Abstract
A comparative pharmacokinetic study was conducted in rats after intratracheal aerosolization of levofloxacin, as a solution, as immediate-release chitosan microspheres or as sustained-release PLGA microspheres. A pharmacokinetic model was constructed to model levofloxacin concentrations both in plasma and in the lung epithelial lining fluid (ELF). The plasma and ELF experimental concentration profiles versus time were similar for the intravenous and intratracheal levofloxacin solutions and for the intratracheal levofloxacin-loaded chitosan microsphere dry powder, indicating that levofloxacin diffused almost instantaneously through the broncho-alveolar barrier and that the chitosan microspheres released levofloxacin very rapidly, as anticipated from in vitro release studies. The bioavailability for the intratracheal levofloxacin solution and intratracheal chitosan microspheres was estimated to be 98% and 71%, respectively, both with a direct release into the ELF compartment. The ELF-to-unbound plasma AUC ratios were slightly above 2 and may result from an efflux transport. For the intratracheal PLGA microspheres, a high ELF-to-unbound plasma AUC concentration ratio (311) was observed and high levofloxacin concentrations were maintained in ELF for at least 72h in consistency with the in vitro release studies. The bioavailability was 92%, with 19% of the dose released immediately (burst release) into the ELF and 73% released slowly into the ELF from a depot compartment, i.e. the PLGA microspheres, according to a Weibull model. These results highlight the benefit of using sustained-release microspheres administered as aerosols to provide and to maintain high pulmonary concentrations of an antibiotic characterized with a high permeability profile through the broncho-alveolar barrier. The sustained-release microsphere dry powder aerosol may therefore provide advantages over solutions or pure drug dry powders for inhalation in terms of treatment efficiency, ease of use and frequency of administration.
Highlights
The pulmonary administration of antibiotics as aerosols has gained increasing interest in the last years since it allows high lung concentrations, improving the antibacterial efficacy, and low systemic exposures, decreasing the toxicity (Hoppentocht et al, 2014)
The drug content determined by HPLC was 48.4 ± 5.8 wt.% and the mass median aerodynamic diameter (MMAD) of the microsphere powder emitted with a Handihaler® Dry Powder Inhaler (DPI) was determined to be 5.4 ± 0.2 μm using a Generation Impactor (NGI, Copley Ltd., Nottingham, UK)
The fact that MMAD was slightly higher than Dv was attributed to microspheres aggregation, as shown by scanning electron microscopy (SEM) (Fig. 2A)
Summary
The pulmonary administration of antibiotics as aerosols has gained increasing interest in the last years since it allows high lung concentrations, improving the antibacterial efficacy, and low systemic exposures, decreasing the toxicity (Hoppentocht et al, 2014). M.C. Gaspar et al / European Journal of Pharmaceutical Sciences 93 (2016) 184–191 sustained-release dry powder formulation of levofloxacin is proposed in the present work. PLGA is a biocompatible and biodegradable polymer and was widely used in the synthesis of sustained release microspheres for inhaled therapy (Doan et al, 2011; Ramazani et al, 2015; Feng et al, 2014; Sah and Sah, 2015). Microspheres were characterized in terms of pharmaceutical properties and a pharmacokinetic study was conducted in rats to assess systemic and pulmonary levofloxacin exposures after intratracheal aerosolization. For pharmacokinetic modeling and for comparison, the study included the intravenous administration or intratracheal aerosolization of a levofloxacin solution, as well as the intratracheal aerosolization of an immediate-release chitosan microsphere-based dry powder formulation (Gaspar et al, 2015)
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