Inhalable Clarithromycin Microparticles for Treatment of Respiratory Infections
The aim of this work was to develop clarithromycin microparticles (CLARI-MP) and evaluate their aerodynamic behavior, safety in bronchial cells and anti-bacterial efficacy.
Microparticles containing clarithromycin were prepared as dry powder carrier for inhalation, using leucine and chitosan. CLARI-MP were deposited on Calu-3 grown at air-interface condition, using the pharmaceutical aerosol deposition device on cell cultures (PADDOCC). Deposition efficacy, transport across the cells and cytotoxicity were determined. Anti-antibacterial effect was evaluated against Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus.
Microparticles were of spherical shape, smooth surface and size of about 765 nm. Aerosolization performance showed a fine particle fraction (FPF) of 73.3%, and a mass median aerodynamic diameter (MMAD) of 1.8 μm. Deposition on Calu-3 cells using the PADDOCC showed that 8.7 μg/cm2 of deposited powder were transported to the basolateral compartment after 24 h. The safety of this formulation is supported by the integrity of the cellular epithelial barrier and absence of toxicity, and the antimicrobial activity demonstrated for Gram positive and Gram negative bacteria.
The appropriate aerodynamic properties and the excellent deposition on Calu-3 cells indicate that clarithromycin microparticles are suitable for administration via pulmonary route and are efficient to inhibit bacteria proliferation.
KEY WORDSaerosol dry powder inhaler lung infection safety
Dry powder inhalers
Differential scanning calorimetry
Fine particle fraction
Liquid chromatography - tandem mass spectrometry
Minimal inhibitory concentration
Mass median aerodynamic diameter
Next-generation pharmaceutical impactor
Pharmaceutical aerosol deposition device on cell cultures
Scanning electron microscopy
Transepithelial electrical resistance
ACKNOWLEDGMENTS AND DISCLOSURES
Frantiescoli Dimer is thankful to the Brazilian Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) program “Ciência sem Fronteiras” project number BEX 18215/12-2. The authors kindly thank Simone Amann for bacteria experiments, Marius Hittinger for NGI and PADDOCC experiments and Dr. Chiara Rossi for technical support of LC-MS/MS and SEM analysis.
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