Engineering of inhalable microparticles containing terbinafine for management of pulmonary fungal infections

 

Khaled Almansour1, Iman M. Alfagih2, Tariq J. Almutairi1, Rakan F. Alshammari1, Raisuddin Ali2, Turki Al Hagbani1 & Mustafa M.A. Elsayed1,3

1Department of Pharmaceutics, College of Pharmacy, University of Hail, Hail, Saudi Arabia

2Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia

3Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt

 

Terbinafine is a broad-spectrum antifungal agent with potential therapeutic value in management of pulmonary aspergillosis. The aim of this work was to engineer a dry powder inhalation formulation of terbinafine hydrochloride by nano spray drying. A factorial experimental design was constructed to study factors influencing characteristics of formulations prepared by nano spray drying. The experimental design involved different excipient and drug-excipient mixtures, different spray solvents (hydroethanolic vs. aqueous), different spray nozzles, and different drying gas inlet temperatures. The nano spray drying products were characterized mainly in terms of the yield, the crystallinity, the disintegration behaviour in a bronchial/alveolar fluid surrogate, and the aerodynamic performance using Cyclohaler® as an inhalation device. Factors influencing characteristics of nano spray drying products are revisited. Most interestingly, a spray solvent composed of 50.5 % w/w ethanol in water was found to result in smaller, up to 3.5-fold more-respirable particles than water. The influence is attributed to the dependence of the size of spray droplets generated by the vibrating-mesh atomizer on the spray solution viscosity. The formulations exhibited partial (< 40 %) drug dissolution after dispersion in the bronchial/alveolar fluid surrogate. Undissolved drug particles were smaller than 160 nm in diameter. The potential of solid dispersions prepared by nano spray drying to avoid clearance by alveolar macrophages and mucociliary escalation and to thus provide prolonged local action is discussed.

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