Co-spray dried resveratrol and budesonide inhalation formulation for reducing inflammation and oxidative stress in rat alveolar macrophages.

Oxidative stress is instrumental in the pathogenesis and progression of chronic obstructive pulmonary disease (COPD). Novel therapeutic strategies that target macrophages, based on the use of antioxidant compounds, could be explored to improve corticosteroids responses in COPD patients. In this study, inhalable microparticles containing budesonide (BD) and resveratrol (RES) were prepared and characterized. This approach was undertaken to develop a multi-drug inhalable formulation with anti-oxidant and anti-inflammatory activities for treatment of chronic lung diseases. The inhalable microparticles containing different ratio of BD and RES were prepared by spray drying. The physico-chemical properties of the formulations were characterized in terms of surface morphology, particle size, physical and thermal stability. Additionally, in vitro aerosol performances of these formulations were evaluated with the multi-stage liquid impinger (MSLI) at 60 and 90 l/min, respectively. The cytotoxicity effect of the formulations was evaluated using rat alveolar macrophages. The biological responses of alveolar macrophages in terms of cytokine expressions, nitric oxide (NO) production and free radical scavenging activities were also tested. The co-spray dried (Co-SD) microparticles of all formulations exhibited morphologies appropriate for inhalation administration. Analysis of the deposition profiles showed an increase in aerosol performance proportional to BD concentration. Cell viability assay demonstrated that alveolar macrophages could tolerate a wide range of RES and BD concentrations. In addition, RES and BD were able to decrease the levels of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) in lipopolysaccharide (LPS) induced alveolar macrophages. 
This study has successfully established the manufacture of Co-SD formulations of RES and BD with morphology and aerosol properties suitable for inhalation drug delivery, negligible in vitro toxicity and enhanced efficacy to control inflammation and oxidative stress in LPS-induced alveolar macrophages.