Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2484884 | Journal of Pharmaceutical Sciences | 2012 | 16 Pages |
Abstract
Monoclonal antibodies continue to command a large market for treatment of a variety of diseases. In many cases, the doses required for therapeutic efficacy are large, limiting options for antibody delivery and administration. We report a novel formulation strategy based on dispersions of antibody nanoclusters that allows for subcutaneous injection of highly concentrated antibody (â¼190âmg/mL). A solution of monoclonal antibody 1B7 was rapidly frozen and lyophilized using a novel spiralâwound inâsitu freezing technology to generate amorphous particles. Upon gentle stirring, a translucent dispersion of approximately 430ânm protein clusters with low apparent viscosity (â¼24âcp) formed rapidly in buffer containing the pharmaceutically acceptable crowding agents such as trehalose, polyethylene glycol, and nâmethylâ2âpyrrolidone. Upon in vitro dilution of the dispersion, the nanoclusters rapidly reverted to monomeric protein with full activity, as monitored by dynamic light scattering and antigen binding. When administered to mice as an intravenous solution, subcutaneous solution, or subcutaneous dispersion at similar (4.6-7.3âmg/kg) or ultraâhigh dosages (51.6âmg/kg), the distribution and elimination kinetics were within error and the protein retained full activity. Overall, this method of generating highâconcentration, lowâviscosity dispersions of antibody nanoclusters could lead to improved administration and patient compliance, providing new opportunities for the biotechnology industry. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:3763-3778, 2012
Keywords
Related Topics
Health Sciences
Pharmacology, Toxicology and Pharmaceutical Science
Drug Discovery
Authors
Maria A. Miller, Tarik A. Khan, Kevin J. Kaczorowski, Brian K. Wilson, Aileen K. Dinin, Ameya U. Borwankar, Miguel A. Rodrigues, Thomas M. Truskett, Keith P. Johnston, Jennifer A. Maynard,