Low Viscosity Highly Concentrated Aqueous Suspension of Protein Particles for Subcutaneous Delivery

Delivery of protein therapeutics has been mainly limited to large volume dilute intravenous injections due to instabilities of the protein and high viscosities of a more concentrated solution. For a subcutaneous injection to be feasible, where the maximum volume is 1.5 mL, a typical dosage would require a protein concentration between 100-400 mg/mL, corresponding to a solution viscosity above what is acceptable for subcutaneous delivery (less than 50 cP). Non-aqueous suspensions at these high concentrations have been formulated and the apparent viscosity through a syringe was found to be below 50 cP, due to a reduction in electroviscous, solvation and shape effects on the viscosity. However, pain on injection due to osmotic effects, makes this approach a less desirable option. The main objective of this study was to formulate protein suspensions of micron-sized protein particles in aqueous-based solvents with viscosities below 50 cP for concentrations greater than 100 mg/mL.

The viscosities of the suspensions at high concentrations are shown to remain below 50 cP. While for the non-aqueous suspensions, the apparent viscosities at various concentrations can be described primarily by excluded volume effects, other factors increase in viscosity for an aqueous suspension of a protein including the electroviscous effects. However, the apparent viscosities remain lower for an aqueous suspension of a protein versus a protein solution due to additional shape and solvation and increased electroviscous effects in a protein solution. Thus, aqueous based subcutaneous injections of protein particles may offer a method to achieve higher dosages than in the case of protein solutions.