title: Enhanced oral delivery of antimony from meglumine antimoniate/beta-cyclodextrin nanoassemblies.
abstract: 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.
authors.affiliation: Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, Pampulha, 31270-901 Belo Horizonte, MG, Brazil. frezard@icb.ufmg.br
authors.forename: Frédéric
authors.initials: F
authors.lastname: Frézard
authors.forename: Patrícia S
authors.initials: PS
authors.lastname: Martins
authors.forename: Ana Paula C O
authors.initials: AP
authors.lastname: Bahia
authors.forename: Laurence
authors.initials: L
authors.lastname: Le Moyec
authors.forename: Alan L
authors.initials: AL
authors.lastname: de Melo
authors.forename: Adriano M C
authors.initials: AM
authors.lastname: Pimenta
authors.forename: Milena
authors.initials: M
authors.lastname: Salerno
authors.forename: José B B
authors.initials: JB
authors.lastname: da Silva
authors.forename: Cynthia
authors.initials: C
authors.lastname: Demicheli
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000965:Antimony / Q000097:blood*; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D002942:Circular Dichroism; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D005612:Freeze Drying; D006358:Hot Temperature; D009682:Magnetic Resonance Spectroscopy; D008536:Meglumine / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D000077485:Meglumine Antimoniate; D051379:Mice; D008954:Models, Biological; D053758:Nanoparticles / Q000737:chemistry*; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D010316:Particle Size; D021241:Spectrometry, Mass, Electrospray Ionization; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D000981:Antiprotozoal Agents; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D009942:Organometallic Compounds; D047392:beta-Cyclodextrins; D008536:Meglumine; D000077485:Meglumine Antimoniate; D000965:Antimony; C031215:betadex