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

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]