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Intestinal Permeability of β-Lapachone and Its Cyclodextrin Complexes and Physical Mixtures

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Abstract

Background and objectives

β-Lapachone (βLAP) is a promising, poorly soluble, antitumoral drug. βLAP combination with cyclodextrins (CDs) improves its solubility and dissolution but there is not enough information about the impact of cyclodextrins on βLAP intestinal permeability. The objectives of this work were to characterize βLAP intestinal permeability and to elucidate cyclodextrins effect on the dissolution properties and on the intestinal permeability. The final goal was to evaluate CDs influence on the oral absorption of βLAP.

Methods

Binary systems (physical mixtures and inclusion complexes) including βLAP and CDs (β-cyclodextrin: βCD, random-methyl-β-cyclodextrin: RMβCD and sulfobutylether-β-cyclodextrin: SBEβCD) have been prepared and analysed by differential scanning calorimetry. βLAP (and its combinations with CDs) absorption rate coefficients and effective permeability values have been determined in vitro in MDCK or MDCK-Mdr1 monolayers and in situ in rat by a closed loop perfusion technique.

Results

DSC results confirmed the formation of the inclusion complexes. βLAP–CDs inclusion complexes improve drug solubility and dissolution rate in comparison with physical mixtures. βLAP presented a high permeability value which can provide complete oral absorption. Its oral absorption is limited by its low solubility and dissolution rate. Cyclodextrin (both as physical mixtures and inclusion complexes) showed a positive effect on the intestinal permeability of βLAP. Complexation with CDs does not reduce βLAP intestinal permeability in spite of the potential negative effect of the reduction in free fraction of the drug.

Conclusions

The use of RMβCD or SBEβCD inclusion complexes could benefit βLAP oral absorption by enhancing its solubility, dissolution rate and permeability.

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Acknowledgments

This work was partially supported by the following projects: Red-Biofarma. Red para el desarrollo de metodologías biofarmacéuticas racionales que incrementen la competencia y el impacto social de las Industrias Farmacéuticas Locales (DCI ALA/19.09.01/10/21526/245-297/ALFA 111(2010)29), Foodomics evaluation of dietary polyphenols against colon cancer using in vitro and in vivo models (AGL2011-29857-C03-03) and “Diseño de formulaciones de fármacos de baja hidrosolubilidad mediante herramientas de Inteligencia Artificial” (SAF 2012-39878-C02-01) from Spanish Ministry of Science and Innovation. VM-S received a grant from Ministry of Education and Science of Spain and Miguel Hernandez University (FPU AP2010-2372). ME-L thanks the Galician Government (Xunta de Galicia) for her financial support by IN.CI.TE. 2009-2013_Isabel Barreto Program.

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    Authors and Affiliations

    1. Department of Engineering, Pharmacy and Pharmaceutical Technology Area, Facultad de Farmacia, University Miguel Hernández, Elche, Carretera Alicante Valencia km 87, San Juan de Alicante, 03550, Alicante, Spain

      Victor Mangas-Sanjuan, Isabel González-Álvarez, Marta González-Álvarez, Vicente-Germán Casabó & Marival Bermejo

    2. Pharmacy and Pharmaceutical Technology Department, University of Valencia, Valencia, Spain

      Victor Mangas-Sanjuan & Jorge Gutiérrez-Nieto

    3. Pharmacy and Pharmaceutical Technology Department, Campus Vida, University of Santiago de Compostela, Santiago de Compostela, Spain

      Magdalena Echezarreta-López & Mariana Landin

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    1. Victor Mangas-Sanjuan
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    Correspondence to Marival Bermejo.

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    VM-S, JG-N, ME-L, IG-A, MG-A, VG-C, MB and ML have no conflicts of interest to declare.

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    V. Mangas-Sanjuan and J. Gutiérrez-Nieto made equal contributions and are considered first co-authors.

    V.-G. Casabó: deceased, July 7, 2013.

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    Mangas-Sanjuan, V., Gutiérrez-Nieto, J., Echezarreta-López, M. et al. Intestinal Permeability of β-Lapachone and Its Cyclodextrin Complexes and Physical Mixtures. Eur J Drug Metab Pharmacokinet 41, 795–806 (2016). https://doi.org/10.1007/s13318-015-0310-5

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