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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]

Abstract: The chemical structures of the pentavalent antimonial drugs, meglumine antimonate (MA) and sodium stibogluconate (SSG), were re-evaluated using electrospray ionization mass spectrometry (ESI-MS) and osmolarity measurements. Both MA and SSG were found to contain 1:1, 1:2, 2:2 and 2:3 SbV-ligand complexes. ESI-MS analysis of MA showed negatively-charged 1:1 (m/z 364) and 2:2 (m/z 765) SbV–meglumine complexes, supporting the predominance of zwitterionic species in solution. Our data are consistent with a structure for the 1:2 SbV–meglumine, which differs from that previously postulated, with two positively-charged amino groups and one negatively-charged antimonate group. Instead of the commonly hypothesized structure for SSG, in which two Sb atoms are linked by an oxygen, an alternative structure is proposed, based on the ability of SbV–gluconate complexes to polymerize. MA (or SSG) in concentrated aqueous solutions, such as of MA (or SSG) in its commercial form, is expected to consist mainly of a mixture of 2:2, 2:3 and 2:1 SbV-ligand complexes, as suggested by the 2:1 Sb-to-particle ratio found by osmometry. 1:1 SbV-ligand complexes in MA and SSG are expected to play an important pharmacological role, as suggested by the slow increase of osmolarity of MA solution upon dilution at 37°C (half-time of 20min). [Copyright &y& Elsevier]

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]