Enhanced oral delivery of antimony from meglumine antimoniate/beta-cyclodextrin nanoassemblies

The composition comprising the highly water-soluble drug meglumine antimoniate (MA) and beta-cyclodextrin (beta-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 beta-CD (first step of preparation of MA/beta-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+beta-CD mixture still produced significantly lower serum Sb levels when compared to the MA/beta-CD composition, indicating that the freeze-drying process (second step of preparation of MA/beta-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/beta-CD composition was further characterized by circular dichroism, (1)H 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 190 nm, comprising 1:2:1, 2:2:1 and 2:2:2 NMG-Sb-beta-CD complexes. Another important observation was the ability of the MA/beta-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/beta-CD composition.