title: Ciprofloxacin-Loaded Inorganic-Organic Composite Microparticles To Treat Bacterial Lung Infection.
abstract: Ciprofloxacin (CIP) is an antibiotic that has been clinically trialed for the treatment of lung infections by aerosolization. However, CIP is rapidly systemically absorbed after lung administration, increasing the risk for subtherapeutic pulmonary concentrations and resistant bacteria selection. In the presence of calcium, CIP forms complexes that reduce its oral absorption. Such complexation may slow down CIP absorption from the lung thereby maintaining high concentration in this tissue. Thus, we developed inhalable calcium-based inorganic-organic composite microparticles to sustain CIP within the lung. The aerodynamics and micromeritic properties of the microparticles were characterized. FTIR and XRD analysis suggest that the inorganic component of the particles comprised amorphous calcium carbonate and amorphous calcium formate, and that CIP and calcium interact in a 1:1 stoichiometry in the particles. CIP was completely released from the microparticles within 7 h, with profiles showing a slight dependence on pH (5 and 7.4) compared to the dissolution of pure CIP. Transport studies of CIP across Calu-3 cell monolayers, in the presence of various calcium concentrations, showed a decrease of up to 84% in CIP apparent permeability. The apparent minimum inhibitory concentration of CIP against Pseudomonas aeruginosa and Staphylococcus aureus was not changed in the presence of the same calcium concentration. These results indicate that the designed particles should provide sustained levels of CIP with therapeutic effect in the lung. With these microparticles, it should be possible to control CIP pharmacokinetics within the lung, based on controlled CIP release from the particles and reduced apparent permeability across the epithelial barrier due to the cation-CIP interaction.
authors.affiliation: INSERM U 1070, Pôle Biologie-Santé, Faculté de Médecine & Pharmacie, Université de Poitiers , CHU de Poitiers, 86022 Poitiers Cedex, France.|School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, University of Dublin , Dublin 2, Ireland.
authors.forename: Frederic
authors.initials: F
authors.lastname: Tewes
authors.affiliation: INSERM U 1070, Pôle Biologie-Santé, Faculté de Médecine & Pharmacie, Université de Poitiers , CHU de Poitiers, 86022 Poitiers Cedex, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Brillault
authors.affiliation: INSERM U 1070, Pôle Biologie-Santé, Faculté de Médecine & Pharmacie, Université de Poitiers , CHU de Poitiers, 86022 Poitiers Cedex, France.
authors.forename: Barbara
authors.initials: B
authors.lastname: Lamy
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, University of Dublin , Dublin 2, Ireland.
authors.forename: Peter
authors.initials: P
authors.lastname: O'Connell
authors.affiliation: INSERM U 1070, Pôle Biologie-Santé, Faculté de Médecine & Pharmacie, Université de Poitiers , CHU de Poitiers, 86022 Poitiers Cedex, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Olivier
authors.affiliation: INSERM U 1070, Pôle Biologie-Santé, Faculté de Médecine & Pharmacie, Université de Poitiers , CHU de Poitiers, 86022 Poitiers Cedex, France.
authors.forename: William
authors.initials: W
authors.lastname: Couet
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, University of Dublin , Dublin 2, Ireland.
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Healy
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002460:Cell Line; D002939:Ciprofloxacin / Q000494:pharmacology*; D006801:Humans; D008168:Lung / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D008855:Microscopy, Electron, Scanning; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D017550:Spectroscopy, Fourier Transform Infrared; D013211:Staphylococcus aureus / Q000187:drug effects; D014961:X-Ray Diffraction
chemical_list: D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin
keywords: amorphous calcium carbonate; ciprofloxacin; composite particles; controlled permeability; pulmonary delivery