title: Amorphous solid dispersion of berberine with absorption enhancer demonstrates a remarkable hypoglycemic effect via improving its bioavailability.
abstract: 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.
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhaojie
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Ming
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Shengnan
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China.
authors.forename: Bi
authors.initials: B
authors.lastname: Xiaojia
authors.affiliation: Department of Pharmacology and Therapeutics, Center for Research and Treatment of Atherosclerosis, DREAM Manitoba Institute of Child Health, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Grant M
authors.initials: GM
authors.lastname: Hatch
authors.affiliation: Clinical Pharmacology Center, Research Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, China. Electronic address: gujk@mail.jlu.edu.cn.
authors.forename: Gu
authors.initials: G
authors.lastname: Jingkai
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China. Electronic address: chen_lab@163.com.
authors.forename: Chen
authors.initials: C
authors.lastname: Li
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001599:Berberine / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D001682:Biological Availability; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D018938:Caco-2 Cells; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D018360:Crystallography, X-Ray; D003652:Decanoic Acids / Q000737:chemistry*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004195:Disease Models, Animal; D005079:Excipients / Q000737:chemistry*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D008055:Lipids / Q000097:blood; D008297:Male; D008855:Microscopy, Electron, Scanning; D010539:Permeability; D033362:Powder Diffraction; D017208:Rats, Wistar; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D013678:Technology, Pharmaceutical
chemical_list: D001786:Blood Glucose; D003652:Decanoic Acids; D005079:Excipients; D007004:Hypoglycemic Agents; D008055:Lipids; D001599:Berberine; C031071:decanoic acid
keywords: Amorphous solid dispersion; Berberine; Bioavailability; Hypoglycemic effect; Sodium caprate; Type 2 diabetes