title: In vitro and ex vivo methods predict the enhanced lung residence time of liposomal ciprofloxacin formulations for nebulisation.
abstract: Liposomal ciprofloxacin formulations have been developed with the aim of enhancing lung residence time, thereby reducing the burden of inhaled antimicrobial therapy which requires multiple daily administration due to rapid absorptive clearance of antibiotics from the lungs. However, there is a lack of a predictive methodology available to assess controlled release inhalation delivery systems and their effect on drug disposition. In this study, three ciprofloxacin formulations were evaluated: a liposomal formulation, a solution formulation and a 1:1 combination of the two (mixture formulation). Different methodologies were utilised to study the release profiles of ciprofloxacin from these formulations: (i) membrane diffusion, (ii) air interface Calu-3 cells and (iii) isolated perfused rat lungs. The data from these models were compared to the performance of the formulations in vivo. The solution formulation provided the highest rate of absorptive transport followed by the mixture formulation, with the liposomal formulation providing substantially slower drug release. The rank order of drug release/transport from the different formulations was consistent across the in vitro and ex vivo methods, and this was predictive of the profiles in vivo. The use of complimentary in vitro and ex vivo methodologies provided a robust analysis of formulation behaviour, including mechanistic insights, and predicted in vivo pharmacokinetics.
authors.affiliation: Respiratory Technology, Woolcock Institute of Medical Research, Glebe, Australia; Discipline of Pharmacology, Sydney Medical School, University of Sydney, Australia.
authors.forename: Hui Xin
authors.initials: HX
authors.lastname: Ong
authors.affiliation: Institute of Pharmaceutical Science, King's College London, London, UK.
authors.forename: Faiza
authors.initials: F
authors.lastname: Benaouda
authors.affiliation: Respiratory Technology, Woolcock Institute of Medical Research, Glebe, Australia; Discipline of Pharmacology, Sydney Medical School, University of Sydney, Australia.
authors.forename: Daniela
authors.initials: D
authors.lastname: Traini
authors.affiliation: Aradigm Corporation, Hayward, CA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Cipolla
authors.affiliation: Aradigm Corporation, Hayward, CA, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Gonda
authors.affiliation: School of Pharmacy, Graduate School of Health, University of Technology Sydney, Broadway, Australia.
authors.forename: Mary
authors.initials: M
authors.lastname: Bebawy
authors.affiliation: Institute of Pharmaceutical Science, King's College London, London, UK.
authors.forename: Ben
authors.initials: B
authors.lastname: Forbes
authors.affiliation: Respiratory Technology, Woolcock Institute of Medical Research, Glebe, Australia; Discipline of Pharmacology, Sydney Medical School, University of Sydney, Australia. Electronic address: paul.young@sydney.edu.au.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Young
mesh_terms: D000042:Absorption; D000280:Administration, Inhalation; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D002460:Cell Line; D002626:Chemistry, Pharmaceutical; D002939:Ciprofloxacin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D003692:Delayed-Action Preparations; D006801:Humans; D008081:Liposomes; D008168:Lung / Q000378:metabolism*; D008297:Male; D008567:Membranes, Artificial; D008954:Models, Biological; D009330:Nebulizers and Vaporizers; D010477:Perfusion; D011237:Predictive Value of Tests; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D000900:Anti-Bacterial Agents; D003692:Delayed-Action Preparations; D008081:Liposomes; D008567:Membranes, Artificial; D002939:Ciprofloxacin
keywords: Calu-3; Ciprofloxacin; Isolated perfused lung; Liposomes; Pulmonary model; Transport