Though subcutaneous (SC) delivery is emerging as the preferred administration route for immunotherapies and other biologics due to better patient compliance and lower healthcare costs, SC delivery requires high-concentration antibody formulations due to the limited injection volume for the subcutaneous space. However, antibody solutions at high concentrations face significant instabilities and high viscosities which render injection impossible. Non-aqueous formulations can bypass these issues, but present problems in clinical applications. Previous work in our group has developed solid antibody formulations encapsulated in hydrogel microparticles to improve the stability and injectability of highly concentrated antibodies. Packaging of the antibody in hydrogel microparticles has been shown to cloak protein-protein interactions and reduce the viscosity of the formulation, and the solid antibody forms show improved stability over liquid forms. But concentrations in previous formulations have been limited (<300 mg/mL) due to the need for centrifugation in the microparticle synthesis process. In this work, we develop a novel formulation process in which the antibody is precipitated into an amorphous solid dispersion (ASD) through solvent-based dehydration of antibody-laden hydrogel microparticles. The microparticles are then suspended in aqueous solution, containing excipients that stabilize the antibody in its amorphous solid form so it remains encapsulated in the hydrogel particles. The final dosage form is an aqueous suspension of concentrations >500 mg/mL, representing the new state-of-the-art for high-concentration subcutaneous formulations. In the proposed formulation process, the microparticles are synthesized continuously, and solvent-based dehydration allows for much higher antibody concentrations than can be achieved with the previous centrifugation-based process. We analyze the precipitative phase behavior of the protein and kinetics of the dehydration process. We also evaluate critical attributes of the final formulation and show that the antibody structure is stable in the ASD-laden microparticle and that injectability of the suspension meets clinical standards for SC injection. For the first time, we present an aqueous antibody formulation at high concentrations comparable to or exceeding that of non-aqueous formulations, ideal for subcutaneous administration. We also envision the process to be generalizable to various modalities, as a formulation platform for SC delivery of biologics in various clinical applications.
