Unidad de Investigación y Desarrollo en Tecnología Farmacéutica (UNITEFA), CONICET and Departamento de Ciencias Farmacéuticas, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, 5000, Cordoba, Argentina.
Instituto de Investigaciones en Recursos Naturales y Sustentabilidad José Sánchez Labrador S. J. (IRNASUS), CONICET and Cátedra de Farmacología y Toxicología, Facultad de Ciencias Agropecuarias, Universidad Católica de Córdoba, Av. Armada Argentina 3555, X5016DHK, Cordoba, Argentina.
Drug Deliv Transl Res. 2021 Jun;11(3):894-908. doi: 10.1007/s13346-020-00847-9. Epub 2020 Sep 8.
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.
利福平和异烟肼（INH）的体内释放分离已被提议作为避免利福平酸降解的策略，利福平酸降解是利福平生物利用度降低的主要因素之一，可导致耐药结核病。到目前为止，这种策略还很少被探索。本研究的目的是研究利福平与 INH 持续释放系统结合后利福平的稳定性和生物利用度。获得并表征了一系列 INH-海藻酸钠复合物（AA-INH）。研究了 AA-INH 在生物相关介质 pH 1.20 和 6.80 中的独立和顺序释放曲线。此外，将 AA-INH 与先前获得的利福平-羧甲基纤维素快速释放复合物（CMC-RIF）结合，并进行酸溶解试验，以评估利福平酸稳定性并确定利福平和 INH 的溶解效率。最后，在狗中进行了药代动力学研究。AA-INH 很容易在固态下获得。其特性表明其具有离子性质，载药量约为 30%。在酸性介质中，15 分钟时的溶解效率证实了释放分离，AA-INH 和 CMC-RIF 分别为 7.8%和 65.6%。在酸性介质中，AA-INH 系统中 INH 的释放速度较慢，在模拟肠液中增加。在顺序释放实验中，AA-INH 系统中的 INH 在模拟肠液中 2 小时后完全释放。当两种系统结合时，利福平的酸降解显著降低（36.7%），并且给狗口服后利福平的生物利用度增加了 42%。总之，CMC-RIF 和 AA-INH 可用于制定局部固体制剂，以克服结核病治疗中的一些主要障碍。
