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Eur J Pharm Biopharm. 2019 Aug 6. pii: S0939-6411(19)30323-6. doi: 10.1016/j.ejpb.2019.08.004. [Epub ahead of print]

Inhalable combination powder formulations of phage and ciprofloxacin for P. aeruginosa respiratory infections.

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Advanced Drug Delivery Group, School of Pharmacy, University of Sydney, Sydney, NSW, Australia.
Centenary Institute and Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
AmpliPhi Biosciences AU, Brookvale, Sydney, NSW, Australia.
The Evergreen State College, Olympia, Washington, USA.
Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, Victoria, Australia.


Recently we showed that nebulized ciprofloxacin and phage PEV20 in combination had a synergistic bactericidal effect against antibiotic-resistant Pseudomonas aeruginosa isolates from patients with cystic fibrosis. Compared to nebulization, dry powders for inhalation may improve patient handling characteristics and compliance. In the present study, we co-spray dried ciprofloxacin and phage PEV20 using L-leucine with or without lactose as excipients. Two formulations were identified for testing in this study. The mass ratios were set at 1:1:1 for ciprofloxacin, lactose and L-leucine (Formulation A) or 2:1 for ciprofloxacin and L-leucine without lactose (Formulation B). Concentrations of PEV20 were set at 108 and 109 PFU/mL for two clinical P. aeruginosa strains FADD1-PA001 and JIP865, respectively. Formulations A and B were characterized as partially crystalline and the powders recrystallized at >40% relative humidity (RH). Both formulations exhibited strong synergistic antimicrobial killing effect on the two strains. Formulations A and B maintained bactericidal synergy after dispersion using both low and high resistance OsmohalerTM. Powder aerosol performance was examined by next generation impactor (NGI) in low resistance inhaler at 100 L/min and by multi-stage liquid impinger (MSLI) in high resistance inhaler at 60 L/min.Fine particle fractions (FPF) obtained by NGI were 64.3 ± 2.9% and 59.7 ± 2.1% for A and B, respectively. FPF obtained by MSLI were 71.0 ± 3.4% and 73.3 ± 5.0%, respectively. In conclusion, it is feasible to prepare stable and inhalable combination powder formulations of phage PEV20 and ciprofloxacin for potential treatment of respiratory infections caused by multi-drug resistant (MDR) P. aeruginosa.


Ciprofloxacin; Cystic fibrosis; Inhalation; L-leucine; Powder formulation; Pseudomonas aeruginosa; Respiratory infection; Spray drying; bacteriophages


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