Abstract
PURPOSE: Rifampicin, a first-line anti-tuberculosis drug, was loaded into a carbohydrate-based spray-dried nanocomposite with the aim to design a dry powder inhalation formulation. This strategy can enable efficient distribution of rifampicin within the lungs, localizing its action, enhancing its bioavailability and reducing its systemic exposure consequently side effects. METHODS: The respirable nanocomposite was developed utilizing spray drying of rifampicin nanosuspension employing a combination of mannitol, maltodextrin and leucine as microparticles matrix formers. Detailed physicochemical characterization and in-vitro inhalation properties of the nanocomposite particles were investigated. Compatibility studies were carried out using differential scanning calorimetry and Infrared spectroscopy techniques. Moreover, pulmonary in-vitro cytotoxicity on alveolar basal epithelial cells was performed and evaluated. RESULTS: Nanocomposite-based rifampicin-loaded dry inhalable powder containing maltodextrin, mannitol and leucine at a ratio of 2:1:1 was successfully formulated. Rifampicin loading efficiency into the carbohydrate nanocomposite was in the range of 89.3% to 99.2% w/w with a suitable particle size (3.47-6.80 µm) and unimodal size distribution. Inhalation efficiency of the spray-dried nanosuspension was significantly improved after transforming into an inhalable carbohydrate composite. Specifically, mannitol-based powder had higher respirable fraction (49.91%) relative to the corresponding formulation of maltodextrin. Additionally, IC(50) value of rifampicin nanocomposite was statistically significantly higher than that of free drug thus providing superior safety profile on lung tissues. CONCLUSION: The obtained results suggested that spray drying of rifampicin nanosuspension utilizing carbohydrates as matrix formers can enhance drug inhalation performance and reduce cellular toxicity. Thus, representing an effective safer pulmonary delivery of anti-tuberculosis drugs.