Inhalable chitosan microparticles as tools in tuberculosis therapy

LC Cunha, AM Rosa da Costa, A Grenha

Lung tuberculosis (TB) represents approximately 80% of total cases and, therefore, the lung has been explored as an effective route for the delivery of drugs in the ambit of pulmonary TB. The pulmonary delivery of antitubercular drugs in a carrier system capable of reaching the alveoli, being recognized and phagocytosed by alveolar macrophages (mycobacterium hosts), would be a significant improvement to current oral drug regimens. Chitosan (CS) is a polysaccharide composed of N-acetylglucosamine and D-glucosamine residues, the former being recognised by macrophages and possibly potentiating phagocytosis. This work aimed at producing chitosan microparticles (CS MP) containing two first-line antitubercular drugs, isoniazid (INH) and rifabutin (RFB). A polymeric solution containing 10% (w/w) of INH and 5% (w/w) RFB (weight respective to CS), was spray-dried and the resulting microparticles evaluated as dry powder inhalation targeting alveolar macrophages. Spray-dried CS MP with theoretically adequate properties for deep lung delivery (aerodynamic diameter of 1.98 μm) were produced, efficiently associating isoniazid (INH) and rifabutin (RFB) – 73% and 97%, respectively – in combination. The effect of drug-loaded CS MP on the viability of two cell lines representative of the environment of relevance in pulmonary TB were assessed and absence of toxicity was observed in human alveolar epithelium (A549) and macrophage-differentiated (THP-1) cells. Human macrophage-differentiated THP-1 cells and rat alveolar macrophages NR8383 were exposed to fluorescein-labelled CS MP to assess the ability of CS MP to be taken up by alveolar macrophages. The analysis was performed by flow cytometry and CS MP evidenced strong ability to be captured by macrophages (percentage of phagocytosis >98%). Overall, the obtained data gave positive indications on the potential of the proposed system for an application as inhalable tuberculosis therapy.

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