Format

Send to

Choose Destination
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.

Author information

1
Advanced Drug Delivery Group, School of Pharmacy, University of Sydney, Sydney, NSW, Australia.
2
Centenary Institute and Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
3
AmpliPhi Biosciences AU, Brookvale, Sydney, NSW, Australia.
4
The Evergreen State College, Olympia, Washington, USA.
5
Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, Victoria, Australia.

Abstract

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.

KEYWORDS:

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

PMID:
31398437
DOI:
10.1016/j.ejpb.2019.08.004

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center