EFFECT OF MANNITOL CRYSTALLIZATION ON THE STABILITY AND AEROSOL PERFORMANCE OF A SPRAY-DRIED PHARMACEUTICAL PROTEIN, RECOMBINANT HUMANIZED ANTI-IGE MONOCLONAL-ANTIBODY

We have examined the stability and aerosol performance of the pharmace utical protein recombinant humanized anti-IgE monoclonal antibody (rhu MAbE25) spray dried with mannitol. The aerosol performance was measure d by the fine particle fraction (FPF), and stability was assessed by t he formation of soluble aggregates. When mannitol was added to the spr ay-dried rhuMAbE25 formulation, its ability to stabilize the protein l eveled off above about 20% (w/w, dry basis). The FPF of the spray-drie d formulations was stable during storage for rhuMAbE25 containing 10% and 20% mannitol, but the 30% formulation exhibited a dramatic decreas e upon storage at both 5 degrees C and 30 degrees C, due to mannitol c rystallization. We tested the addition of sodium phosphate to a 60:40 rhuMAbE25:mannitol (w:w) mixture, which otherwise crystallized upon sp ray drying and yielded a nonrespirable powder. The presence of sodium phosphate was successful in inhibiting mannitol crystallization upon s pray drying and dramatically lowering the rate of solid-state aggregat ion. However, over long-term storage some crystallization was observed even for the phosphate-containing samples, concomitantly with increas ed particle size and decreased suitability for aerosol delivery. There fore, the physical state of mannitol (i.e., amorphous or crystalline) plays a role both in maintaining protein stability and providing suita ble aerosol performance when used as an excipient for spray-dried powd ers. Agents which retard mannitol crystallization, e.g., sodium phosph ate, may be useful in extending the utility of mannitol as an excipien t in spray-dried protein formulations.