Effect on lung permeation of various formulation efforts invested in the inhaled antibiotic apramycin as measured in the ex vivo isolated, perfused, and ventilated rat lung

Per Gerde¹, Ewa Selg¹, Lina Nyström², Sofie Alvér², Denny Mahlin², José Carlos Ibañez^3,4, Julie Movellan³, Damien Dupin^3,4, Iraida Loinaz^3,4, José Maria Marimón⁵, Anissa Benkhaled⁶, Rodolfo Molina Pena⁶ & Frédéric Tewes⁶

¹Inhalation Sciences, Hälsovägen 7, Huddinge, 141 57, Sweden

²RISE Research Institutes of Sweden, Department of Chemical Processes and Drug Development, Forskargatan 18, SE-151 36 Södertälje, Sweden

³CIDETEC, Basque Research and Technology Alliance (BRTA), Po. Miramón 196, 20014 Donostia-San Sebastián, Spain

⁴Biogipuzkoa Health Research Institute, Innovation group, Donostia-San Sebastián, Spain

 ⁵ Biogipuzkoa Health Research Institute, Infectious Diseases Area, Microbiology Department, Donostia University Hospital, 20014 Donostia-San Sebastian, Spain

⁶Université de Poitiers, UFR Santé, INSERM U1070 PHAR2, Pharmacology of Antimicrobial Agents and Resistances

Summary

To increase the effect duration and local efficiency of the inhaled antibiotic apramycin lung permeation of three different formulations was measured in the isolated, ventilated, and perfused lung of the rat (IPL). The studied formulations of apramycin were; one nebulized reference solution (Ref), one dextran-based nanoparticle suspension (KuDa), and one micronized powder formulation coated with phospholipid (DSPC). All three formulations generated aerosols in the PreciseInhale^® exposure platform with mass-median aerodynamic diameters (MMAD) ranging from 2.8 to 3.6 µm. Lungs were exposed to nebulized- or dry-power aerosols for up to 7 min. Fractions of single-pass perfusate were collected for 120 min after which BAL fluid, lungs, and perfusate were collected for quantitation of apramycin. Results show that whereas the nebuliser reference solution had a distinctive Cmax during the first hour after dosing, both engineered formulations of apramycin had a slower and nearly constant permeability from 10 to 120 min after the initial break-through to the perfusate. At 120 min the overall rate of permeation was similar for Ref and DSPC formulations with a 4 hr half time, whereas KuDa had a slower 6 h half time. In summary, it is possible to increase the lung retention of water soluble apramycin by either crystal coating or dextran entrapment of the API.