Effect of formulation composition on stability and aerosol performance of respirable high load monoclonal antibody...

Inhalation-based delivery can efficiently transport monoclonal antibodies (mAbs) to the lungs for respiratory and other diseases. While several attempts have been made to develop inhaled formulations of mAbs in the nebulized or dry powder form, these formulations typically rely on high quantities of sugar stabilizers. While sugars can stabilize the mAbs during processing and storage, they are characterized by high hygroscopicity, which could hamper product's physical stability in certain drug product configurations and requires aggressive moisture protection during storage and use. The addition of stabilizing excipients like sugars may also lead to a higher powder burden for high-dose therapies. Additionally, sugars may react adversely with certain mAbs via reactions such as the Maillard reaction. This study aimed at delivering mAbs in lipid-based formulations and abrogate potential storage issues that limit typical sugar-based formulations by reducing hygroscopicity and cohesivity while maintaining high doses of the mAb. The broader goal was to evaluate if the dry powder formulation approach could enable a patient-friendly system that allows a minimal number of inhalations to achieve therapeutic efficacy by increasing the payload of IgG, reducing excipients, in each actuation. Anti-streptavidin IgG1 antibody was used as a model biologic and a series of formulations were prepared using one representative lipid, amino acid, and surfactant in different compositions. A "mixture design of experiments" was utilized to identify stability and dose constraints using these excipients when processed via spray drying. Three formulations containing high IgG content (50 %, 73 %, and 79 % w/w) were chosen for further characterization and assessment of storage stability. The prepared IgG powders exhibited excellent aerosol performance, with over 80 % fine particle fraction and more than 85 % emitted fraction. The powders also had reduced moisture sorption relative to control powders. Additionally, size exclusion chromatography showed that the powders remained stable for at least one month under accelerated conditions (e.g., 40°C with 75 % relative humidity). These findings suggest lipid-based mAb formulations can provide enhanced physical stability to the protein, while exhibiting superior aerosol performance and hence may offer promise for dry powder inhaled therapies.