Barbosa Jahamunna A A, Zoppi Ariana, Quevedo Mario A, de Melo Polyanne N, de Medeiros Arthur S A, Streck Letícia, de Oliveira Alice R, Fernandes-Pedrosa Matheus F, Longhi Marcela R, da Silva-Júnior Arnóbio A
Graduate Program on Pharmaceutical Sciences, Department of Pharmacy, Federal University of Rio Grande do Norte (UFRN), Av. General Gustavo Cordeiro de Farias, Petrópolis, 59072-570 Natal, Brazil.
Research and Pharmaceutical Technology Development Unit (UNITEFA, CONICET-UNC) and Department of Pharmacy, Faculty of Chemical Sciences, National University of Córdoba, Ciudad Universitaria, X5000HUA Córdoba, Argentina.
Int J Mol Sci. 2014 Sep 25;15(9):17077-99. doi: 10.3390/ijms150917077.
The interaction of methotrexate (MTX) with beta-cyclodextrin (β-CD) in the presence of triethanolamine (TEA) was investigated with the aim to elucidate the mechanism whereby self-assembly cyclodextrin systems work in association with this third component. Solubility diagram studies showed synergic increment of the MTX solubility to be about thirty-fold. Experiments using 2D ROESY and molecular modeling studies revealed the inclusion of aromatic ring III of the drug into β-CD cavity, in which TEA contributes by intensifying MTX interaction with β-CD and stabilizes MTX:β-CD:TEA ternary complex by electrostatic interaction. The maintenance of these interactions in solid phase was also studied in ternary MTX:β-CD:TEA and comparisons were made with freeze dried binary MTX:β-CD and physical mixtures. FTIR studies evidenced that MTX-β-CD interaction remained in solid ternary complexes, which was also supported by thermal (differential scanning calorimetry (DSC), thermogravimetric analysis (TG)/first derivative of TG analysis (DTG) and C,N,H elementary analysis) and structural (X-ray diffraction analysis, (XRD)) studies, mainly regarding the increment of drug stability. The efficient in vitro drug dissolution studies successfully demonstrated the contribution of ternary complexes, which highlights the importance of this possible new raw material for further applications in drug delivery systems.
研究了甲氨蝶呤（MTX）与β-环糊精（β-CD）在三乙醇胺（TEA）存在下的相互作用，旨在阐明自组装环糊精系统与该第三种成分协同作用的机制。溶解度图研究表明，MTX的溶解度协同增加了约30倍。使用二维ROESY和分子建模研究的实验表明，药物的芳香环III被包合在β-CD腔内，其中TEA通过增强MTX与β-CD的相互作用发挥作用，并通过静电相互作用稳定MTX:β-CD:TEA三元复合物。还研究了三元MTX:β-CD:TEA中这些相互作用在固相中是否保持，并与冻干的二元MTX:β-CD和物理混合物进行了比较。FTIR研究证明MTX-β-CD相互作用在固体三元复合物中仍然存在，热分析（差示扫描量热法（DSC）、热重分析（TG）/TG分析的一阶导数（DTG）和C、N、H元素分析）和结构分析（X射线衍射分析（XRD））也支持这一点，主要涉及药物稳定性的提高。高效的体外药物溶出研究成功证明了三元复合物的作用，这突出了这种可能的新原料在药物递送系统进一步应用中的重要性。
