Spray-dried polysaccharide microparticles aimed at pulmonary delivery of antitubercular drugs

Dissertação de mestrado, Ciências Biomédicas, Departamento de Ciências Biomédicas e Medicina, Universidade do Algarve, 2015

Microparticles (MPs) of konjac glucomannan (KGM) are proposed in this thesis as an alternative therapeutic approach for antitubercular drug delivery to the lung, in the ambit of tuberculosis (TB) therapy. KGM is composed of mannose groups that might comprise an entry mechanism in macrophages infected with Mycobacterium tuberculosis, mimicking one of the input paths of this infectious agent causer of TB. For this purpose, KGM MPs need to have certain properties, in particular an aerodynamic diameter between 1 and 3 μm that enables reaching the alveolar zone. These properties might be attained by a production using spray-drying technology. The objective of this work was to produce MPs of KGM through this process and associate two first-line antitubercular drugs, isoniazid (INH) and rifabutin (RFB). Furthermore, the effect of incorporating mannitol or leucine in the microparticle formulations was evaluated, regarding MPs aerodynamic characteristics, drug association and release, and biocompatibility profile. After an initial optimization that required a hydrolysis of the original KGM polymer to enable spray-drying, several formulations of MPs were produced and characterised. The use of mannitol or leucine has demonstrated to improve the flow properties of some formulations, as did the association of RFB. However, the incorporation of excipients brought some disadvantages, especially regarding the in vitro release rate of the drug, which became faster. Additionally, the incorporation of mannitol was found to affect the association of INH, which became lower, suggesting a competing effect between INH and mannitol. Cytotoxicity assays in alveolar epithelial cells revealed that RFB-loaded KGM MPs may have a considerably toxic effect when used at a concentration of 1 mg/mL, in particular if MPs are also comprised of leucine. The obtained results indicate that KGM MPs are suitable inhalable delivery systems for antitubercular drugs. Considering that a combination of drugs is advised by WHO in TB treatment, no benefit was found to occur from the incorporation of either leucine or mannitol in the formulation of KGM MPs.