Inhalable nano-composite microparticles with enhanced dissolution and superior aerosol performance

Previous studies have shown that combining colistin (Col), a cationic polypeptide antibiotic, with ivacaftor (Iva), a cystic fibrosis (CF) drug, could achieve synergistic antibacterial effects against Pseudomonas aeruginosa. The purpose of this study was to develop dry powder inhaler (DPI) formulations for co-delivery of Col and Iva, aiming to treat CF and lung infection simultaneously. In order to improve solubility and dissolution for the water insoluble Iva, Iva was encapsulated into bovine serum albumin (BSA) nanoparticles (Iva-BSA-NPs). Inhalable composite microparticles of Iva-BSA-NPs were produced by spray-freeze-drying using water-soluble Col as the matrix material and L-leucine as an aerosol enhancer. The optimal formulation showed irregular-shaped morphology with fine particle fraction (FPF) values of 73.8 ± 5.2% for Col and 80.9 ± 4.1% for Iva. Correlations between "D×√(ρ_tapped )" and FPF were established for both Iva and Col. The amorphous solubility of Iva is 66 times higher than the crystalline solubility in the buffer. Iva-BSA-NPs were amorphous and remained in the amorphous state after spray-freeze-drying as examined by powder X-ray diffraction. In-vitro dissolution profiles of the selected DPI formulation indicated that Col and Iva were almost completely released within 3 hours, which was substantially faster regarding Iva release than the jet milled physical mixture of the two drugs. In summary, this study developed a novel inhalable nano-composite microparticle using a synergistic water-soluble drug as the matrix material, which achieved reduced use of excipients for high-dose medications, improved dissolution rate for the water-insoluble drug and superior aerosol performance.