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Abstract: The composition comprising the highly water-soluble drug meglumine antimoniate (MA) and β-cyclodextrin (β-CD) was shown previously to enhance the absorption of Sb by oral route and render MA orally active in a murine model of cutaneous leishmaniasis. This unexpected behaviour was attributed, in part, to the fact that the heating of equimolar mixture of MA and β-CD (first step of preparation of MA/β-CD composition) induced the depolymerization of MA from high-molecular weight Sb complexes into 1:1 Sb–meglumine complex, resulting in an enhanced oral bioavailability of Sb. In the present work, we demonstrate that the heated MA+β-CD mixture still produced significantly lower serum Sb levels when compared to the MA/β-CD composition, indicating that the freeze-drying process (second step of preparation of MA/β-CD composition) is required for achieving a high absorption of Sb by oral route. To get insight into the physicochemical alterations induced by the freeze-drying step, the MA/β-CD composition was further characterized by circular dichroism, 1H NMR and ESI(−)-MS and photon correlation spectroscopy. The freeze-drying process was found to promote the formation of supramolecular nanoassemblies with a mean hydrodynamic diameter of 190nm, comprising 1:2:1, 2:2:1 and 2:2:2 NMG–Sb–β-CD complexes. Another important observation was the ability of the MA/β-CD composition to act as a sustained release system of the antimonial drug MA, suggesting that this property may result in the change of the drug absorption site in the gastrointestinal tract. A model is proposed for the mechanisms involved in the enhanced absorption of Sb from the MA/β-CD composition. [Copyright &y& Elsevier]

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 >300mg/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 100Lmol−1 was determined for this association compound. When MA solution was heated for 48h 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. [Copyright &y& Elsevier]