Inhalable Nanocomposite Microparticles with Enhanced Dissolution and Superior Aerosol Performance

Abstract

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 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 an irregularly 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 tapped ρ × " 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 h, 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 nanocomposite 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 waterinsoluble drug, and superior aerosol performance.

Drug Release and Nanodroplet Formation from Amorphous Solid Dispersions: Insight into the Roles of Drug Physicochemical Properties and Polymer Selection

“… a Average value ± standard deviation of three measurements. b Undetectable by HPLC where the limit of detection was ∼1 μg/mL. c Could not be measured due to crystallization. d Unable to pellet down amorphous drug-rich nano species. e Could not be determined. f Measured from flux studies; a detailed description can be found in ref . …”

Inhalable Protein Powder Prepared by Spray-Freeze-Drying Using Hydroxypropyl-β-Cyclodextrin as Excipient

“…This was also reflected in the higher FPF values. Solute concentration also contributed to this effect, as the lower the solute concentration was, the more porous and thus less dense the particles became, improving airflow and facilitating powder aerosolization [ 26 , 27 ]. In contrast, solute concentration did not appear to have a major role, despite the statistical analysis, which indicated that it had a negative impact on powder dispersibility.…”

Membrane-disruptive peptides/peptidomimetics-based therapeutics: Promising systems to combat bacteria and cancer in the drug-resistant era

“…Recently, many successful examples of MDP-loaded DPI formulations have been reported in the literature 314 , 337 , 338 , 339 . Among them, the development of DPI formulations for the co-delivery of MDP and other drugs has gradually become a research hotspot, not only because of their potential to afford enhanced therapeutic effects but also because of their potential to increase the aerosol performance of formulations.…”

“…In order to simultaneously treat cystic fibrosis and its complications, such as multidrug-resistant Gram-negative lung infections, Zhou's group 339 recently reported a novel, inhalable nanocomposite microparticle formulation for co-delivery of colistin and ivacaftor. The authors demonstrated that colistin could work not only as a synergistic antimicrobial agent, but also as a unique matrix material for reducing the use of excipients for high-dose medications, improving the dissolution rate of ivacaftor, and increasing the aerosol performance of formulations.…”