RESUMEN
The selectivity of encapsulation of leflunomide and teriflunomide by native α-, ß- and γ-cyclodextrins was investigated through 1H NMR and molecular modeling. Thermodynamic analysis revealed the main driving forces involved in the binding. For α-cyclodextrin, the partial encapsulation was obtained while deep penetration was characterized for the other two cyclodextrins, where the remaining polar fragment of the molecule is located outside the macrocyclic cavity. The interactions via hydrogen bonding are responsible for high negative enthalpy and entropy changes accompanying the complexation of cyclodextrins with teriflunomide. These results were in agreement with the molecular modeling calculations, which provide a clearer picture of the involved interactions at the atomic level.
Asunto(s)
Crotonatos/química , Ciclodextrinas/química , Leflunamida/química , Toluidinas/química , Entropía , Hidroxibutiratos , Modelos Moleculares , Nitrilos , Espectroscopía de Protones por Resonancia Magnética , TermodinámicaRESUMEN
In this work, metal-organic frameworks on the basis of γ-cyclodextrin (γCD-MOF) were proposed as carriers for methotrexate (MTX) which is widely used as chemotherapy agent and immune system suppressant. The synthesized γCD-MOF was loaded with MTX by impregnation and co-crystallization. The obtained composites were characterized using powder X-ray diffraction, N2 adsorption/desorption, FTIR spectroscopy, solid-state 13C MAS CP/TOSS NMR and scanning electron microscopy. Pharmaceutically relevant properties of MTX alone and loaded in γCD-MOF were investigated in vitro and in vivo. The faster dissolution of MTX incorporated in γCD-MOF was demonstrated in blank buffers and biorelevant media (FaSSGF, FaSSIF) simulating the gastrointestinal fluids. Inclusion complex formation of MTX with γ-CD enhances the drug dissolution rate and, at the same time, slightly decreases the drug permeability through the lipophilic membrane. The in vivo experiments showed the improved pharmacokinetic parameters of MTX loaded in γCD-MOF.
Asunto(s)
Portadores de Fármacos/química , Estructuras Metalorgánicas/química , Metotrexato/química , gamma-Ciclodextrinas/química , Adsorción , Animales , Diseño de Fármacos , Liberación de Fármacos , Femenino , Semivida , Metotrexato/farmacocinética , Microscopía Electrónica de Rastreo , Permeabilidad , Ratas , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
γ-Cyclodextrin-based metal-organic framework (γCD-MOF) crystals were successfully synthesized using a vapor diffusion method. An applicability of γCD-MOF for encapsulation of immunosuppressive disease-modifying antirheumatic drug leflunomide (LEF) was examined. Loading of LEF in γCD-MOF was performed by impregnation and co-crystallization. The empty and loaded γCD-MOFs were characterized using X-ray powder diffraction, N2 adsorption/desorption, thermogravimetric analysis, 1H NMR and FTIR spectroscopy. It was shown that in the presence of γCD-MOF leflunomide is transformed into its pharmacologically active form - teriflunomide that can be also applied alone in the treatment of multiple sclerosis. It was demonstrated that teriflunomide released from γCD-MOF has improved pharmacologically relevant properties such as solubility, dissolution rate and membrane permeability. It can be proposed that γCD-MOF can be considered as novel strategy for delivery of leflunomide.