RESUMO
Low oral bioavailability of berberine due to poor solubility and membrane permeability limits its clinical use for treatment of diabetes. We developed an amorphous solid dispersion of berberine with absorption enhancer sodium caprate, referred to as Huang-Gui Solid Dispersion (HGSD) preparations, and examined them for improvement of dissolution and oral bioavailability. HGSDs were prepared by solvent evaporation, and the formulations of amorphous solid dispersions were characterized by X-ray diffraction, differential scanning calorimetry and scanning electron microscopy. According to in vitro solubility and dissolution studies, P9, the 9th production of HGSDs based on orthogonal test, was sorted out. Then pharmacokinetic behavior of P9 was evaluated by in vitro membrane permeation, in situ intestinal perfusion, and in vivo bioavailability in rats. Furthermore, the anti-diabetic effect of P9 was examined in a type 2 diabetic rat model. It was found that majority of berberine in P9 existed in an amorphous form, and its solubility and dissolution rate were significantly increased. Pharmacokinetic studies demonstrated a 3-fold increase in in vitro membrane permeation, a 4-fold increase in in situ intestinal perfusion and a 5-fold increase in vivo bioavailability of P9 compared to berberine or berberine tablets. In addition, oral administration of P9 (100mg/kg) improved glucose and lipid metabolism in diabetic rats compared to pure berberine (100mg/kg), berberine tablets (100mg/kg) or metformin (300 mg/kg) treatment. These findings indicate that P9 enhances oral bioavailability of berberine and may be a potential candidate drug for treatment of diabetes.
Assuntos
Berberina/farmacocinética , Ácidos Decanoicos/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Excipientes/química , Hipoglicemiantes/farmacocinética , Absorção Intestinal , Administração Oral , Animais , Berberina/administração & dosagem , Berberina/química , Disponibilidade Biológica , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Células CACO-2 , Varredura Diferencial de Calorimetria , Química Farmacêutica , Cristalografia por Raios X , Diabetes Mellitus Tipo 2/sangue , Modelos Animais de Doenças , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Lipídeos/sangue , Masculino , Microscopia Eletrônica de Varredura , Permeabilidade , Difração de Pó , Ratos Wistar , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Tecnologia FarmacêuticaRESUMO
Objective To investigate the protective effect of nimodipine on neuron of the rats with focal cerebral ischemia-reperfusion injury and the expressions of Bax and Bcl-2,and to clarify their mechanisms.Methods The focal cerebral-ischemia reperfusion model was induced by the middle cerebral artery occlusion(MCAO)method. 30 male Wistar rats were randomly divided into sham operation,model,and nimodipine groups(n=10).The neurological deficit score was performed after 2 h ischemia following 2 h reperfusion.The infarction was observed by TUNEL staining and the expressions of Bax and Bcl-2 were detected by SP immunohistochemistry method. Results Compared with model group, the number of apoptotic cells of the rats in nimodipine group was significantly decreased(P<0.05),the expression of Bax was significantly decreased (P<0.05),and the Bcl-2 expression was increased significantly(P<0.05).The morphological examination showed that the neurons of the rats in model group had serious necrosis and edema while the number of dead cells in nimodipine treatment group was reduced and the edema was improved.Conclusion Nimodipine has a protective effect on brain tissue of the rats with focal cerebral ischemia-reperfusion inj ury, which is closely related to the down-regulation of Bax and up-regulation of Bcl-2 and inhibition of the apoptosis of neuron.