Rifampicin-Loaded ‘Flower-Like’ Polymeric Micelles for Enhanced Oral Bioavailability in An Extemporaneous Liquid Fixed-Dose Combination with Isoniazid

Abstract

Background: Coadministration of rifampicin (RIF)/isoniazid (INH) is clinically recommended to improve the treatment of tuberculosis. Under gastric conditions, RIF undergoes fast hydrolysis (a pathway hastened by INH) and oral bioavailability loss. Aim: We aimed to assess the chemical stabilization and the oral pharmacokinetics of RIF nanoencapsulated within poly(ε-caprolactone)-b-PEG-b-poly(ε-caprolactone) ‘flower-like’ polymeric micelles. Materials & methods: The chemical stability of RIF was evaluated in vitro under acid conditions with and without INH, and the oral pharmacokinetics of RIF-loaded micelles in rats was compared with those of a suspension coded by the US Pharmacopeia. Results: Nanoencapsulation decreased the degradation rate of RIF with respect to the free drug. Moreover, in vivo data showed a statistically significant increase of RIF oral bioavailability (up to 3.3-times) with respect to the free drug in the presence of INH. Conclusion: Overall results highlight the potential of this nanotechnology platform to develop an extemporaneous liquid RIF/INH fixed-dose combination suitable for pediatric administration.

Original submitted 6 April 2013; Revised submitted 7 August 2013

Keywords::

• extemporaneous liquid rifampicin/isoniazid fixed-dose combination
• improved oral pharmacokinetics
• pediatric tuberculosis
• poly(ε-caprolactone)-b-PEG-b-poly(ε-caprolactone) ‘flower-like’ polymeric micelle
• rifampicin chemical stabilization

Financial & competing interests disclosure

MA Moretton thanks PhD scholarships from Consejo Nacional de Investigaciones Científicas y Técnicas. The work was supported by grants from University of Buenos Aires (UBACyT 20020090200189) and Consejo Nacional de Investigaciones Científicas y Técnicas (PIP0220). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Acknowledgements

The authors thank D Chiappetta for technical assistance.

Additional information

Funding

MA Moretton thanks PhD scholarships from Consejo Nacional de Investigaciones Científicas y Técnicas. The work was supported by grants from University of Buenos Aires (UBACyT 20020090200189) and Consejo Nacional de Investigaciones Científicas y Técnicas (PIP0220). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.