International Journal of Pharmaceutics

International Journal of Pharmaceutics 325 (2006) 39–47

Mode of action of -cyclodextrin as an absorption enhancer of the water-soluble drug meglumine antimoniate
Patr´cia S. Martins a , Rosemary Ochoa b , Adriano M.C. Pimenta c , Lucas A.M. Ferreira d , ı Alan L. Melo e , Jos´ B.B. da Silva b , Rub´ n D. Sinisterra b , e e Cynthia Demicheli b , Fr´ d´ ric Fr´ zard a,∗ e e e
Departamento deFisiologia e Biof´sica, Instituto de Ciˆ ncias Biol´ gicas, Universidade Federal de Minas Gerais, ı e o Av. Antˆ nio Carlos 6627, Pampulha, 31270-901 Belo Horizonte, MG, Brazil o b Departamento de Qu´mica, Instituto de Ciˆ ncias Exatas, Universidade Federal de Minas Gerais, ı e Av. Antˆ nio Carlos 6627, Pampulha, 31270-901 Belo Horizonte, MG, Brazil o c Departamento de Bioqu´mica e Imunologia,Instituto de Ciˆ ncias Biol´ gicas, Universidade Federal de Minas Gerais, ı e o Av. Antˆ nio Carlos 6627, Pampulha, 31270-901 Belo Horizonte, MG, Brazil o d Faculdade de Farm´ cia, Universidade Federal de Minas Gerais, a Av. Antˆ nio Carlos 6627, Pampulha, 31270-901 Belo Horizonte, MG, Brazil o e Departamento de Parasitologia, Instituto de Ciˆ ncias Biol´ gicas, Universidade Federal de MinasGerais, e o Av. Antˆ nio Carlos 6627, Pampulha, 31270-901 Belo Horizonte, MG, Brazil o Received 17 April 2006; received in revised form 1 June 2006; accepted 7 June 2006 Available online 13 June 2006
a

Abstract It has been previously reported that -cyclodextrin ( -CD) enhances the oral absorption of the pentavalent antimony (Sb) drug, meglumine antimoniate (MA). Contrary to the drugs commonly usedin association with -CD, MA is highly soluble in water (solubility >300 mg/mL) and, therefore, the mode of action of -CD in this system requires clarification. ESI(−)-MS analysis of MA and of the MA/ -CD composition indicated the formation of a 1:1 association compound between 1:1 Sb–meglumine complex and -CD. A stability constant on the order of 100 L mol−1 was determined for this associationcompound. When MA solution was heated for 48 h at 55 ◦ C to mimic the conditions used to prepare MA/ -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 usingMA and MA/ -CD indicated a two-fold increase in the Sb flux for MA/ -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. © 2006 Elsevier B.V. All rights reserved.
Keywords: Cyclodextrin; Oral; Topical; Antimony; Meglumine antimoniate;ESI-MS

1. Introduction Cyclodextrins are cyclic oligosaccharides composed of glucose units joined through -1,4 glycosidic bonds, which are well known in recognition chemistry as molecular hosts capable of including, with a degree of selectivity, water-insoluble guest molecules via non-covalent interactions within their

∗

Corresponding author. Tel.: +55 31 34992940; fax: +55 31 34992924.E-mail address: frezard@icb.ufmg.br (F. Fr´ zard). e

hydrophobic cavity (Szejtli, 1998). The ability of cyclodextrins to enhance oral or dermal absorption of drugs is a well-documented property, especially in the case of poorly water-soluble drugs (Rajewski and Stella, 1996; Szejtli, 1998; Hirayama and Uekama, 1999; Matsuda and Arima, 1999; Loftsson and Masson, 2001). This property has beenattributed to the increase in thermodynamic activity of the drug in the vehicle and/or to the enhancement of the rate of drug dissolution. The pentavalent organoantimonial drug, meglumine antimoniate (MA), has been used as the first-line drug for the treatment of leishmaniasis (Berman, 1997). Recently, pentavalent antimo-

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