Hydrophobic salts markedly diminish viscosity of concentrated protein solutions.
Reducing viscosities of concentrated solutions of therapeutic proteins is important for their subcutaneous and intravenous delivery. Although inorganic salts and optimizing the pH were previously reported to dramatically lower the viscosity of a monoclonal antibody solution, herein we have determined these effects not to be general. Separately, we have found that hydrophobic ionic excipients, both anionic and cationic, substantially decrease the viscosity of concentrated (300-400 mg/mL) aqueous solutions of bovine serum albumin and γ-globulin. The more hydrophobic the excipient, the greater its viscosity-lowering effect is. With cationic ones, the concomitant contribution of the counter-ion broadly follows the chaotropic order. The most potent excipients lower the viscosity over fourfold to levels far below the 50 cP threshold for subcutaneous injections. The observed viscosity reductions are rationalized in terms of three-dimensional transient protein networks formed in concentrated solutions due to hydrophobic and, to a lesser extent, ionic interactions. These reversible protein aggregates are responsible for strong resistance to flow in concentrated protein solutions and hence their high viscosity; hydrophobic ions apparently effectively compete for these interprotein interactions, thereby giving rise to less viscous solutions.
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Wei
W
Du
Alexander M
AM
Klibanov
D000818:Animals; D001702:Biopharmaceutics / Q000379:methods*; D002417:Cattle; D002645:Chickens; D057927:Hydrophobic and Hydrophilic Interactions; D007136:Immunoglobulins / Q000737:chemistry; D011506:Proteins / Q000737:chemistry*; D012492:Salts / Q000737:chemistry*; D012710:Serum Albumin, Bovine / Q000737:chemistry; D012996:Solutions / Q000737:chemistry*; D014783:Viscosity
C016512:IgY; D007136:Immunoglobulins; D011506:Proteins; D012492:Salts; D012996:Solutions; D012710:Serum Albumin, Bovine