ArticlePharmaceutical research2015
Purification and identification of high molecular weight products formed during storage of neutral formulation of human insulin.
Article in Pharmaceutical research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 25 citations in OpenAlex.
- Comparative physicochemical and structural characterisation studies establish high biosimilarity between BGL-ASP and reference insulin aspart.Scientific reports · 2024Article
- Behavior of Regular Insulin in a Parenteral Nutrition Admixture: Validation of an LC/MS-MS Assay and the In Vitro Evaluation of Insulin Glycation.Pharmaceutics · 2022Article
- Long-Term Stability Prediction for Developability Assessment of Biopharmaceutics Using Advanced Kinetic Modeling.Pharmaceutics · 2022Article
- The Peptide Ligase Activity of Human Legumain Depends on Fold Stabilization and Balanced Substrate Affinities.ACS catalysis · 2021Article
- Spray Freeze Dried LyospheresPharmaceutics · 2021Article
- Mechanism of protein cleavage at asparagine leading to protein-protein cross-links.The Biochemical journal · 2019Article
- Identification of N-Terminally Truncated Derivatives of Insulin Analogs Formed in Pharmaceutical Formulations.Pharmaceutical research · 2018Article
- Insulin Formulation Characterization-the Thioflavin T Assays.The AAPS journal · 2017Review
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeTo identify High Molecular Weight Products (HMWP) formed in human insulin formulation during storage.
methodsCommercial formulation of human insulin was stored at 37°C for 1 year and HMWP was isolated using preparative size exclusion chromatography (SEC) and reverse phase (RP) chromatography. The primary structure of the isolated species was analysed using liquid chromatography mass spectrometry (LC-MS) and tandem mass spectrometry (MS/MS). To test the hypothesis that amino groups of insulin are involved in HMWP formation, the HMWP content of various formulations spiked with amine compounds or formulations of insulin with modified amino groups was measured.
resultsMore than 20 species of HMWP were observed and 16 species were identified using LC-MS. All identified species were covalent dimers of human insulin linked via A21Asn and B29Lys, formed via the formation of an anhydride intermediate at A21Asn. Two types of HMWP were identified, with the covalent link in the open or closed (succinimidyl) form. Some species also contained single deamidation at B3 or the desPhe(B1)-N-oxalyl-Val(B2) modification. Reduced rate of HMWP formation was observed after addition of L-lysine, L-arginine or piperazine or when insulin analogues with methylated N-terminals and side chain amines and A21Gly mutation were used. Formulations of human insulin without zinc and m-cresol were found to contain a different pool of HMWP.
conclusionsHMWP formed in formulation of human insulin at pH 7.4 with zinc and m-cresol consists primarily of covalent dimers linked via A21Asn and B29Lys. Insulin formulation properties determine the amount and identity of formed HMWP.
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