Bayomi M A
Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Boll Chim Farm. 2003 Oct;142(8):336-42.
Optimization of formulation for chitosan-carboxymethyl cellulose (CH-CMC) microspheres that contain a drug of narrrow therapeutic index was the interest of this study. Theophylline (TPH) was chosen as a model drug. The effects of chitosan:sodium carboxymethyl cellulose (CH:SCMC) weight ratio (X1) and pH of polymers solution (X2) as independent variables on the physical characteristics of the microspheres as well as release profile of TPH from microspheres prepared by the emulsion coacervation-phase separation technique were studied. The influence of each of the two variables on responses such as angle of repose, compressibility index, incorporation efficiency particle size, initial drug release, time for 50% drug release (T50%) and % drug released in 8 hours was investigated. Generally, the increase in CH:SCMC weight ratio showed to increase the incorporation efficiency of the drug, increase the particle size and decrease the flowability of the microspheres. The increase of CH:SCMC ratio was also responsible to get low initial drug release, slow drug release (long T50%) and incomplete total drug released in 8 hours. On the other hand, high and low pHs of polymers solution were responsible to decrease drug incorporation in the microspheres and to produce small particles while, good flowability was obtained at pHs 2.5 and 4. A full factorial experimental design was employed to investigate the effect of the two independent variables on the responses. The results were analyzed by a general quadratic equation and response surfaces generated. From the obtained regression, it was concluded that the effect of CH:SCMC polymers ratio is more significant in changing the values of flowability particle size and drug release in 8 hours while pH values were more significant in changing the values of initial drug release and T50%. On the other hand the interaction coefficients of the two variables showed synergistic effect on flowability and drug release in 8 hours while, there were antagonist effects on particle sizes and T50%. From the optimization studies it is possible to choose the conditions required for the preparation of microspheres with the desired characteristics.
本研究旨在优化含有窄治疗指数药物的壳聚糖-羧甲基纤维素（CH-CMC）微球的配方。选择茶碱（TPH）作为模型药物。研究了壳聚糖与羧甲基纤维素钠（CH:SCMC）的重量比（X1）和聚合物溶液的pH值（X2）这两个自变量对微球物理特性以及通过乳液凝聚相分离技术制备的微球中TPH释放曲线的影响。研究了这两个变量对诸如休止角、压缩性指数、包封率、粒径、初始药物释放、50%药物释放时间（T50%）和8小时药物释放百分比等响应的影响。一般来说，CH:SCMC重量比的增加显示出提高了药物的包封率，增大了粒径，并降低了微球的流动性。CH:SCMC比例的增加还导致初始药物释放较低、药物释放缓慢（T50%长）以及8小时内药物总释放不完全。另一方面，聚合物溶液的高pH值和低pH值会导致微球中药物包封减少并产生小颗粒，而在pH值为2.5和4时可获得良好的流动性。采用全因子实验设计来研究这两个自变量对响应的影响。通过一般二次方程对结果进行分析并生成响应面。从得到的回归分析得出结论，CH:SCMC聚合物比例在改变流动性、粒径和8小时药物释放值方面的影响更为显著，而pH值在改变初始药物释放和T50%值方面更为显著。另一方面，这两个变量的相互作用系数对8小时的流动性和药物释放显示出协同作用，而对粒径和T50%则有拮抗作用。通过优化研究，可以选择制备具有所需特性微球所需的条件。
