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Chemical Stability of Insulin. 2. Formation of Higher Molecular Weight Transformation Products During Storage of Pharmaceutical Preparations

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Abstract

Formation of covalent, higher molecular weight transformation (HMWT) products during storage of insulin preparations at 4–45°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 ≥25°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.

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  1. Novo Research Institute, Novo Alle, DK-2880, Bagsvaerd, Denmark

    Jens Brange, Svend Havelund & Philip Hougaard

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  1. Jens Brange
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  2. Svend Havelund
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  3. Philip Hougaard
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To whom correspondence should be addressed at Nove Research Institute, Novo Alle, DK-2880Bagsvaerd, Denmark

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Brange, J., Havelund, S. & Hougaard, P. Chemical Stability of Insulin. 2. Formation of Higher Molecular Weight Transformation Products During Storage of Pharmaceutical Preparations. Pharm Res 9, 727–734 (1992). https://doi.org/10.1023/A:1015887001987

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