Zaghloul Abdel-Azim, Mustafa Fatima, Siddiqui Afzal, Khan Mansoor
Faculty of Pharmacy, Kuwait University, Safat, Kuwait.
Pharm Dev Technol. 2006;11(3):377-87. doi: 10.1080/10837450600770478.
The purpose of this work was to evaluate the main and interaction effects of formulation factors on the drug encapsulation efficiency of beta-estradiol biodegradable microspheres by applying response surface methodology. A secondary purpose was to obtain an optimized formula for long-term therapy of osteoporosis. A three factor, three level Box-Behnken experimental design was used to get 15 experimental runs. The independent variables were drug/polymer ratio (X1), dispersing agent concentration (X2), and deaggregating agent concentration (X3). The dependent variables were percentage encapsulation efficiency (Y1), cumulative percent drug released (Y2), and percentage yield of the microspheres (Y3). The formulations were prepared by emulsion solvent evaporation technique using ethyl acetate as organic solvent. The optimized formulation was maximized for encapsulation efficiency and further characterized for the particle size distribution, scanning electron microscopy (SEM), X-ray diffraction (XRD), and Fourier transform infrared (FT-IR). The mathematical relationship obtained between X1, X2, X3, and Y1 was: Y1 = -129.85 + 29.35X1 + 129.99X2 + 64.82X3 - 3.2X1X2 - 0.29X1X3 - 35.83X2X3 - 2.05X(2)(1) - 13.23X(2)(2) - 5.92X(2)(3) (R2 = 0.99) The equation showed that X1, X2, and X3 affect Y1 positively but interaction between any two of these factors affects Y1 negatively. The most significant interaction was between X2 and X3. The finding indicated that controlled releases beta-estradiol biodegradable microspheres with high encapsulation efficiency and low pulsatile release can be prepared and the quantitative response surface methodology applied helped in understanding the effects and the interaction effects between the three factors applied.
本研究旨在通过应用响应面法评估制剂因素对β-雌二醇可生物降解微球药物包封率的主要及交互作用。次要目的是获得用于骨质疏松症长期治疗的优化配方。采用三因素三水平的Box-Behnken实验设计进行15次实验。自变量为药物/聚合物比例（X1）、分散剂浓度（X2）和解聚剂浓度（X3）。因变量为包封率百分比（Y1）、药物累积释放百分比（Y2）和微球产率百分比（Y3）。采用乙酸乙酯作为有机溶剂，通过乳液溶剂蒸发技术制备制剂。优化后的制剂包封率最大化，并进一步对其粒径分布、扫描电子显微镜（SEM）、X射线衍射（XRD）和傅里叶变换红外光谱（FT-IR）进行表征。X1、X2、X3与Y1之间得到的数学关系式为：Y1 = -129.85 + 29.35X1 + 129.99X2 + 64.82X3 - 3.2X1X2 - 0.29X1X3 - 35.83X2X3 - 2.05X(2)(1) - 13.23X(2)(2) - 5.92X(2)(3) （R2 = 0.99）该方程表明，X1、X2和X3对Y1有正向影响，但这些因素中任意两个因素之间的相互作用对Y1有负向影响。最显著的相互作用存在于X2和X3之间。该研究结果表明，可以制备出具有高包封率和低脉冲释放的控释β-雌二醇可生物降解微球，所应用的定量响应面法有助于理解所应用的三个因素的影响及其相互作用。
