Nano spray-dried powders for efficient pulmonary delivery of proteins: an emphasis on comparisons of derived metrics determined by chapters <601> and <1604>.

Pulmonary protein delivery has proven to be an effective approach for the treatment of local and systemic diseases, and particles that can be efficiently inhaled into peripheral regions should possess aerodynamic sizes of <2 µm, for which nano-spray-drying (NSD) is a powerful tool for fabrication. However, NSD powders have a high specific surface area and surface energy, which causes severe agglomeration and poor aerosolization performance. To solve these problems, cyclodextrin/leucine delivery systems were constructed, which can evidently protect alkaline phosphatases (AKP) with >94% of their biological activities retained in NSD powders and endow nanoparticle-based AKP-cyclodextrin-leucine (ACL) powders with improved aerosolization behavior. This can be evidenced by the fine particle (<4.46 µm) fraction (FPF<4.46) and FPF<1.66 (in unit percentage), of only 49.9% and 18.7% for the leucine-free ACL0, while significantly increased to 82.1% and 33.1% for ACL15, and further increased to >88% and >41% for ACL30/ACL45. The USP Chapters of traditional <601> and newly published <1604> were employed to determine derived metrics for aerodynamic particle size distribution (APSD). It was demonstrated that the authenticity of fitted values calculated in Chapter <601> was severely influenced by APSD profiles, and the fitted values can have immense differences from the actual values determined in Chapter <1604> . The differences can be minimized when the APSD is unimodal and normal across sized impactor stages. Hence, the authenticity of the fitted values can be improved. These new data deepen the understanding of APSD analyses and generate insights into the improvement of value authenticity for derived metrics, henceforward facilitating continuous improvements in quality control of inhaled products.