Formulation and In Vitro Studies of a Fixed-Dose Combination of a Bilayer Matrix Tablet Containing Metformin HCl as Sustained Release and Glipizide as Immediate Release

The emerging new fixed dose combination of metformin hydrocholride (HCl) as sustained release and glipizide as immediate release were formulated as a bilayer matrix tablet using hydroxy propyl methyl cellulose (HPMC) as the matrix-forming polymer, and the tablets were evaluated via in vitro studies. Three different grades of HPMC (HPMC K 4M, HPMC K 15M, and HPMC K 100M) were used. All tablet formulations yielded quality matrix preparations with satisfactory tableting properties. In vitro release studies were carried out at a phosphate buffer of pH 6.8 with 0.75% sodium lauryl sulphate w/v using the apparatus I (basket) as described in the . The release kinetics of metformin were evaluated using the regression coefficient analysis. There was no significant difference in drug release for different viscosity grade of HPMC with the same concentration. Tablet thus formulated provided sustained release of metformin HCl over a period of 8 hours and glipizide as immediate release.     

格列吡嗪-β-环糊精包合物的制备及其理化性质考察

研究了格列吡嗪 β 环糊精包合物的制备方法,考察了包合物的理化性质。通过实验优化了格列吡嗪 β 环糊精包合物的制备工艺,确定n(格列吡嗪)∶n(β 环糊精)=1∶2,包合时间为8h;制得产物的包合率为91 73%。HPLC图谱显示,格列吡嗪被β 环糊精包合前后的主成分没有发生变化,包合物的DSC图谱和X射线粉末衍射图谱与格列吡嗪、格列吡嗪 β 环糊精混合物的图谱具有显著性差异。格列吡嗪包合物的溶解度是格列吡嗪的10倍,体外溶出速率有显著提高。实验表明,格列吡嗪被β 环糊精包合后呈现出新的物相特征,与格列吡嗪相比其理化性质有显著的改变。     

环丙沙星对美吡达的药代学和药效学的影响

目的 研究美吡达与环丙沙星联合应用时环丙沙星对美吡达药代动力学及药效学的影响。方法 糖尿病大鼠24 只分为联合用药组(环丙沙星+美吡达)及单独用药组(美吡达),治疗9 d 后分别测定两组美吡达血药浓度并计算药代动力学参数及血糖。结果 两组大鼠美吡达的药代动力学过程均符合一房室模型。且联合用药组美吡达血药浓度显著升高,清除率下降50%(P<0.05),吸收半衰期延长63.7 %(P<0.05),单独应用美吡达治疗后血糖为5.978 mmol·L^-1,联合应用环丙沙星治疗后血糖为5.301 mmol·L^-1;两组降糖效果差异具有显著性。结论 环丙沙星对美吡达的吸收药代动力学有影响,美吡达联合应用环丙沙星降糖效果比单独应用美吡达时强。故同时给药时应注意调整美吡达的用药剂量以保证用药安全。     

乙基纤维素用于渗透泵片包衣的处方研究

目的研究乙基纤维素(EC)用于渗透泵包衣对药物释放的影响。方法以EC和醋酸纤维素(CA)复合材料为控释衣膜,制备格列吡嗪双层渗透泵控释片,以自制片与市售对照药的体外释药数据的相似因子?2以及释药速率作为评价指标,考察EC:CA比例、包衣增重、EC型号等因素对药物体外释放的影响。结果确定最优处方为包衣增重10%,EC与CA比例1:10,EC型号100cp,其体外释药特征与对照基本一致。结论通过EC和CA混合包衣,可实现药物控释,有效地降低包衣增重,缩短包衣时长。     

Synchronized and controlled release of metformin hydrochloride/glipizide from elementary osmotic delivery

Abstract

The combination of metformin hydrochloride (MTF) and glipizide (GLZ) is second-line medication for diabetes mellitus type 2 (DMT2). In the present study, elementary osmotic pump ( EOP) tablet is designed to deliver the combination of MTF and GLZ in a sustained and synchronized manner. By analyzing different variables of the formulation, sodium hydrogen carbonate is introduced as pH modifier to improve the release of GLZ, while ethyl cellulose acts as release retardant to reduce the burst release phase of MTF. A two-factor, three-level face-centered central composite design (FCCD) is applied to investigate the impact of different factors on drug release profile. Compared with conventional tablets, the EOP tablet demonstrates a controlled release behavior with relative bioavailability of 99.2% for MTF and 99.3% for GLZ. Data also shows EOP tablet is able to release MTF and GLZ in a synchronized and sustained manner both in vitro and in vivo.     

格列嗪及二甲双胍对Ⅱ型糖尿病人血清胰岛素样生长因子-1,2的影响

目的 探讨临床常用的口服降糖药物格列吡嗪及二甲双胍和对Ⅱ型糖尿病人血清胰岛素样生长因子-1, 2(IG F-1, 2)的影响。方法 采用治疗前后自身对照研究, 分别给予格列吡嗪或二甲双胍治疗2w k, 比较两种药物对Ⅱ型糖尿病患者空腹IGF-1,IGF-2 血清水平的影响。结果 二甲双胍治疗组(25例)空腹血清IGF-1, IGF-2 治疗后无明显变化;格列吡嗪(40 例) 治疗后空腹血清IGF-1 升高[ (181.8±104.5)v s (209.0 ±88.2)ng·ml^-1 ,(P <0.05)], IGF-2 治疗后无明显变化;治疗后2组血糖均明显下降(P 均<0.01), 格列吡嗪组治疗后C 肽水平明显升高(P <0.05), 二甲双胍组治疗后C 肽水平无明显变化。结论 格列吡嗪和二甲双胍对Ⅱ型糖尿病患者血清IGF-1 水平有不同的影响。     

Inlay osmotic pump tablets containing metformin and glipizide

The goal of diabetes therapy today is to achieve and maintain as near normal glycemia as possible to prevent the long-term microvascular and macrovascular complications of an elevated blood glucose. A newly developed inlay osmotic pump tablet (IOPT) can deliver glipizide (GLZ) and metformin HCl (MET) gradually in controlled manner. The aim of present investigation was to prepare the IOPT that can deliver >75% of GLZ in 2?h, whereas MET released after 2?h and sustained up to 12?h. In the present work, HP-β-CD was used to modify the solubility of GLZ before incorporating in the osmotic system and MET was spray-dried with HPMC A15C to modify its release profile, flow property, and compressibility. Various parameters mainly G_75% (75% GLZ release), t_LMET (lag time of MET release from device), Q_{10 h} (percent of MET released within 10?h), and RSQ_ZERO (R² of release data fitted to zero-order equation) were used to compare different formulations. The effects of different formulation variables, that is, osmagents, concentration of hydrophilic polymer, diameter of drug releasing orifice, and coating composition on the drug release profile were investigated. The release rate of GLZ could be effectively modified by the addition of sodium carbonate and sodium chloride, whereas the release rate of MET was adjusted by dual-coating system and by addition of hydrophilic polymer. The developed inlay osmotic system could be effective in the multidrug therapy of diabetes by delivering both drugs in a controlled manner.     

Solid Carriers for Improved Solubility of Glipizide in Osmotically Controlled Oral Drug Delivery System

The purpose of this study was to increase the solubility of glipizide (gli) by solid dispersions SDs technique with polyvinylpyrrolidone (PVP) in aqueous media. The gli–PVP solid dispersion systems was prepared by physical mixing or spray drying method, and characterized by differential scanning calorimetry (DSC), X-ray powder diffraction (XRD) analysis, Fourier transformation-infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM). The elementary osmotic pumps (EOPs) were prepared with gli–PVP complex and the effect of the PVP percentages on the enhancing of gli dissolution rate was studied. The influences of various parameters e.g., drug- PVP ratio, level of solubility modifier, coating weight gain and diameter of drug releasing orifice on drug release profiles were also investigated. The solubility and dissolution rates of gli were significantly increased by solid dispersion using spray dried method as well as their physical mixture. The obtained results indicated that gli–PVP solid dispersion system has suitable solubility behavior in EOP tablets.     

Formulation and in vitro studies of a fixed-dose combination of a bilayer matrix tablet containing metformin HCl as sustained release and glipizide as immediate release

The emerging new fixed dose combination of metformin hydrocholride (HCl) as sustained release and glipizide as immediate release were formulated as a bilayer matrix tablet using hydroxy propyl methyl cellulose (HPMC) as the matrix-forming polymer, and the tablets were evaluated via in vitro studies. Three different grades of HPMC (HPMC K 4M, HPMC K 15M, and HPMC K 100M) were used. All tablet formulations yielded quality matrix preparations with satisfactory tableting properties. In vitro release studies were carried out at a phosphate buffer of pH 6.8 with 0.75% sodium lauryl sulphate w/v using the apparatus I (basket) as described in the United States Pharmacopeia (2000). The release kinetics of metformin were evaluated using the regression coefficient analysis. There was no significant difference in drug release for different viscosity grade of HPMC with the same concentration. Tablet thus formulated provided sustained release of metformin HCl over a period of 8 hours and glipizide as immediate release.     

格列吡嗪控释片治疗II 型糖尿病的临床疗效评价

目的: 对比研究格列吡嗪控释片与格列吡嗪速释片对Ⅱ型糖尿病的疗效。方法: 选择80 例Ⅱ型糖尿病患者, 给予格列吡嗪控释片( n =50) 和格列吡嗪速释片( n =30) 治疗, 观察两组治疗前后血糖和胰岛素的变化。结果: 格列吡嗪控释片每日一次服用的降糖效果与格列吡嗪速释片每日2 ～ 3 次服用效果相同;后者治疗后空腹和餐后胰岛素较前者明显升高。结论: 格列吡嗪控释片有较好的降糖效果, 同时不引起高胰岛素血症。