Novel copolymers of poly(sebacic anhydride) and poly(ethylene glycol) as azithromycin carriers to the lungs

Abstract

By many chronic lung diseases, there is a problem of recurrent bacterial infections that require frequent usage of antibiotics. They can be more effective and cause fewer side effects when administrated directly via the pulmonary route. For such purposes, various types of inhalers are used of which dry powder inhalers (DPIs) are one of the most common. Formulations such as dry powders usually consist of an active pharmaceutical ingredient (API) and a carrier material that is supposed to provide adequate properties to deliver the bioactive molecules to the site of action, effectively. Copolymers of sebacic acid (SA) and poly(ethylene glycol) (PEG) have been regarded as suitable materials for such formulations. Here, we present a study about the manufacturing of microparticles from such materials dedicated to inhalation which have been loaded with azithromycin (AZM). The microparticles (MPs) were 0.5 to 5 µm in size, presenting either a spherical or elongated shape depending on the material type and composition. The encapsulation efficiency (EE) of the MPs were almost complete with the drug loading up to 23.1 %. The powders had fair or good flowability based on Carr’s index and Hausner ratio. Due to the presence of the drug, the tendency to agglomerate decreased. As a result, up to 90 % of the obtained powders showed diameters below 5 µm. Also, the fine particles fraction (FPF) of the chosen formulation reached 66.3 ± 4.5 % and the mass median aerodynamic diameter was 3.8 ± 0.4 µm. The microparticles degraded quickly in vitro losing up to 50 % of their mass within 24 h and up to 80 % within 96 h of their incubation in phosphate-buffered saline (PBS). They were also nontoxic up to 100 µg/ml when added to cultures of A549 and BEAS-2B lung epithelial cells as well as to rat lung tissue slices tested ex vivo. The microparticles showed bactericidal effects against various strains of Staphylococcus aureus in lower than cytotoxic concentrations.