Bioneer: FARMA, Department of Pharmacy, DK-2100 Copenhagen, Denmark.
Department of Pharmacy, University of Copenhagen, DK-2100 Copenhagen, Denmark; Drug Product Development, Janssen Research and Development, Johnson & Johnson, BE-2430 Beerse, Belgium.
Eur J Pharm Biopharm. 2018 Sep;130:290-295. doi: 10.1016/j.ejpb.2018.07.005. Epub 2018 Jul 3.
In this study, the performance of phase separated and crystallized amorphous solid dispersions (ASDs) was evaluated by non-sink in vitro dissolution testing in fasted-state simulated intestinal fluid (FaSSIF) and in vivo in rats. The amorphous phase-separated or crystallized ASDs were prepared by mixing an ASD of the model drug celecoxib (CCX) in polyvinylpyrrolidone (PVP) with pure amorphous or micronized crystalline CCX at 20, 40, 60 or 100% of the total drug load (25:75 w/w CCX:PVP), respectively. As expected, crystallization of CCX in the ASDs generally had a negative influence on both the area under the curve of the dissolution curve (in vitro AUC) and the plasma concentration-time profile (in vivo AUC) in rats compared to the pure ASD. However, the difference between the in vivo AUC of the pure ASD and the 20% and 40% crystallized ASDs was not statistically significant, which could indicate that a low fraction of crystallization of a drug in an ASD may only have limited impact on in vivo performance and hence bioavailability. In comparison, amorphous phase separation of CCX in the ASDs did not negatively influence the in vitro AUC and in vivo AUC to the same degree as crystallization and the dissolution profiles of all the amorphous phase-separated ASDs were similar to that of the pure ASD. In fact, even though a slight decrease of in vivo AUC with increasing fraction of amorphous phase separation was observed, the 20% and 40% amorphous phase-separated ASDs were bioequivalent with the pure ASD.
在这项研究中，通过在空腹模拟肠液（FaSSIF）中的非饱和体外溶解试验和在大鼠体内评估了相分离和结晶无定形固体分散体（ASD）的性能。通过将模型药物塞来昔布（CCX）的 ASD 与纯无定形或微粉化结晶 CCX 在 20、40、60 或 100%总药物负载（25:75 w/w CCX:PVP）下混合，制备了相分离或结晶 ASD。正如预期的那样，与纯 ASD 相比，CCX 在 ASD 中的结晶通常对溶解曲线的曲线下面积（体外 AUC）和大鼠的血浆浓度-时间曲线（体内 AUC）都有负面影响。然而，纯 ASD 的体内 AUC 与 20%和 40%结晶 ASD 之间的差异没有统计学意义，这可能表明 ASD 中药物的结晶分数较低可能对体内性能和生物利用度的影响有限。相比之下，CCX 在 ASD 中的无定形相分离不会像结晶那样对体外 AUC 和体内 AUC 产生负面影响，所有无定形相分离 ASD 的溶解曲线都与纯 ASD 相似。事实上，尽管观察到体内 AUC 随着无定形相分离分数的增加而略有下降，但 20%和 40%的无定形相分离 ASD 与纯 ASD 具有生物等效性。
