Abstract:
PURPOSE:Basal insulins with improved kinetic properties can potentially be produced using acylation by fatty acids that enable soluble, high-molecular weight complexes to form post-injection. A series of insulins, acylated at B29 with fatty acids via glutamic acid spacers, were examined to deduce the structural requirements. METHODS:Self-association, molecular masses and hexameric conformations of the insulins were studied using size exclusion chromatography monitored by UV or multi-angle light scattering and dynamic light scattering, and circular dichroism spectroscopy (CDS) in environments (changing phenol and zinc concentration) simulating a pharmaceutical formulation and changes following subcutaneous injection. RESULTS:With depletion of phenol, insulin degludec and another fatty diacid-insulin analogue formed high molecular mass filament-like complexes, which disintegrated with depletion of zinc. CDS showed these analogues adopting stable T(3)R(3) conformation in presence of phenol and zinc, changing to T(6) with depletion of phenol. These findings suggest insulin degludec is dihexameric in pharmaceutical formulation becoming multihexameric after injection. The analogues showed weak dimeric association, indicating rapid release of monomers following hexamer disassembly. CONCLUSIONS:Insulins can be engineered that remain soluble but become highly self-associated after injection, slowly releasing monomers; this is critically dependent on the acylation moiety. One such analogue, insulin degludec, has therapeutic potential.
journal_name
Pharm Resjournal_title
Pharmaceutical researchauthors
Jonassen I,Havelund S,Hoeg-Jensen T,Steensgaard DB,Wahlund PO,Ribel Udoi
10.1007/s11095-012-0739-zsubject
Has Abstractpub_date
2012-08-01 00:00:00pages
2104-14issue
8eissn
0724-8741issn
1573-904Xjournal_volume
29pub_type
杂志文章abstract:PURPOSE:To identify the aggregation mechanism and the stability characteristics of three different monoclonal antibodies under acidic conditions. METHODS:The aggregation kinetics is analyzed by a combination of light scattering, size exclusion chromatography and fluorescence techniques and the aggregation data are cor...
journal_title:Pharmaceutical research
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journal_title:Pharmaceutical research
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pub_type: 杂志文章
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pub_type: 杂志文章
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更新日期:2007-03-01 00:00:00
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journal_title:Pharmaceutical research
pub_type: 杂志文章
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pub_type: 杂志文章
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更新日期:2009-07-01 00:00:00
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更新日期:2007-09-01 00:00:00
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更新日期:2020-02-26 00:00:00