Mode of action of β-cyclodextrin as an absorption enhancer of the water-soluble drug meglumine antimoniate

Abstract It has been previously reported that β-cyclodextrin (β-CD) enhances the oral absorption of the pentavalent antimony (Sb) drug, meglumine antimoniate (MA). Contrary to the drugs commonly used in association with β-CD, MA is highly soluble in water (solubility >300 mg/mL) and, therefore, the mode of action of β-CD in this system requires clarification. ESI(−)-MS analysis of MA and of the MA/β-CD composition indicated the formation of a 1:1 association compound between 1:1 Sb–meglumine complex and β-CD. A stability constant on the order of 100 L mol −1 was determined for this association compound. When MA solution was heated for 48 h at 55 °C to mimic the conditions used to prepare MA/β-CD, MA was found to suffer dissociation, from high molecular weight Sb complexes into species of lower molecular weight. Strikingly, heated MA was found to be more extensively absorbed in mice by the oral route than MA freshly prepared at room temperature. In vitro skin permeation experiments using MA and MA/β-CD indicated a two-fold increase in the Sb flux for MA/β-CD. These findings support the hypothesis that the improved oral absorption of Sb arises from the increased permeation of MA across lipid bilayers, as a result of the enhanced availability of 1:1 Sb–meglumine complex.