Anti-tuberculosis site-specific oral delivery system that enhances rifampicin bioavailability in a fixed-dose...

The in vivo release segregation of rifampicin (RIF) and isoniazid (INH) has been proposed as a strategy to avoid RIF acid degradation, which is known as one of the main factors for reduced RIF bioavailability and can result in drug-resistant tuberculosis. So far, this strategy has been scarcely explored. The aims of this study were to investigate the stability and bioavailability of RIF after combination of a very fast release matrix of RIF with a sustained delivery system of INH. A series of INH-alginic acid complexes (AA-INH) was obtained and characterized. Independent and sequential release profile of AA-INH at biorrelevant media of pH 1.20 and 6.80 was explored. In addition, AA-INH was combined with a RIF-carboxymethylcellulose very fast release complex (CMC-RIF) obtained previously and subjected to acid dissolution assays to evaluate RIF acid stability and determine RIF and INH dissolution efficiencies. Finally, a pharmacokinetic study in dogs was carried out. The AA-INH was easily obtained in solid-state. Their characterization revealed its ionic nature, with a loading capacity of around 30%. The dissolution efficiencies (15 min) confirmed release segregation in acid media with 7.8 and 65.6% for AA-INH and CMC-RIF, respectively. INH release rate from the AA-INH system was slow in acid media and increased in simulated intestinal media. The complete release of INH was achieved after 2 h in simulated intestinal media in the sequential release experiments. The acid degradation of RIF was significantly reduced (36.7%) when both systems were combined and oral administration to dogs revealed a 42% increase in RIF bioavailability. In conclusion, CMC-RIF and AA-INH may be useful for the formulation of a site-specific solid dosage form to overcome some of the main obstacles in tuberculosis treatment. Graphical abstract.