Preparation, characterization and pharmacokinetics of an inhalable dry powder formulation of a new hydrophobic antibiotic derivative for the treatment of lung infections

Styliani Xiroudaki


Delivering antibiotics directly to the major site of infection in the lungs is challenging. Inhaled antibiotic therapy may increase dramatically the local drug exposure at the respiratory tract, reducing thus the systemic adverse effects for which antibiotics are notorious. However, efficient nebulization delivery, distribution throughout the lungs, and penetration into biofilms and macrophages are significant challenges. In the current study, we aimed to develop an excipient-free inhalable dry powder formulation of a novel hydrophobic amikacin-deoxycholic acid derivative (Amk-DCA). An experimental design study was applied to assess the effect of spray-drying conditions (atomizing air input rate, fluid feed rate and Amk-DCA concentration) on process yield, particle characteristics and aerosolization performance. The potential benefits of the hydrophobic antibiotic derivative were investigated in in vivo pharmacokinetic studies after intranasal administration on a well-studied murine experimental model. Spray-dried Amk-DCA particles exhibited irregular surface morphology with mean geometric diameters lower than 4 microns. Process conditions for the preparation of highly respirable aminoglycoside derivative microparticles were determined with an emitted dose of 85±1% and a fine particle fraction of 60±2%. Pharmacokinetic studies showed high drug retention in the lungs compared to blood with a slight prevalence of Amk-DCA. Either local or systemic levels were maintained above potential therapeutic effective concentrations over a 48-hour time period investigated. The enhanced hydrophobicity as well as the satisfying nebulization properties of such a novel aminoglycoside derivative without the addition of any carrier or dispersibility enhancer may result advantageous for the treatment of problematic lung infections.

Key Message

The simplicity of preparation and the fact that such a derivative does not constitute a new chemical entity but an ionic complex of a well-known aminoglycoside may shrink processing and time to reach the market, whereas the improved pharmacokinetic properties may contribute to the inhaled antibiotic therapy progress.

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