ABSTRACT
BACKGROUND AND OBJECTIVES: ß-Lapachone (ßLAP) is a promising, poorly soluble, antitumoral drug. ßLAP combination with cyclodextrins (CDs) improves its solubility and dissolution but there is not enough information about the impact of cyclodextrins on ßLAP intestinal permeability. The objectives of this work were to characterize ßLAP 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 ßLAP. METHODS: Binary systems (physical mixtures and inclusion complexes) including ßLAP and CDs (ß-cyclodextrin: ßCD, random-methyl-ß-cyclodextrin: RMßCD and sulfobutylether-ß-cyclodextrin: SBEßCD) have been prepared and analysed by differential scanning calorimetry. ßLAP (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. ßLAP-CDs inclusion complexes improve drug solubility and dissolution rate in comparison with physical mixtures. ßLAP 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 ßLAP. Complexation with CDs does not reduce ßLAP intestinal permeability in spite of the potential negative effect of the reduction in free fraction of the drug. CONCLUSIONS: The use of RMßCD or SBEßCD inclusion complexes could benefit ßLAP oral absorption by enhancing its solubility, dissolution rate and permeability.
