College of Pharmacy, Freie Universität Berlin, Kelchstrasse 31, 12169 Berlin, Germany.
Int J Pharm. 2010 May 10;390(2):165-73. doi: 10.1016/j.ijpharm.2010.01.039. Epub 2010 Feb 10.
Solid dispersions were prepared by a melting method from the water-insoluble model drugs carbamazepine and nifedipine and polyethylene glycol 1500 (PEG 1500) or 1:1 mixtures of PEG 1500 and the polymers polyvinylpyrrolidone (PVP 30, PVP 12), polyvinylpyrrolidone-co-vinylacetate (PVPVA) and Eudragit EPO (Eudragit) in order to combine advantages of the different carrier polymers (recrystallization inhibition, processability and stability). The solid dispersions were characterized by dissolution, powder X-ray diffractometry and microscopy directly after preparation and after storage for 3 and 6 months at 25 degrees C/0% relative humidity (RH) or 3 months at 40 degrees C/75% RH. More than 80% drugs were released from all solid dispersions within 20min. The dissolution rate of carbamazepine decreased in the order of PEG 1500>PEG 1500/Eudragit>PEG 1500/PVP 30>PEG 1500/PVPVA>PEG 1500/PVP 12. The dissolution rank order was not directly correlated to the amorphous/crystalline state of the drugs, but rather to the properties of the PEG 1500/polymer compositions. Nifedipine was released in the order of PEG 1500>PEG 1500/PVPVA>PEG 1500/PVP 30>PEG 1500/PVP 12>PEG 1500/Eudragit. Amorphous nifedipine was present in all PEG 1500/polymer dispersions except in pure PEG 1500 solid dispersion. The significant increase in dissolution rate of PEG 1500 solid dispersions was due to the reduced crystallinity of the drug and the excellent solubilisation properties of PEG 1500. After 6 months storage at 25 degrees C/0% RH, the solid dispersions released both drugs in the order PEG 1500/PVPVA>PEG 1500/PVP 30>PEG 1500/PVP 12>PEG 1500/Eudragit>PEG 1500. The stabilized amorphous state of the drug resulted in stable dissolution profiles of PEG 1500/PVPVA, PEG 1500/PVP 30 and PEG 1500/PVP 12 when compared to the PEG 1500 solid dispersions, which contained a higher amount of crystalline drug. The solid dispersions with PEG 1500/PVPVA or PEG 1500/PVP stored for 3 months at 40 degrees C/75% RH showed phase separation due to the hygroscopic properties of the polymers. The influence of 10% (w/w) of the solubilisers polyoxyl 40 hydrogenated castor oil (Cremophor), macrogol-15-hydroxystearate (Solutol) and fatty alcohol alkoxylate (Pluronic) on the dissolution rate and the physical state of the drug was significant.
采用熔融法制备了难溶性模型药物卡马西平和硝苯地平的固体分散体，所用载体聚合物为聚乙二醇 1500（PEG 1500）和 1:1 混合物 PEG 1500 与聚合物聚乙烯吡咯烷酮（PVP 30、PVP 12）、聚乙烯吡咯烷酮-醋酸乙烯共聚物（PVPVA）和 Eudragit EPO（Eudragit）。目的是将不同载体聚合物（抑制重结晶、加工性能和稳定性）的优势结合起来。直接在制备后以及在 25°C/0%相对湿度（RH）下储存 3 个月和 6 个月或在 40°C/75%RH 下储存 3 个月时，通过溶出度、粉末 X 射线衍射和显微镜对固体分散体进行了表征。所有固体分散体在 20min 内释放超过 80%的药物。卡马西平的溶出速率按以下顺序降低：PEG 1500>PEG 1500/Eudragit>PEG 1500/PVP 30>PEG 1500/PVPVA>PEG 1500/PVP 12。溶出顺序与药物的无定形/晶态状态没有直接关系，而是与 PEG 1500/聚合物组合物的性质有关。硝苯地平的释放顺序为 PEG 1500>PEG 1500/PVPVA>PEG 1500/PVP 30>PEG 1500/PVP 12>PEG 1500/Eudragit。除纯 PEG 1500 固体分散体外，所有 PEG 1500/聚合物分散体中均存在无定形硝苯地平。PEG 1500 固体分散体溶出率的显著增加是由于药物结晶度降低和 PEG 1500 优异的增溶性能所致。在 25°C/0%RH 下储存 6 个月后，固体分散体以 PEG 1500/PVPVA>PEG 1500/PVP 30>PEG 1500/PVP 12>PEG 1500/Eudragit 的顺序释放两种药物。药物的稳定无定形状态导致 PEG 1500/PVPVA、PEG 1500/PVP 30 和 PEG 1500/PVP 12 固体分散体与含有更高量结晶药物的 PEG 1500 固体分散体相比，具有稳定的溶出曲线。PEG 1500/PVPVA 或 PEG 1500/PVP 固体分散体在 40°C/75%RH 下储存 3 个月后，由于聚合物的吸湿性而发生相分离。增溶剂聚氧乙烯 40 氢化蓖麻油（Cremophor）、聚乙二醇-15-羟基硬脂酸酯（Solutol）和脂肪酸醇乙氧基化物（Pluronic）的 10%（w/w）对药物的溶出速率和物理状态有显著影响。
