenolic additives. The disadvantage of the long dissociation times of lispro and aspart can be diminished by a rapid depletion of the concentration of phenolic additives independent of the insulin dilution. This is especially important in conditions similar to those after subcutaneous injection, where only minor dilution of the insulins occurs.
Knowledge of the diverging dissociation mechanisms of lispro and aspart compared to glulisine will be helpful for optimizing formulation conditions of rapid-acting insulins.
在生理相关条件下比较速效胰岛素赖脯、门冬、谷赖与人胰岛素的解离动力学。
通过组合静态和动态光散射，直接监测稀释后解离动力学的平均分子量。通过近紫外圆二色性检测三级结构的变化。
谷赖即使在没有 Zn 的情况下，在制剂中也能形成紧凑的六聚体。在严重稀释的情况下，这些六聚体在不到 10 秒内迅速解离成单体。相比之下，在赖脯和门冬的制剂中，Zn 和酚类化合物的存在对于形成紧凑的 R6 六聚体是必不可少的。这些六聚体的解离时间从几秒钟到一个小时不等，具体取决于酚类添加剂的浓度。赖脯和门冬解离时间长的缺点可以通过独立于胰岛素稀释的酚类添加剂浓度的快速耗尽来减轻。这在类似于皮下注射后的条件下尤为重要，因为胰岛素在此条件下只会发生轻微稀释。
了解赖脯和门冬与谷赖解离机制的差异将有助于优化速效胰岛素的配方条件。
