The formulation of a novel macrolide solution pressurised metered dose inhaler: the use of Clarithromycin as an anti-inflammatory for bronchiectasis therapy

Alessandro Saadat, Mehra Haghi, Bing Zhu, Gregory King, Gaia Colombo, Paul Young, Daniela Traini

Background: Several studies have corroborated that clarithromycin, a macrolide antibiotic, has anti-inflammatory effects in respiratory diseases. Currently, 250mg of oral clarithromycin is prescribed three times a week to reduce inflammation in asthma, bronchiectasis and chronic obstructive pulmonary disease. To date, no studies have focused on the local administration of clarithromycin.
Methods: The formulation and characterisation of a clarithromycin pressurised metered dose inhaler (pMDI) solutions was investigated. The solubility of the drug in propellant/co-solvent mixtures was measured using an in in situ solubility apparatus. Particle size distribution was investigated using the Andersen cascade impactor. Calu-3 sub bronchial epithelial cell line in the air interface culture model was used to further study the effectiveness of the formulation in terms of toxicity, barrier integrity and inhibitory effects on inflammation and mucus secretion
Results: Clarithromycin pMDI formulation containing 10% ethanol/HFA was chosen for further aerosol deposition studies. Fine particle fraction (FPF), mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) were 47.15 ± 2.91%, 1.58 ± 0.07% and 1.71 ± 0.03 %, respectively.
Particle deposition on the surface of Calu-3 using a modified Anderson cascade impactor, where the impaction plate was modified to accommodate up to eight Snapwells, showed no significant effect on barrier integrity, but resulted in a significant decrease in mucus secretion after 3 days in culture.
Conclusion: The novel clarithromycin solution pMDI was formulated and had suitable aerosol properties for lung delivery. This formulation demonstrated to be non-toxic at the administered doses and had in vitro inhibitory effects on mucus secretion of Calu-3. Further investigations on the anti-inflammatory activity are ongoing.

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