Co-spray drying of cannabidiol and vancomycin combination powder formulations for the treatment of methicillin-resistant Staphylococcus aureus respiratory infections

Methicillin-resistant Staphylococcus aureus (MRSA) can cause life-threatening respiratory infections. Conventional oral and parenteral antibiotic treatments are often inefficient in targeting the lower respiratory tract and could cause systemic adverse effects. In this study, the 24-hour time-kill assay revealed that the co-delivery of cannabidiol (CBD) and vancomycin synergistically eradicated three clinical strains of MRSA. The combinations had rapid and sustained bactericidal activity over 24 h at the ½ x minimum inhibitory concentration (MIC). Four synergistic mass ratios of CBD and vancomycin (1:1, 2:1, 1:3, and 1:6, respectively) were co-spray dried with trehalose dihydrate and leucine to form inhalable powders. The powders were evaluated for their physicochemical and antimicrobial properties, including particle size distribution and morphology, solid-state characteristics, water sorption behaviour, aerosol performance, and 24-hour time-kill assay. Scanning electron microscopy images showed that the particles of all formulations were hollow and wrinkled. X-ray diffraction analysis confirmed that all formulations were amorphous. Moreover, moisture-induced recrystallisation occurred between 70 % and 80 % relative humidity as determined by dynamic vapour sorption. The spray-dried combinations were inhalable, achieving a fine particle fraction < 5 µm of at least 30 % upon dispersion. The formulation with the highest vancomycin content had the highest fine particle fraction, reaching approximately 53 % for both drugs. The fine particle dose < 5 µm achieved drug concentrations above the MICs when dissolved in the lung fluid after inhalation. The antimicrobial activity of the combinations was preserved after spray drying. In conclusion, CBD and vancomycin formulations were stable, inhalable, and effective in vitro against MRSA clinical strains.