Segregated Delivery of Rifampicin and Isoniazid from Fixed Dose Combination Bilayer Tablets for the Treatment of Tuberculosis
A. M. Silva
Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Rio de Janeiro, Brazil.
B. Abrahim-Vieira
Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Rio de Janeiro, Brazil.
F. A. do Carmo
Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Rio de Janeiro, Brazil.
L. H. do Amaral
Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Rio de Janeiro, Brazil.
L. C. Silva
Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Rio de Janeiro, Brazil.
C. S. Escudini
Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Rio de Janeiro, Brazil.
M. A. Lopes
Centre for Pharmaceutical Studies, Faculty of Pharmacy, University of Coimbra, Azinhaga de Coimbra, 3000-548 Coimbra, Portugal.
V. P. Sousa
Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Rio de Janeiro, Brazil.
H. C. Castro
Institute of Biology, Federal University of Fluminense, Niterói 24210-130, Rio de Janeiro, Brazil.
F. Veiga
Centre for Pharmaceutical Studies, Faculty of Pharmacy, University of Coimbra, Azinhaga de Coimbra, 3000-548 Coimbra, Portugal.
C. R. Rodrigues
Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Rio de Janeiro, Brazil.
A. J. Ribeiro
Centre for Pharmaceutical Studies, Faculty of Pharmacy, University of Coimbra, Azinhaga de Coimbra, 3000-548 Coimbra, Portugal.
L. M. Cabral *
Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Rio de Janeiro, Brazil.
*Author to whom correspondence should be addressed.
Abstract
Aims: Develop an anti-tuberculosis (TB) Fixed Dose Combination (FDC) tablet containing an immediate release layer (IRL) composed of both rifampicin (RIF) and pyrazinamide (PYR) and a retarded release layer (RRL) comprised of isoniazid (INH) which would allow segregated delivery of RIF and INH.
Study Design: Trials were conducted on the pre-formulations and formulations to assess the compatibility of excipients and obtain a modified release profile, for an IRL consisting of both RIF and PYR and a RRL containing INH.
Place and Duration of Study: This study was performed at the Laboratory of Pharmaceutical Industrial Technology, Drug and Pharmaceutical Department, Faculty of Pharmacy, between March 2008 and April 2010.
Methodology: Preformulation studies were performed on RIF and PYR, alone and in combination with excipients. The pharmacopeic attributes of the distinct layers and the FDC tablets were evaluated for hardness, friability and disintegration time. The FDC bilayer tablets were analyzed for their drug content and cumulative dissolution of the drug.
Results: Fourier transform infrared, x-ray diffraction and differential scanning calorimetry results revealed the presence of amorphous and crystalline RIF forms and no potentially relevant incompatibilities were identified in the kneaded system containing RIF, PYR and excipients. In vitro drug release from the FDC tablets revealed that the intragranular addition of croscarmellose sodium into the IRL rendered a cumulative dissolution of RIF and PYR within the limits of simulated gastric fluid. And, for RRL, the most effective retardant matrix excipient was found to be hydroxypropyl methylcellulose.
Conclusion: Segregated delivery of RIF and INH from bilayer tablets is an option for the development of immediate release FDC tablets and the retarded release of INH, this strategy proved suitable for preventing contact of these two drugs under acidic conditions. This finding suggested that RIF had a high in vivo bioavailability which qualifies this FDC for future bioavailability studies.
Keywords: Tuberculostatic drugs, bilayer tablet, drug interactions, fixed dose combination, segregated release