Albumin as an alternative dispersion enhancer for inhalable siRNA spray dried powders

Abstract

Respiratory diseases such as asthma or infections are often attributed to the (over)expression of disease-causing genes. Exploiting RNA interference (RNAi), local administration of RNAi molecules has become an attractive treatment strategy. Our previous study has shown that leucine could promote the aerosol performance of otherwise poorly dispersed siRNA powders to achieve a fine particle fraction (FPF) of 44.4%. However, the need of a large amount of leucine (50% w/w) and its hydrophobic nature posed limitations such as restricting siRNA load and solubility issues. In this study, we investigated human serum albumin (HSA) as an alternative dispersion enhancer to leucine in improving the aerosol performance of spray dried siRNA powders. At 2% w/w siRNA, the highest siRNA concentration in an inhalable solid formulation ever reported, we prepared and characterised siRNA powders co-spray dried with HSA (5% or 35% w/w) and mannitol as the bulking agent. The solutions were prepared at 1% or 2% w/v solute concentrations. The result of cascade impactor assay showed that at 35% HSA and at 1% solute concentration, the resultant powder exhibited a FPF of 68.9%. Scanning electron microscopy images revealed that particles with higher HSA composition exhibited less regular shape with wrinkled surfaces. The median physical size of the particles was between 1.5 to 2.2 μm as measured by laser diffraction. The structure of siRNA was also preserved as shown in gel retardation assay. This study demonstrated that HSA could serve as an effective dispersion enhancer of spray dried siRNA powders.