Abstract:
PURPOSE:This study was designed to investigate the stability of recombinant FVIII (rFVIII) in solution at different pHs and to probe the cause(s) of rFVIII inactivation under accelerated storage conditions. METHODS:Aqueous stability samples of full-length rFVIII at different pHs were incubated at 40 degrees C for several days and analyzed by the one-stage clotting assay. SEC-HPLC, SDS-PAGE, and UV spectrophotometry. RESULTS:Incubation of liquid rFVIII at 40 degrees C inactivated the protein rapidly and linearly with time on a semi-log scale at all pHs, suggesting a first order or pseudo first order process. A U-shaped relationship was found between the rate constant for loss of rFVIII activity and the solution pH. The minimal rate of inactivation was found between pH 6.6 and 7.0 with a half-life of approximately 4 days. The SEC-HPLC results indicated pH-dependent aggregation of rFVIII during incubation. It was found that the disappearance of monomeric rFVIII by SEC-HPLC correlated with the loss of rFVIII activity (r2 = 0.97). Both the SDS-PAGE and UV results confirmed the aggregation pathway of rFVIII. In addition, the SDS-PAGE results suggest involvement of three aggregation mechanisms--disulfide-bond formation/exchange, non-reducible crosslinking, and physical interactions. CONCLUSIONS:The full-length rFVIII is unstable in solution at 40 degrees C and loses activity rapidly through a first order or pseudo first order aggregation process, which consists of both physical and chemical pathways. SEC-HPLC may be used in monitoring rFVIII stability studies in lieu of the clotting assay under the incubation conditions used in this study.
journal_name
Pharm Resjournal_title
Pharmaceutical researchauthors
Wang W,Kelner DNdoi
10.1023/a:1023271405005subject
Has Abstractpub_date
2003-04-01 00:00:00pages
693-700issue
4eissn
0724-8741issn
1573-904Xjournal_volume
20pub_type
杂志文章abstract::We describe an assay for acrolein in urine, employing derivatization with m-aminophenol in the presence of ferrous sulfate solution in sulfuric acid. The derivative (7-OH quinoline; DER) and the internal standard (quinine-bisulfate; IS) were separated on a 10-micron particle, 8 mm x 10-cm C18 cartridge in conjunction ...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1018964401677
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journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/A:1016327822325
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journal_title:Pharmaceutical research
pub_type: 杂志文章
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更新日期:2018-01-05 00:00:00
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journal_title:Pharmaceutical research
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更新日期:1987-04-01 00:00:00
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journal_title:Pharmaceutical research
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更新日期:2007-02-01 00:00:00
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journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1022273115847
更新日期:2003-02-01 00:00:00
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journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1007/s11095-005-8815-2
更新日期:2006-01-01 00:00:00
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更新日期:2010-01-01 00:00:00
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journal_title:Pharmaceutical research
pub_type: 杂志文章
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journal_title:Pharmaceutical research
pub_type: 杂志文章,评审
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更新日期:2002-06-01 00:00:00
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更新日期:2016-01-01 00:00:00
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journal_title:Pharmaceutical research
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journal_title:Pharmaceutical research
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journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1018928329824
更新日期:1994-05-01 00:00:00
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journal_title:Pharmaceutical research
pub_type: 杂志文章
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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
pub_type: 杂志文章
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更新日期:1999-03-01 00:00:00
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更新日期:2000-09-01 00:00:00
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更新日期:2004-04-01 00:00:00
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journal_title:Pharmaceutical research
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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
pub_type: 杂志文章
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更新日期:2016-05-01 00:00:00
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journal_title:Pharmaceutical research
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journal_title:Pharmaceutical research
pub_type: 杂志文章
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更新日期:1993-03-01 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:2016-11-01 00:00:00
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journal_title:Pharmaceutical research
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更新日期:2003-09-01 00:00:00