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首页> 外文学位 >Development and characterization of a solid self-microemulsifying drug delivery system (SMEDDS) of albendazole and evaluation of oral bioavailability in rabbits.
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Development and characterization of a solid self-microemulsifying drug delivery system (SMEDDS) of albendazole and evaluation of oral bioavailability in rabbits.

机译：阿苯达唑固体自微乳化药物递送系统（SMEDDS）的开发和表征以及兔口服生物利用度的评估。

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摘要

Albendazole's (ABZ) poor aqueous solubility is a major determinant of its variable therapeutic response (20 to 50%). The primary objectives of the present work were, first, to develop, optimize and characterize the composition of a stable liquid and solid self-microemulsifying drug delivery system (SMEDDS) of ABZ and second, to evaluate its oral bioavailability in healthy rabbits. In this study, the process parameters of the fluid bed processes impacting the quality attribute of a solid SMEDDS system of ABZ were also evaluated. A D-optimal mixture design of experiments was used to select the levels of constraints of the liquid SMEDDS formulation variables. The predicted composition was optimized using four responses such as dispersion performance, droplet sizes, dissolution efficiency (DE) and time for 85% drug release ( t85%). The optimized liquid SMEDDS formulation of ABZ (5 mg/g) was characterized by its droplet size, zeta potential and viscosity. Based on the core liquid SMEDDS composition, a supersaturating solid SMEDDS formulation containing higher amount of ABZ (10 mg/g) was prepared by fluid-bed granulating the liquid SMEDDS using granular sorbitol as a carrier and acidified PEG 4000 as a supersaturating polymer. The in vitro dissolution studies were performed at pH 1.2--7.4. Solid state characterization of the solid SMEDDS was performed by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRPD). The chemical and thermodynamic stability of both liquid and solid SMEDDS formulations of ABZ was evaluated by stressing them at higher temperatures (up to 60°C) for 60 days. A randomized cross-over pharmacokinetic study was conducted using three rabbits by giving them an oral dose of 10 mg/kg of body weight. The relative bioavailability was calculated against a commercial suspension of ABZ (Zentel(TM), GlaxoSmithKline). A fractional factorial design (4x2) with four parameters (spray rate, inlet air temperature, inlet air flow and atomization air pressure) was used to evaluate the fluid bed process to manufacture solid SMEDDS particles. The optimal composition of ABZ-SMEDDS formulation of ABZ with approximately 5 mg/g drug loading was predicted to have Cremophor EL (30% w/w), Tween 80 (15% w/w), Capmul PG-8 (10% w/w) and acidified PEG 400 (45% w/w). When dispersed in water, it produced droplet sizes of 37.3 +/- 2.7 nm. The zeta potential was found to be neutral (-1.562 mV) whereas the initial viscosity was high (1244 cp at 24°C). The droplet size analysis of reconstituted microemulsion revealed no difference between liquid and solid SMEDDS formulation. The in vitro dissolution profiles were found to be pH independent for both SMEDDS formulations. The DSC theromogranms and XRD study revealed absence of crystallinity of ABZ in the solid SMEDDS formulations. The solid SMEDDS showed an improved chemical stability at higher temperature than its liquid counterpart, although both formulations were thermodynamically stable at room temperature. The same dose of ABZ in the solid SMEDDS and in the liquid SMEDDS resulted in similar AUC 0&rarr24h and Cmax values, but the maximum absorption was resulted by the solid SMEDDS. The AUC0&rarr24h and Cmax after oral administration of the solid SMEDDS were 1.86- and 1.64-fold higher, respectively, compared with those of the commercial suspension (ZentelRTM, GlaxoSmithKline, USA). For process development study, spray rate was found to increase the sauter-mean diameter (SMD). The effect of inlet air temperature on the peak moisture which is directly related to the mean particle size was found to be significant. This study demonstrated a strategy for the development of a supersaturated SMEDDS formulation and of a drug with low aqueous solubility. These results showed that the solid SMEDDS may produce an improved bioavailability with releasing microemulsion lipid droplets from the formulation in vivo.
机译：阿苯达唑（ABZ）的水溶性差是其可变治疗反应（20％至50％）的主要决定因素。当前工作的主要目标是，首先，开发，优化和表征ABZ稳定的液体和固体自微乳化药物递送系统（SMEDDS）的组成，其次，评估其在健康兔中的口服生物利用度。在这项研究中，流化床工艺的工艺参数也影响了ABZ固态SMEDDS系统的质量属性。 D-最佳混合实验设计用于选择液体SMEDDS配方变量的约束水平。使用四个响应（例如分散性能，液滴大小，溶出效率（DE）和85％药物释放时间（t85％））优化了预测的组成。优化的ABZ液体SMEDDS配方（5 mg / g）的特征在于其液滴尺寸，ζ电位和粘度。基于核心液态SMEDDS组合物，通过使用粒状山梨糖醇作为载体和酸化PEG 4000作为超饱和聚合物对液态SMEDDS进行流化床制粒，制得了含量更高的ABZ（10 mg / g）的过饱和固态SMEDDS制剂。体外溶出度研究在pH 1.2--7.4下进行。固态SMEDDS的固态表征通过扫描电子显微镜（SEM），差示扫描量热法（DSC）和X射线粉末衍射（XRPD）进行。通过在更高的温度（最高60°C）下施加应力60天来评估ABZ液体和固体SMEDDS制剂的化学和热力学稳定性。通过给三只兔子口服剂量为10 mg / kg体重的动物进行随机交叉药代动力学研究。针对ABZ的商业悬浮液（Zentel TM，葛兰素史克公司）计算相对生物利用度。使用具有四个参数（喷雾速率，入口空气温度，入口空气流量和雾化空气压力）的分数阶乘设计（4x2）来评估流化床工艺以生产固体SMEDDS颗粒。预计ABZ的ABZ-SMEDDS制剂的最佳组成约为5 mg / g药物负载，其中包括Cremophor EL（30％w / w），Tween 80（15％w / w），Capmul PG-8（10％w / w）并酸化PEG 400（45％w / w）。当分散在水中时，产生的液滴尺寸为37.3 +/- 2.7 nm。发现ζ电位为中性（-1.562mV），而初始粘度高（24℃下为1244cp）。重构微乳液的液滴尺寸分析表明，液体和固体SMEDDS配方之间没有差异。对于两种SMEDDS制剂，发现体外溶出曲线与pH无关。 DSC燃烧器和XRD研究表明，固态SMEDDS配方中没有ABZ的结晶性。固态SMEDDS在高温下的化学稳定性比液态SMEDDS高，尽管两种配方在室温下均具有热力学稳定性。固体SMEDDS和液体SMEDDS中相同剂量的ABZ导致相似的AUC 0rarr24h和Cmax值，但是最大吸收是由固体SMEDDS引起的。口服SMEDDS固体后，AUC0＆rarr24h和Cmax分别比市售悬浮液（ZentelRTM，GlaxoSmithKline，USA）高1.86倍和1.64倍。对于工艺开发研究，发现喷雾速率会增加Sauter平均直径（SMD）。发现进气温度对与平均粒径直接相关的峰值水分的影响是显着的。这项研究证明了开发过饱和SMEDDS制剂和低水溶性药物的策略。这些结果表明，固体SMEDDS可以在体内从制剂中释放微乳化脂质液滴的情况下产生改善的生物利用度。

著录项

  • 作者

    Mukherjee, Tusharmouli.;

  • 作者单位

    Long Island University, The Brooklyn Center.;

  • 授予单位 Long Island University, The Brooklyn Center.;
  • 学科 Health Sciences Pharmacology.Health Sciences Pharmacy.Chemistry Physical.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 229 p.
  • 总页数 229
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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