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Research Article Open access CC BY 3.0

Segregated Delivery of Rifampicin and Isoniazid from Fixed Dose Combination Bilayer Tablets for the Treatment of Tuberculosis

A. M. Silva, B. Abrahim-Vieira, F. A. do Carmo, L. H. do Amaral, L. C. Silva, C. S. Escudini, M. A. Lopes, V. P. Sousa, H. C. Castro, F. Veiga, C. R. Rodrigues, A. J. Ribeiro, L. M. Cabral

Journal of Pharmaceutical Research International · pp. 1781–1801 · Published 19 Jul 2014

10.9734/BJPR/2014/11525

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.

Tuberculostatic drugs bilayer tablet drug interactions fixed dose combination segregated release

References (46)

  1. 1 A new evolutionary scenario for the Mycobacterium tuberculosis complex [DOI]
  2. 2 THE UNITED STATES PHARMACOPEIA. [DOI]
  3. 3 Fixed-Dose Combinations Improve Medication Compliance: A Meta-Analysis [DOI]
  4. 4 Global Tuberculosis Control 2011, WHO Report 2011
  5. 5 Global Tuberculosis Control: WHO Report 2011 [DOI]
  6. 6 New old challenges in tuberculosis: Potentially effective nanotechnologies in drug delivery [DOI]
  7. 7 The rationale for recommending fixed-dose combination tablets for treatment of tuberculosis.
  8. 8 Solid-state characterization of rifampicin samples and its biopharmaceutic relevance [DOI]
  9. 9 Fixed dose drug combinations (FDCs): rational or irrational: a view point [DOI]
  10. 10 Application of thermal analysis to the study of antituberculosis drugs–excipient compatibility [DOI]
  11. 11 Infrared spectra of pyrazine, pyrimidine and pyridazine in solid argon [DOI]
  12. 12 Cellulose Matrices for Zero-Order Release of Soluble Drugs [DOI]
  13. 13 Impaired bioavailability of rifampicin in presence of isoniazid from fixed dose combination (FDC) formulation [DOI]
  14. 14 Pyrazinamide Polymorphs: Relative Stability and Vibrational Spectroscopy [DOI]
  15. 15 A New Insight into Pyrazinamide Polymorphic Forms and their Thermodynamic Relationships [DOI]
  16. 16 A critical review of the probable reasons for the poor variable bioavailability of rifampicin from anti-tubercular fixed-dose combination (FDC) products, and the likely solutions to the problem [DOI]
  17. 17 Encapsulation of Rifampicin in a solid lipid nanoparticulate system to limit its degradation and interaction with Isoniazid at acidic pH [DOI]
  18. 18 FTIR, FT Raman spectra and molecular structural confirmation of isoniazid
  19. 19 Regional gastrointestinal permeability of rifampicin and isoniazid (alone and their combination) in the rat.
  20. 20 The Reason for an Increase in Decomposition of Rifampicin in the Presence of Isoniazid under Acid Conditions [DOI]
  21. 21 Controlled Release Hydrophilic Matrix Tablet Formulations of Isoniazid: Design and In Vitro Studies [DOI]
  22. 22 Solubility and Dissolution Properties of Generic Rifampicin Raw Materials [DOI]
  23. 23 Preparation and evaluation of the effect of particle size on the properties of chitosan-montmorillonite nanoparticles loaded with isoniazid [DOI]
  24. 24 Comparative bioavailability of rifampicin, isoniazid and pyrazinamide from a four drug fixed dose combination with separate formulations at the same dose levels [DOI]
  25. 25 World Health Organization [DOI]
  26. 26 Tuberculosis: from molecular pathogenesis to effective drug carrier design [DOI]
  27. 27 Exploration of the Pyrazinamide Polymorphism at High Pressure [DOI]
  28. 28 A novel solid dosage form of rifampicin and isoniazid with improved functionality [DOI]
  29. 29 Adherence to Self-Administered Tuberculosis Treatment in a High HIV-Prevalence Setting: A Cross-Sectional Survey in Homa Bay, Kenya [DOI]
  30. 30 Exploring prospects of novel drugs for tuberculosis [DOI]
  31. 31 Biopharmaceutic and pharmacokinetic aspects of variable bioavailability of rifampicin [DOI]
  32. 32 Assessment of bioequivalence of rifampicin, isoniazid and pyrazinamide in a four drug fixed dose combination with separate formulations at the same dose levels [DOI]
  33. 33 The physical and chemical stability of anti-tuberculosis fixed-dose combination products under accelerated climatic conditions.
  34. 34 Fixed dose combinations for tuberculosis: Lessons learned from clinical, formulation and regulatory perspective [DOI]
  35. 35 Oral matrix tablet formulations for concomitant controlled release of anti-tubercular drugs: Design and in vitro evaluations [DOI]
  36. 36 Kinetics for degradation of rifampicin, an azomethine-containing drug which exhibits reversible hydrolysis in acidic solutions [DOI]
  37. 37 Bioequivalence trials of rifampicin containing formulations: extrinsic and intrinsic factors in the absorption of rifampicin [DOI]
  38. 38 Effect of source variation on drug release from HPMC tablets: Linear regression modeling for prediction of drug release [DOI]
  39. 39 Evaluation of bioequivalence of isoniazid and pyrazinamide in three and four drugs fixed dose combinations using WHO simplified protocol [DOI]
  40. 40 Stability of isoniazid, rifampin and pyrazinamide in suspensions used for the treatment of tuberculosis in children [DOI]
  41. 41 Recent developments in the epidemiology and management of tuberculosis – new solutions to old problems? [DOI]
  42. 42 Cost-Effectiveness of Directly Observed Versus Self-Administered Therapy for Tuberculosis [DOI]
  43. 43 The FT-IR spectra of pyrazinamide complexes of transition metal(II) tetracyanonickelate [DOI]
  44. 44 Tailored release drug delivery system for Rifampicin and Isoniazid for enhanced bioavailability of Rifampicin [DOI]
  45. 45 An experimental and theoretical vibrational spectra of isoniazide [DOI]
  46. 46 A decision tree for rapid quality assurance and control of rifampicin-containing oral dosage forms for global distribution for tuberculosis treatment [DOI]

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