Heinrich-Heine-Universität, Institut für Pharmazeutische Technologie und Biopharmazie, Düsseldorf, Germany.
Eur J Pharm Biopharm. 2010 Mar;74(3):503-12. doi: 10.1016/j.ejpb.2009.12.005. Epub 2009 Dec 22.
The one-step preparation of sustained release matrix pellets, using a melting procedure in a fluidized bed apparatus, was tested in a 2(3) full factorial design of experiments, using microcrystalline wax as lipophilic binder, theophylline as model drug and talc as additional matrix forming agent. The three influence parameters were (A) size of binder particles, (B) fraction of theophylline in solid particles and (C) fraction of microcrystalline wax in formulation. The response variables were agglomerate size and size distribution, dissolution time, agglomerate crush resistance, sphericity, yield and porosity. Nearly spherical pellets comprising a smooth, closed surface could be obtained with the used method, exhibiting the hollow core typical for the immersion and layering mechanism. The reproducibility was very good concerning all responses. The size of agglomerates is proportional to the size of the binder particles, which serve as cores for pellet formation in the molten state in the fluidized bed. Additionally, the agglomerate size is influenced by the volume of the solid particles in relation to the binder particles, with more solid particles leading to larger agglomerates and vice versa. Dissolution times vary in a very wide range, resulting from the interplay between amount of drug in relation to the meltable matrix substance microcrystalline wax and the non-meltable matrix substance talc. The change of binder particle size does not lead to a structural change of the matrix; both dissolution times and porosity are not significantly altered. Agglomerate crush resistance is low due to the hollow core of the pellets. However, it is significantly increased if the volume fraction of microcrystalline wax in the matrix is high, which means that the matrix is mechanically better stabilized. A theoretical model has been established to quantitatively explain agglomerate growth and very good accordance of the full particle size distributions between predicted and actual values could be shown. A low volumetric binder to solids ratio is compensated by a more porous layer. On the basis of this model, in-depth understanding on the mechanism and influence of product properties could be gained; and an a priori estimation of particle size distributions for new formulas can be performed, with densities, formula, and binder particle size distribution as input parameters.
采用流化床装置的熔融法，通过 2(3)完全析因实验设计，对一步法制备缓释基质丸进行了研究，其中微晶蜡作为亲脂性粘结剂，茶碱作为模型药物，滑石作为额外的基质形成剂。三个影响参数为：（A）粘结剂颗粒的大小、（B）固体颗粒中茶碱的比例和（C）制剂中微晶蜡的比例。响应变量为团聚体的大小和分布、溶出时间、团聚体抗碎强度、球形度、收率和孔隙率。使用该方法可以获得几乎呈球形的丸剂，表面光滑、闭合，呈典型的浸入和分层机制的中空核。所有响应的重现性都非常好。团聚体的大小与粘结剂颗粒的大小成正比，后者在流化床中的熔融状态下作为形成丸剂的核心。此外，团聚体的大小还受到固体颗粒与粘结剂颗粒体积比的影响，固体颗粒越多，团聚体越大，反之亦然。由于药物量与可熔融基质物质微晶蜡和不可熔融基质物质滑石之间的相互作用，溶出时间变化范围很宽。粘结剂颗粒大小的变化不会导致基质结构发生变化；溶出时间和孔隙率都没有明显改变。由于丸剂的中空核，团聚体的抗碎强度较低。然而，如果基质中微晶蜡的体积分数较高，团聚体的抗碎强度会显著增加，这意味着基质在机械上得到了更好的稳定。建立了一个理论模型来定量解释团聚体的生长，并且可以很好地证明实际和预测的完整粒径分布之间的一致性。低体积比的粘结剂与固体的比例可以通过更多孔的层来补偿。基于该模型，可以深入了解产品性能的机制和影响；并且可以对新配方的粒径分布进行先验估计，密度、配方和粘结剂颗粒大小分布作为输入参数。
