Thiol-Disulfide Interchange in the Tocinoic Acid/Glutathione System During Freezing and Drying
dc.contributor.author | Thing, Mette | |
dc.contributor.author | Zhang, Jun | |
dc.contributor.author | Laurence, Jennifer S. | |
dc.contributor.author | Topp, Elizabeth M. | |
dc.date.accessioned | 2017-04-26T18:41:59Z | |
dc.date.available | 2017-04-26T18:41:59Z | |
dc.date.issued | 2010-12 | |
dc.identifier.citation | THING, M., ZHANG, J., LAURENCE, J., & TOPP, E. M. (2010). Thiol-Disulfide Interchange in the Tocinoic Acid/Glutathione System During Freezing and Drying. Journal of Pharmaceutical Sciences, 99(12), 4849–4856. http://doi.org/10.1002/jps.22206 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/23816 | |
dc.description.abstract | Thiol-disulfide interchange (“disulfide scrambling”) is a common mechanism of covalent aggregation for protein drugs. Using tocinoic acid (cyclo-S-Cys-Tyr-Ile-Gln-Asn-Cys-(S); TA(ox)) and glutathione (γGlu-Cys-Gly; GSH), our previous work demonstrated that thiol/disulfide interchange is affected by lyophilization in a manner consistent with irreversible and regioselective loss of TA(ox) (Zhang et al., 2009, J Pharm Sci 98/9: 3312–3318). Here, we explore the contributions of stages of the lyophilization cycle to perturbations in thiol/disulfide interchange in the TA/GSH system. TA(ox) and GSH were co-lyophilized from phosphate buffer in the presence or absence of various excipients, then analyzed for TA(ox) and mixed disulfide products by reverse phase high performance liquid chromatography (rp-HPLC). Perturbations were found to occur primarily during freezing, before significant amounts of ice were removed by sublimation. Addition of a lyoprotectant (sucrose), a cryoprotectant (Tween-20) and flash-freezing influenced the product distribution only while ice was still present. Decreasing the redox potential by the addition of oxidized glutathione (GSSG) affected the product distribution differently in lyophilized samples and solution controls, but in neither case led to increased conservation of TA(ox). | en_US |
dc.publisher | Elsevier | en_US |
dc.rights | This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 4.0 (CC BY-NC-ND 4.0), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | en_US |
dc.subject | Protein aggregation | en_US |
dc.subject | Peptide | en_US |
dc.subject | Solid state | en_US |
dc.subject | Lyophilization | en_US |
dc.subject | Freeze drying | en_US |
dc.subject | Thiol/disulfide interchange | en_US |
dc.title | Thiol-Disulfide Interchange in the Tocinoic Acid/Glutathione System During Freezing and Drying | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Thing, Mette | |
kusw.kuauthor | Laurence, Jennifer S. | |
kusw.kudepartment | Pharmaceutical Chemistry | en_US |
dc.identifier.doi | 10.1002/jps.22206 | en_US |
kusw.oaversion | Scholarly/refereed, author accepted manuscript | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.identifier.pmid | PMC3032634 | en_US |
dc.rights.accessrights | openAccess |
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Except where otherwise noted, this item's license is described as: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 4.0 (CC BY-NC-ND 4.0), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.