Optimization of Sugar-Derivatives Mixtures for Stabilizing Polyclonal Immunoglobulin G in Spray-Dried Inhalable...

Background/Objectives: The development of dry powder formulations for pulmonary delivery of therapeutic antibodies requires careful stabilization strategies to preserve protein integrity during spray-drying and long-term storage. This study investigates the impact of various sugar-derivatives, a polyol (D-mannitol), a disaccharide (D-sucrose) and a polysaccharide (dextran 10 kDa), used individually or in combination, on the physical stability of bovine polyclonal immunoglobulin G (pAb) in dry powders for inhalation (DPIs). Methods: A design of experiments (DoE) approach was employed to evaluate the effects of these excipients on residual moisture (RM), low-order aggregates (LOA) and high-order aggregates (HOA), immediately after spray-drying (T0) and after 10 months of storage at room temperature in a desiccator (T10). Results: All DPIs exhibited a high amorphous content and a favorable glass transition temperature, with RM decreasing over time. The combination of D-mannitol and dextran 10 kDA (DPI-MD) demonstrated the most effective stabilization, minimizing LOA and HOA formation at T0 and T10. Although the ternary mixture, including D-sucrose (DPI-MSD) exhibited higher process stability, it was less stable over time in comparison to the binary mixture. The aerodynamic performance of these carrier-free DPIs, assessed via laser diffraction (% ˂ 5 µm), were between 51 ± 3 (DPI-MD) and 67 ± 4 (DPI MSD) and a Next Generation Impactor, confirmed that formulation produced aerosol with suitable size distribution and fine particle fractions (FPFn upt to 71 ± 5% for DPI-MSD), for deep pulmonary deposition. Conclusions: These findings highlight the importance of combining excipients with complementary physical properties to achieve robust protein stabilization. The DPI-MD emerged as the most promising candidate for pAb lung delivery, balancing protein integrity, powder stability, and aerodynamic efficiency.