Abstract：
PURPOSE:To identify High Molecular Weight Products (HMWP) formed in human insulin formulation during storage. METHODS:Commercial 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. RESULTS:More 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. CONCLUSIONS:HMWP 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.
journal_name
Pharm Resjournal_title
Pharmaceutical researchauthors
Hjorth CF,Hubálek F,Andersson J,Poulsen C,Otzen D,Naver Hdoi
10.1007/s11095-014-1600-3subject
Has Abstractpub_date
2015-06-01 00:00:00pages
2072-85issue
6eissn
0724-8741issn
1573-904Xjournal_volume
32pub_type
杂志文章abstract：PURPOSE:Type I collagen accumulates during liver fibrosis primarily because α-complex protein-2 (αCP(2)), encoded by the poly(rC) binding protein 2 (PCBP2) gene, binds to the 3' end of the collagen mRNA and increases its half-life. This study aimed to reverse the pro-fibrogenic effect of alcohol on hepatic stellate cel...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-011-0475-9
更新日期：2011-12-01 00:00:00
abstract：PURPOSE:In this study we aimed to evaluate adaptive designs (ADs) by clinical trial simulation for a pharmacokinetic-pharmacodynamic model in oncology and to compare them with one-stage designs, i.e., when no adaptation is performed, using wrong prior parameters. METHODS:We evaluated two one-stage designs, ξ0 and ξ*, ...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-015-1693-3
更新日期：2015-10-01 00:00:00
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journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-016-2085-z
更新日期：2017-03-01 00:00:00
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journal_title：Pharmaceutical research
pub_type： 杂志文章
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更新日期：2014-08-01 00:00:00
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journal_title：Pharmaceutical research
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更新日期：2008-02-01 00:00:00
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journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1015935031933
更新日期：1990-10-01 00:00:00
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更新日期：2009-01-01 00:00:00
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journal_title：Pharmaceutical research
pub_type： 杂志文章
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更新日期：1991-07-01 00:00:00
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journal_title：Pharmaceutical research
pub_type： 临床试验,杂志文章,随机对照试验
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pub_type： 杂志文章
doi：10.1007/s11095-005-9042-6
更新日期：2006-01-01 00:00:00
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journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1016484522113
更新日期：1996-11-01 00:00:00
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journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1015866420836
更新日期：1991-06-01 00:00:00
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pub_type： 杂志文章
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更新日期：2020-03-25 00:00:00
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pub_type： 杂志文章
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更新日期：2019-02-01 00:00:00
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doi：10.1007/s11095-009-9876-4
更新日期：2009-07-01 00:00:00
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pub_type： 杂志文章
doi：10.1007/s11095-012-0855-9
更新日期：2013-01-01 00:00:00
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journal_title：Pharmaceutical research
pub_type： 临床试验,杂志文章,随机对照试验
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journal_title：Pharmaceutical research
pub_type： 杂志文章,评审
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更新日期：2010-09-01 00:00:00
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更新日期：1997-09-01 00:00:00
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journal_title：Pharmaceutical research
pub_type： 杂志文章
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更新日期：1990-12-01 00:00:00
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journal_title：Pharmaceutical research
pub_type： 杂志文章
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更新日期：2005-10-01 00:00:00
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journal_title：Pharmaceutical research
pub_type： 杂志文章
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更新日期：2010-02-01 00:00:00
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journal_title：Pharmaceutical research
pub_type： 杂志文章,评审
doi：
更新日期：1999-11-01 00:00:00
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journal_title：Pharmaceutical research
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更新日期：1998-06-01 00:00:00
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pub_type： 杂志文章
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更新日期：2013-03-01 00:00:00
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更新日期：2018-06-25 00:00:00
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journal_title：Pharmaceutical research
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更新日期：2015-02-01 00:00:00
