Cargando…

Formulation Stabilization and Disaggregation of Bevacizumab, Ranibizumab and Aflibercept in Dilute Solutions

PURPOSE: Studies were conducted to investigate dilute solutions of the monoclonal antibody (mAb) bevacizumab, mAb fragment ranibizumab and fusion protein aflibercept, develop common procedures for formulation of low concentration mAbs and identify a stabilizing formulation for anti-VEGF mAbs for use...

Descripción completa

Detalles Bibliográficos
Autores principales: Giannos, Steven A., Kraft, Edward R., Zhao, Zhen-Yang, Merkley, Kevin H., Cai, Jiyang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830485/
https://www.ncbi.nlm.nih.gov/pubmed/29492680
http://dx.doi.org/10.1007/s11095-018-2368-7
_version_ 1783303006393991168
author Giannos, Steven A.
Kraft, Edward R.
Zhao, Zhen-Yang
Merkley, Kevin H.
Cai, Jiyang
author_facet Giannos, Steven A.
Kraft, Edward R.
Zhao, Zhen-Yang
Merkley, Kevin H.
Cai, Jiyang
author_sort Giannos, Steven A.
collection PubMed
description PURPOSE: Studies were conducted to investigate dilute solutions of the monoclonal antibody (mAb) bevacizumab, mAb fragment ranibizumab and fusion protein aflibercept, develop common procedures for formulation of low concentration mAbs and identify a stabilizing formulation for anti-VEGF mAbs for use in in vitro permeation studies. METHODS: Excipient substitutions were screened. The most stabilizing formulation was chosen. Standard dilutions of bevacizumab, ranibizumab and aflibercept were prepared in PBS, manufacturer’s formulation, and the new formulation. Analysis was by SE-HPLC and ELISA. Stability, disaggregation and pre-exposure tests were studied. RESULTS: When Avastin, Lucentis and Eylea are diluted in PBS or manufacturer’s formulation, there is a 40–50% loss of monomer concentration and drug activity. A formulation containing 0.3% NaCl, 7.5% trehalose, 10 mM arginine and 0.04% Tween 80 at a pH of 6.78 stabilized the mAbs and minimized the drug loss. The formulation also disaggregates mAb aggregation while preserving the activity. Degassing the formulation increases recovery. CONCLUSIONS: We developed a novel formulation that significantly stabilizes mAbs under unfavorable conditions such as low concentration or body temperature. The formulation allows for tissue permeation experimentation. The formulation also exhibits a disaggregating effect on mAbs, which can be applied to the manufacture/packaging of mAbs and bioassay reagents. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11095-018-2368-7) contains supplementary material, which is available to authorized users.
format Online
Article
Text
id pubmed-5830485
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Springer US
record_format MEDLINE/PubMed
spelling pubmed-58304852018-03-05 Formulation Stabilization and Disaggregation of Bevacizumab, Ranibizumab and Aflibercept in Dilute Solutions Giannos, Steven A. Kraft, Edward R. Zhao, Zhen-Yang Merkley, Kevin H. Cai, Jiyang Pharm Res Research Paper PURPOSE: Studies were conducted to investigate dilute solutions of the monoclonal antibody (mAb) bevacizumab, mAb fragment ranibizumab and fusion protein aflibercept, develop common procedures for formulation of low concentration mAbs and identify a stabilizing formulation for anti-VEGF mAbs for use in in vitro permeation studies. METHODS: Excipient substitutions were screened. The most stabilizing formulation was chosen. Standard dilutions of bevacizumab, ranibizumab and aflibercept were prepared in PBS, manufacturer’s formulation, and the new formulation. Analysis was by SE-HPLC and ELISA. Stability, disaggregation and pre-exposure tests were studied. RESULTS: When Avastin, Lucentis and Eylea are diluted in PBS or manufacturer’s formulation, there is a 40–50% loss of monomer concentration and drug activity. A formulation containing 0.3% NaCl, 7.5% trehalose, 10 mM arginine and 0.04% Tween 80 at a pH of 6.78 stabilized the mAbs and minimized the drug loss. The formulation also disaggregates mAb aggregation while preserving the activity. Degassing the formulation increases recovery. CONCLUSIONS: We developed a novel formulation that significantly stabilizes mAbs under unfavorable conditions such as low concentration or body temperature. The formulation allows for tissue permeation experimentation. The formulation also exhibits a disaggregating effect on mAbs, which can be applied to the manufacture/packaging of mAbs and bioassay reagents. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11095-018-2368-7) contains supplementary material, which is available to authorized users. Springer US 2018-02-28 2018 /pmc/articles/PMC5830485/ /pubmed/29492680 http://dx.doi.org/10.1007/s11095-018-2368-7 Text en © The Author(s) 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Research Paper
Giannos, Steven A.
Kraft, Edward R.
Zhao, Zhen-Yang
Merkley, Kevin H.
Cai, Jiyang
Formulation Stabilization and Disaggregation of Bevacizumab, Ranibizumab and Aflibercept in Dilute Solutions
title Formulation Stabilization and Disaggregation of Bevacizumab, Ranibizumab and Aflibercept in Dilute Solutions
title_full Formulation Stabilization and Disaggregation of Bevacizumab, Ranibizumab and Aflibercept in Dilute Solutions
title_fullStr Formulation Stabilization and Disaggregation of Bevacizumab, Ranibizumab and Aflibercept in Dilute Solutions
title_full_unstemmed Formulation Stabilization and Disaggregation of Bevacizumab, Ranibizumab and Aflibercept in Dilute Solutions
title_short Formulation Stabilization and Disaggregation of Bevacizumab, Ranibizumab and Aflibercept in Dilute Solutions
title_sort formulation stabilization and disaggregation of bevacizumab, ranibizumab and aflibercept in dilute solutions
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830485/
https://www.ncbi.nlm.nih.gov/pubmed/29492680
http://dx.doi.org/10.1007/s11095-018-2368-7
work_keys_str_mv AT giannosstevena formulationstabilizationanddisaggregationofbevacizumabranibizumabandafliberceptindilutesolutions
AT kraftedwardr formulationstabilizationanddisaggregationofbevacizumabranibizumabandafliberceptindilutesolutions
AT zhaozhenyang formulationstabilizationanddisaggregationofbevacizumabranibizumabandafliberceptindilutesolutions
AT merkleykevinh formulationstabilizationanddisaggregationofbevacizumabranibizumabandafliberceptindilutesolutions
AT caijiyang formulationstabilizationanddisaggregationofbevacizumabranibizumabandafliberceptindilutesolutions