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Structure-Activity Relationship for Hydrophobic Salts as Viscosity-Lowering Excipients for Concentrated Solutions of Monoclonal Antibodies

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ABSTRACT

Purpose

To discover, elucidate the structure-activity relationship (SAR), and explore the mechanism of action of excipients able to drastically lower the viscosities of concentrated aqueous solutions of humanized monoclonal antibodies (MAbs).

Methods

Salts prepared from hydrophobic cations and anions were dissolved into humanized MAbs solutions. Viscosities of the resulting solutions were measured as a function of the nature and concentration of the salts and MAbs.

Results

Even at moderate concentrations, some of the salts prepared herein were found to reduce over 10-fold the viscosities of concentrated aqueous solutions of several MAbs at room temperature.

Conclusions

To be potent viscosity-lowering excipients, the ionic constituents of the salts must be hydrophobic, bulky, and aliphatic. A mechanistic hypothesis explaining the observed salt effects on MAb solutions’ viscosities was proposed and verified.

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Abbreviations

CHO:

Chinese hamster ovary

MAb:

monoclonal antibody

SAR:

structure-activity relationship

SC:

subcutaneous

SD:

standard deviation

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ACKNOWLEDGMENTS AND DISCLOSURES

This study was financially supported by Novartis AG, which also kindly supplied the humanized MAbs used by us.

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Authors and Affiliations

  1. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA

    Zheng Guo, Roger A. Nassar & Alexander M. Klibanov

  2. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA

    Alvin Chen & Alexander M. Klibanov

  3. Department of Engineering, Faculty of Science and Technology, Aarhus University, Gustav Wieds Vej 10, 8000, Aarhus C, Denmark

    Zheng Guo

  4. Novartis Pharma AG, 4057, Basel, Switzerland

    Bernhard Helk & Claudia Mueller

  5. Novartis Institutes for BioMedical Research, Inc., Cambridge, Massachusetts, 02139, USA

    Yu Tang & Kapil Gupta

Authors
  1. Zheng Guo
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  2. Alvin Chen
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  3. Roger A. Nassar
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  4. Bernhard Helk
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  5. Claudia Mueller
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  6. Yu Tang
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  7. Kapil Gupta
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  8. Alexander M. Klibanov
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Corresponding author

Correspondence to Alexander M. Klibanov.

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Guo, Z., Chen, A., Nassar, R.A. et al. Structure-Activity Relationship for Hydrophobic Salts as Viscosity-Lowering Excipients for Concentrated Solutions of Monoclonal Antibodies. Pharm Res 29, 3102–3109 (2012). https://doi.org/10.1007/s11095-012-0802-9

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  • DOI: https://doi.org/10.1007/s11095-012-0802-9

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