RESUMEN
OBJECTIVES: Glyburide, an important drug for type 2 diabetes, has extremely poor aqueous solubility and resulting low bioavailability. This study describes the ability of hydroxybutenyl-beta-cyclodextrin (HBenBCD) to form complexes with glyburide, with enhanced solubility and dissolution rate in vitro. METHOD: Glyburide and glyburide-HBenBCD were evaluated in various test media known to simulate human gastrointestinal conditions in the fasted and fed states, respectively. KEY FINDINGS: At approximately 14 wt% drug load, in the presence of HBenBCD, an almost 400-fold increase in glyburide aqueous solubility was observed. In the presence of HBenBCD, glyburide solubility was also significantly improved in all physiologically relevant test media. Subsequent dissolution experiments confirmed the solubility study results; the dissolution rate and total amount of drug released were significantly increased. CONCLUSIONS: Complexation with HBenBCD may be an effective way to increase the bioavailability of glyburide.
Asunto(s)
Química Farmacéutica/métodos , Gliburida/química , beta-Ciclodextrinas/química , Cápsulas/química , Fenómenos Químicos , Cromatografía Líquida de Alta Presión/métodos , Análisis Diferencial Térmico/métodos , Jugo Gástrico/química , Gelatina/química , Concentración de Iones de Hidrógeno , Preparaciones Farmacéuticas/síntesis química , Preparaciones Farmacéuticas/química , Solubilidad , Tecnología Farmacéutica/métodos , TemperaturaRESUMEN
The solubility and dissolution of tamoxifen base and tamoxifen citrate with and without hydroxybutenyl-beta-cyclodextrin (HBenBCD) in aqueous and organic media were examined. The solubility of tamoxifen was greatly enhanced by complexation with HBenBCD; pH of the medium, and choice of buffer significantly impacted the amount of drug that could be solubilized. Different tamoxifen:HBenBCD formulations were prepared, including liquid fill capsule formulations, and their dissolution profiles were obtained. These dissolution studies demonstrated that enhanced solubilization of tamoxifen with HBenBCD was effective across a wide variety of formulation options. By complexation of tamoxifen base with HBenBCD, it was possible to obtain solubility and dissolution profiles for tamoxifen base that were essentially identical to that of tamoxifen citrate.
Asunto(s)
Ciclodextrinas/química , Tamoxifeno/química , Tampones (Química) , Química Farmacéutica , Concentración de Iones de Hidrógeno , Moduladores Selectivos de los Receptores de Estrógeno/química , SolubilidadRESUMEN
We have examined the synthesis of hydroxybutenyl cyclomaltooligosaccharides (cyclodextrins) and the ability of these cyclodextrin ethers to form guest-host complexes with guest molecules. The hydroxybutenyl cyclodextrin ethers were prepared by a base-catalyzed reaction of 3,4-epoxy-1-butene with the parent cyclodextrins in an aqueous medium. Reaction byproducts were removed by nanofiltration before the hydroxybutenyl cyclodextrins were isolated by co-evaporation of water-EtOH. Hydroxybutenyl cyclodextrins containing no unsubstituted parent cyclodextrin typically have a degree of substitution of 2-4 and a molar substitution of 4-7. These hydroxybutenyl cyclodextrins are randomly substituted, amorphous solids. The hydroxybutenyl cyclodextrin ethers were found to be highly water soluble. Complexes of HBen-beta-CD with glibenclamide and ibuprofen were prepared and isolated. In both cases, the guest content of the complexes was large, and a significant increase in the solubility of the free drug was observed. Dissolution of the complexes in pH 1.4 water was very rapid, and significant increases in the solubility of the free drugs were observed. Significantly, after reaching equilibrium concentration, a decrease in the drug concentration over time was not observed.