Van Eerdenbrugh Bernard, Froyen Ludo, Van Humbeeck Jan, Martens Johan A, Augustijns Patrick, Van den Mooter Guy
Laboratory for Pharmacotechnology and Biopharmacy, K.U. Leuven, Gasthuisberg O&N2, 3000 Leuven, Belgium.
Eur J Pharm Sci. 2008 Sep 2;35(1-2):127-35. doi: 10.1016/j.ejps.2008.06.009. Epub 2008 Jul 3.
d-alpha-Tocopherol polyethylene glycol 1000 succinate (TPGS)-stabilized nanosuspensions (25wt%, relative to the drug weight) were produced by media milling for 9 model drug compounds [cinnarizine, griseofulvin, indomethacin, itraconazole, loviride, mebendazole, naproxen, phenylbutazone and phenytoin]. After 3 months of storage at room temperature, Ostwald ripening occurred in all of the samples, except for indomethacin. Whereas lowering the temperature could slow down the ripening, it markedly increased upon storage at 40 degrees C. As for ripening, settling generally became more pronounced at 40 degrees C compared to 4 degrees C. As the nanosuspensions were afflicted by Ostwald ripening and settling, we explored nanosuspension drying as a strategy to circumvent these stability issues. Spray-drying and freeze-drying were evaluated for nanosuspensions and coarse reference suspensions of the compounds. Nanoparticle agglomeration could be visually observed in all of the powders. To evaluate the effect of agglomeration on the key characteristic of drug nanocrystals (i.e. rapid dissolution), dissolution experiments were performed under poor sink conditions. It was found that the compounds could be categorized into 3 groups: (i) compounds for which it was impossible to differentiate between coarse and nanosized products (griseofulvin, mebendazole, naproxen), (ii) compounds that gave clear differences in dissolution profiles between the nanosized and the coarse products, but for which drying of the nanosuspensions did not decrease the dissolution performance of the product (indomethacin, loviride, phenytoin) and (iii) compounds that showed differences between coarse and nanosized products, but for which drying of the nanosuspensions resulted in a significant decrease of the dissolution rate (cinnarizine, itraconazole, phenylbutazone). To gain insight on the influence of the drug compound characteristics on the dissolution of the dried products, the dissolution behavior of the compounds of the second and the third group was linked to the compound's characteristics. It was found that compounds with a more hydrophobic surface resulted in agglomerates which were harder to disintegrate, for which dissolution was compromised upon drying. The same was found for compounds having higher logP values.
通过介质研磨法制备了d-α-生育酚聚乙二醇1000琥珀酸酯（TPGS）稳定的纳米混悬液（相对于药物重量为25wt%），其中包含9种模型药物化合物[桂利嗪、灰黄霉素、吲哚美辛、伊曲康唑、洛匹那韦、甲苯达唑、萘普生、保泰松和苯妥英]。在室温下储存3个月后，除吲哚美辛外，所有样品均发生了奥斯特瓦尔德熟化。降低温度可减缓熟化过程，但在40℃储存时熟化明显加剧。至于沉降，与4℃相比，在40℃时沉降通常更为明显。由于纳米混悬液受到奥斯特瓦尔德熟化和沉降的影响，我们探索了纳米混悬液干燥作为解决这些稳定性问题的策略。对这些化合物的纳米混悬液和粗品对照混悬液进行了喷雾干燥和冷冻干燥评估。在所有粉末中均可肉眼观察到纳米颗粒团聚现象。为评估团聚对药物纳米晶体关键特性（即快速溶解）的影响，在漏槽条件较差的情况下进行了溶出实验。结果发现，这些化合物可分为3组：（i）无法区分粗品和纳米尺寸产品的化合物（灰黄霉素、甲苯达唑、萘普生）；（ii）纳米尺寸产品和粗品在溶出曲线方面有明显差异，但纳米混悬液干燥并未降低产品溶出性能的化合物（吲哚美辛、洛匹那韦、苯妥英）；（iii）粗品和纳米尺寸产品之间存在差异，但纳米混悬液干燥导致溶出速率显著降低的化合物（桂利嗪、伊曲康唑、保泰松）。为深入了解药物化合物特性对干燥产品溶出的影响，将第二组和第三组化合物的溶出行为与化合物特性联系起来。结果发现，具有更疏水表面的化合物会形成更难崩解的团聚物，干燥后其溶出会受到影响。对于具有较高logP值的化合物也有同样的发现。
