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Low Viscosity Highly Concentrated Suspensions of Protein Particles for Subcutaneous Delivery

Maria Andrea Miller1, Joshua D. Engstrom2, and Keith P. Johnston1. (1) Chemical Engineering, The University of Texas at Austin, 1 University Station C0400, Austin, TX 78712, (2) Engineering Technology, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08903

Delivery of protein therapeutics has been largely limited to large volume intravenous injections due to physical and chemical instabilities of proteins at high concentrations. In addition, monoclonal antibody delivery has been limited to low concentrations due to the dramatic increase in viscosity of a solution at a concentration greater than approximately 125 mg/mL. For subcutaneous delivery, the maximum volume is about 1.5 mL, corresponding to a dose of less than 200 mg for a concentration of 125 mg/mL. The main objective of this study was to formulate a protein suspension that is syringeable through a 27 gauge needle and at a concentration greater than 100 mg/mL in order to deliver a larger dose for a given injection volume.

As the volume fraction of particles increases above 100 mg/mL, the viscosity of the formulated suspension remains low enough to allow syringeability. Here, the low volume fraction approximation of Einstein is no longer accurate, and the viscosities were correlated with the Krieger-Dougherty Equation for concentrated suspensions. The experimental settling rates are correlated with a modified Stokes settling model to account for the high particle volume fraction. The protein particle size and shape are designed with milling and precipitation based processes. In addition, the protein particles must be designed to prevent particle and protein aggregation. Even with concentrations above 100 mg/mL, samples were shown to be syringeable through a 27 gauge needle. In addition, these samples were redispersible by manual shaking after exposure for one year and did not show evidence of particle growth or aggregation.