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Pharm Res (2011) 28:15521560 DOI 10.1007/s11095-011-0388-7
RESEARCH PAPER
Effect of Sugar Molecules on the Viscosity of High Concentration Monoclonal Antibody Solutions
Feng He & Christopher E. Woods & Jennifer R. Litowski & Lauren A. Roschen & Himanshu S. Gadgil & Vladimir I. Razinkov &
Bruce A. Kerwin
Received: 13 November 2010 /Accepted: 31 January 2011 /Published online: 15 May 2011 # Springer Science+Business Media, LLC 2011
ABSTRACTPurpose To assess the effect of sugar molecules on solution viscosity at high protein concentrations.
Methods A high throughput dynamic light scattering method was used to measure the viscosity of monoclonal antibody solutions. The effects of protein concentration, type of sugar molecule (trehalose, sucrose, sorbitol, glucose, fructose, xylose and galactose), temperature and ionic strength were evaluated. Differential scanning fluorimetry was used to reveal the effect of the same sugars on protein stability and to provide insight into the mechanism by which sugars increase viscosity.
Results The addition of all seven types of sugar molecules studied result in a significant increase in viscosity of high concentration monoclonal antibody solutions. Similar effects of sugars were observed in the two mAbs examined; viscosity could be reduced by increasing the ionic strength or temperature. The effect by sugars was enhanced at higher protein concentrations.
Conclusions Disaccharides have a greater effect on the solution viscosity at high protein concentrations compared to monosaccharides. The effect may be explained by commonly
accepted mechanisms of interactions between sugar and protein molecules in solution.
KEY WORDS dynamic light scattering . high throughput . monoclonal antibody. preferential exclusion . preferential hydration . sugar molecule . viscosity
ABBREVIATIONScP centipoiseDLS dynamic light scatteringDSF differential scanning fluorimetry Igg Immunoglobulin GmAb monoclonal antibody
INTRODUCTION
Monoclonal antibodies are one of the most common classes of biotherapeutic molecules, with more than 150 products on the market and in development (1). To improve patient convenience, there has been a movement towards the use of high concentration protein solutions (i.e. > 100 mg/mL) in pre-filled syringes. At these concentrations, many protein solutions become highly viscous, posing considerable challenges for both processing and delivery (2). In ultrafiltration/diafiltration systems, high viscosity leads to high membrane backpressures and reduction in the flow rate. In pre-filled syringes, increases in viscosity may lead to difficulties during injection. Consequently, controlling solution viscosity is...