Effects of the antibiotic component on in-vitro bacterial killing, physico-chemical properties, aerosolization and dissolution of a ternary-combinational inhalation powder formulation of antibiotics for pan-drug resistant Gram-negative lung infections

Abstract

Combinational antibiotic formulations have emerged as an important strategy to combat antibiotic resistance. The main objective of this study was to examine effects of individual components on the antimicrobial activity, physico-chemical properties, aerosolization and dissolution of powder aerosol formulations when three synergistic drugs were co-spray dried. A ternary dry powder formulation consisting of meropenem (75.5 %w/w), colistin (15.1 %w/w) and rifampicin (9.4 %w/w) at the selected ratio was produced by spray drying. The ternary formulation was characterized for in-vitro antibacterial activity, physico-chemical properties, surface composition, aerosol performance and dissolution. All of the formulations demonstrated excellent aerosolization behavior achieving a fine particle fraction of >70%, which was substantially higher than those for the Meropenem-SD and Colistin-Meropenem formulations. The results indicated that rifampicin controlled the surface morphology of the ternary and binary combination formulations resulting in the formation of highly corrugated particles. Advanced characterization of surface composition by XPS supported the hypothesis that rifampicin was enriched on the surface of the combination powder formulations. All spray-dried formulations were amorphous and absorbed substantial amount of water at the elevated humidity. Storage at the elevated humidity caused a substantial decline in aerosolization performance for the Meropenem-SD and Colistin-Meropenem, which was attributed to increased inter-particulate capillary forces or particle fusion. In contrast, the ternary combination and binary Meropenem-Rifampicin formulations showed no change in *

Co-Delivery of D-LAK Antimicrobial Peptide and Capreomycin as Inhaled Powder Formulation to Combat Drug-Resistant Tuberculosis

“…A possible strategy for formulation improvement is to incorporate an excipient with high surface activity, such as leucine, to create a hydrophobic coating on the particles, thereby enhancing powder flowability and drug stability [ 38 , 39 ]. A first-line anti-TB drug, rifampicin, was found to preferentially deposit on the particle surface during spray drying and constituted a hydrophobic coating in the powders, resulting in high aerosol efficiency and offering moisture protection without affecting drug dissolution [ 40 – 42 ]. As such, rifampicin can also be considered in this co-spray dried system as it not only enhances powder physicochemical and aerosol properties but also serves as an additional drug against susceptible Mtb .…”

Excipient-Free Inhalable Microparticles of Azithromycin Produced by Electrospray: A Novel Approach to Direct Pulmonary Delivery of Antibiotics

“…The internal lung high surface area (>100 m 2 ) allows drugs to be distributed and absorbed efficiently, with high effective drug concentrations reaching the lung. This allows for the decrease of the total administered dose, systemic exposure and toxicity, and, as a consequence, the main adverse effects generated by drugs, in particular antibiotics [1,2]. These features are especially interesting in the treatment of pulmonary infections, since local delivery of antibiotics in the lungs could allow for early bacterial eradication and, thus, enable a shorter treatment of minimal systemic exposure.…”