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

Abstract

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.

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Data availability

All data generated or analyzed during this study are included in this published article (and its supplementary information file).

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Acknowledgments

Luciani-Giacobbe thanks CONICET for her postdoctoral scholarship. We thank Dr. Paul Hobson, native speaker, for revision of the manuscript.

Funding

This work was supported by Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET, grant number 11220120100461), the Fondo para la Investigación Científica y Tecnológica (FonCyT, grant number PICT 0173), and the Universidad Nacional de Córdoba (SECYT-UNC, grant number 162/12).

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Luciani-Giacobbe, L.C., Lorenzutti, A.M., Litterio, N.J. et al. Anti-tuberculosis site-specific oral delivery system that enhances rifampicin bioavailability in a fixed-dose combination with isoniazid. Drug Deliv. and Transl. Res. 11, 894–908 (2021). https://doi.org/10.1007/s13346-020-00847-9

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Keywords

  • Swellable drug-polyelectrolyte matrices
  • Solid state characterization
  • Dissolution
  • Stability
  • Pharmacokinetics