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

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

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Item Type: Article
Status: Published
Official URL:
Journal or Publication Title: European Journal of Pharmaceutics and Biopharmaceutics
Volume: 142
Page Range: pp. 543-552
Date: 2019
Divisions: Tuberculosis
Depositing User: General Admin
Identification Number: 10.1016/j.ejpb.2019.08.004
ISSN: 09396411
Date Deposited: 21 Dec 2020 23:17

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 Osmohaler™. 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 59.7 ± 2.1% and 64.3 ± 2.9% 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: Bacteriophages; Ciprofloxacin; Cystic fibrosis; Inhalation; L-leucine; Powder formulation; Pseudomonas aeruginosa; Respiratory infection; Spray drying.

Copyright © 2019 Elsevier B.V. All rights reserved.

Lin, Yu
Chang, Rachel Yoon Kyung
Britton, Warwick J.
Morales, Sandra
Kutter, Elizabeth
Li, Jian
Chan, Hak-Kim
Last Modified: 21 Dec 2020 23:17

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