Zerrouk N, Chemtob C, Arnaud P, Toscani S, Dugue J
Laboratoire de Pharmacotechnie et de Biopharmacie, Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes, 4, Avenue de l'observatoire, 75270 Cedex 06, Paris, France.
Int J Pharm. 2001 Aug 28;225(1-2):49-62. doi: 10.1016/s0378-5173(01)00741-4.
The present work extended previous physico-chemical investigations on the effects of solid dispersion on the solubility, the dissolution rate and the pharmacokinetic profile of carbamazepine. Solubility studies showed a linear increase in carbamazepine solubility with the increase of PEG 6000 concentration. There is no marked difference between physical mixtures and solid dispersions for the enhancement of carbamazepine solubility by PEG 6000. Less than 60% of pure carbamazepine was dissolved in 90 min. Physical mixtures (carbamazepine phase III) and solid dispersions (carbamazepine phase II) dissolution rates were higher in comparison of the parent drug. The dissolution of carbamazepine phase III was more pronounced than that evoked by the phase II. The dissolution profiles indicated that the percentage of the drug dissolved was dependent on the proportion of PEG 6000. In solid dispersions there was a remarkable enhancement in the dissolution rates of the drug in the vicinity of the eutectic composition as compared with those of corresponding physical mixtures. Hence, the optimum value for the solid dispersion was 80.5+/-1.7% of carbamazepine having dissolved within the first 10 min compared to 40+/-1% for the corresponding physical mixtures of the same composition. Statistical analysis of pharmacokinetic parameters confirmed that the carbamazepine:PEG 6000 binary systems displayed higher bioavailability of the drug than the pure carbamazepine. The area under the curve (AUC) values highlighted the evidence that only slight differences in the bioavailability of the drug occur between physical mixtures and solid dispersions prepared at the 80:20 and 50:50 drug:carrier compositions. However, the mean normalized plasma concentrations showed that standard error deviations are rather wide intervals for pure drug and physical mixtures in comparison to solid dispersions. One additional interesting point to consider is the disappearance of the multiple peaks on the individual kinetic curves of the 50:50 solid dispersion composition. Furthermore, our investigations have highlighted the interest of solid dispersions prepared at <
本研究扩展了先前关于固体分散体对卡马西平溶解度、溶解速率和药代动力学特征影响的物理化学研究。溶解度研究表明，随着聚乙二醇6000浓度的增加，卡马西平的溶解度呈线性增加。在通过聚乙二醇6000提高卡马西平溶解度方面，物理混合物和固体分散体之间没有显著差异。在90分钟内，纯卡马西平的溶解量不到60%。与原料药相比，物理混合物（卡马西平III相）和固体分散体（卡马西平II相）的溶解速率更高。卡马西平III相的溶解比II相引起的溶解更明显。溶解曲线表明，药物溶解的百分比取决于聚乙二醇6000的比例。与相应的物理混合物相比，在共晶组成附近的固体分散体中，药物的溶解速率有显著提高。因此，固体分散体的最佳值是在最初10分钟内溶解80.5±1.7%的卡马西平，而相同组成的相应物理混合物为40±1%。药代动力学参数的统计分析证实，卡马西平：聚乙二醇6000二元体系显示出比纯卡马西平更高的药物生物利用度。曲线下面积（AUC）值突出表明，在80:20和50:50药物：载体组成下制备的物理混合物和固体分散体之间，药物生物利用度仅存在微小差异。然而，平均归一化血浆浓度表明，与固体分散体相比，纯药物和物理混合物的标准误差偏差区间相当宽。另一个需要考虑的有趣点是50:50固体分散体组成的个体动力学曲线上多重峰的消失。此外，我们的研究突出了在“近”共晶组成下制备固体分散体的意义，因为我们的初步数据表明，含有150毫克卡马西平的15:85分散样品的药物血浆浓度（C(5h)）与含有300毫克药物的50:50分散样品所获得的血浆浓度没有显著差异。
