Brange J, Havelund S, Hougaard P
Novo Research Institute, Bagsvaerd, Denmark.
Pharm Res. 1992 Jun;9(6):727-34. doi: 10.1023/a:1015887001987.
Formation of covalent, higher molecular weight transformation (HMWT) products during storage of insulin preparations at 4-45 degrees C was studied by size exclusion chromatography. The main products are covalent insulin dimers (CID), but in protamine-containing preparations the concurrent formation of covalent insulin-protamine (CIP) products takes place. At temperatures greater than or equal to 25 degrees C parallel or consecutive formation of covalent oligo- and polymers can also be observed. Rate of HMWT is only slightly influenced by species of insulin but varies with composition and formulation, and for isophane (NPH) preparations, also with the strength of preparation. Temperature has a pronounced effect on CID, CIP, and, especially, covalent oligo- and polymer formation. The CIDs are apparently formed between molecules within the hexameric unit common for all types of preparations and rate of formation is generally faster in glycerol-containing preparations. Compared with insulin hydrolysis reactions (see the preceding paper), HMWT is one order of magnitude slower, except for NPH preparations.
通过尺寸排阻色谱法研究了胰岛素制剂在4至45摄氏度储存期间共价、高分子量转化（HMWT）产物的形成。主要产物是共价胰岛素二聚体（CID），但在含鱼精蛋白的制剂中，会同时形成共价胰岛素-鱼精蛋白（CIP）产物。在温度大于或等于25摄氏度时，也可观察到共价寡聚体和聚合物的平行或连续形成。HMWT的速率仅受胰岛素种类的轻微影响，但随组成和配方而变化，对于低精蛋白锌胰岛素（NPH）制剂，也随制剂强度而变化。温度对CID、CIP，尤其是共价寡聚体和聚合物的形成有显著影响。CID显然是在所有类型制剂共有的六聚体单元内的分子之间形成的，并且在含甘油的制剂中形成速率通常更快。与胰岛素水解反应（见前文）相比，除NPH制剂外，HMWT慢一个数量级。
