Combination of Hydroxypropyl-Beta-Cyclodextrin and Trehalose for Improved Stability of Spray-Dried Monoclonal...

Developing a stabilized spray-dried formulation for proteins is one key approach to extending the stability of a dehydrated drug product and providing a broad range of different drug delivery applications. Trehalose has been extensively studied as an excipient to preserve the protein stability in spray-dried formulations. However, the hygroscopic nature of amorphous trehalose makes it prone to recrystallization upon exposure to high temperature and humidity conditions, which can be detrimental to protein stability in the solid state. Herein, we report a formulation approach with the use of 2-hydroxypropyl-β-cyclodextrin (HPβCD) in combination with trehalose to enhance the physical stability of spray-dried solids by inhibiting or delaying the recrystallization of trehalose. Specifically, the effect of HPβCD and trehalose as an excipient alone or the combination of both excipients in stabilizing a model therapeutic monoclonal antibody (mAb1) in a spray-dried formulation has been evaluated at 25 °C/60% relative humidity (RH) and 40 °C/75% RH over 4 weeks. In the solid state, HPβCD can inhibit trehalose recrystallization of spray-dried solids exposed to stress conditions of higher temperatures and humidity. The recrystallization tendency of trehalose was found to be dependent on the protein-to-excipient mass ratios. At a 1:1 protein-to-excipient mass ratio, trehalose is insufficient to ensure adequate protein stability after stress under high humidity, which leads to a significant change in conformational stability and the highest degree of subvisible particle formation for mAb1, primarily due to trehalose recrystallization and high-temperature stresses, while the combination of HPβCD and trehalose has resulted in improved protein stability with a reduction in aggregation propensity. These results show that a combination of HPβCD and trehalose is a viable approach in mitigating trehalose recrystallization and maintaining protein stability of mAbs in spray-dried formulations.