Amorphous solid dispersion of berberine with absorption enhancer demonstrates a remarkable hypoglycemic effect via improving its bioavailability

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• 作者：Meng Zhaojie^a ; ¹ ; Zhang Ming^a ; ¹ ; Wei Shengnan^a ; Bi Xiaojia^a ; Grant M. Hatch^c ; Gu Jingkai^b ; ^{gujk@mail.jlu.edu.cn" class="auth_mail} ; Chen Li^a ; ^{chen_lab@163.com" class="auth_mail} ; ^{chen_lab@hotmail.com" class="auth_mail}
• 关键词：AUC0  ; 鉄?#xA0 ; t ; t  ; =  ; 24  ; h ; area under the plasma concentration versus time curve from zero to last sampling time point ; Cmax ; peak plasma concentration ; CL ; plasma clearance ; dhBer ; dihydroberberine ; DM ; Type 2 Diabetes mellitus ; DSC ; Differential Scanning Calorimetry ; HGSD ; Huang-Gui Solid Dispersion ; Papp ; apparent coefficient of permeation ; PM ; physical mixtures ; PXRD ; Powder X-ray Diffraction ; SC ; sodium caprate ; SEM ; Scanning Electron Microscopy ; STZ ; streptozotocin ; TEER
• 刊名：International Journal of Pharmaceutics
• 出版年：5 June 2014
• 年：2014
• 卷：467
• 期：1-2
• 页码：50-59
• 全文大小：1462 K

文摘

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 (100 mg/kg) improved glucose and lipid metabolism in diabetic rats compared to pure berberine (100 mg/kg), berberine tablets (100 mg/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.