Law Devalina, Schmitt Eric A, Marsh Kennan C, Everitt Elizabeth A, Wang Weili, Fort James J, Krill Steven L, Qiu Yihong
Global Pharmaceutical Research and Development, Abbott Laboratories, R4P7, R1B, 1400 Sheridan Road, North Chicago, IL 60064-6254, USA.
J Pharm Sci. 2004 Mar;93(3):563-70. doi: 10.1002/jps.10566.
Ritonavir is a large, lipophilic molecule that is practically insoluble in aqueous media and exhibits an exceedingly slow intrinsic dissolution rate. Although it has favorable lipophilicity, in vitro permeability studies have shown that ritonavir is a substrate of P-glycoprotein. Thus, the oral absorption of ritonavir could be limited by both dissolution and permeability, thereby making it a Class IV compound in the Biopharmaceutics Classification System. Because formulations rarely exert direct influence on local intestinal permeability, the effect of enhanced dissolution rate on oral absorption was explored. More specifically, poly(ethylene glycol) (PEG)-amorphous ritonavir solid dispersions were prepared with different drug loadings, and the in vitro and in vivo performances of the dispersions were evaluated. In vitro dissolution was conducted in 0.1N HCl with a USP Apparatus I. A crossover design was used to evaluate the oral bioavailability of amorphous dispersions relative to crystalline drug in beagle dogs. Intrinsic dissolution measurements of the two solid phases indicated a 10-fold improvement in intrinsic dissolution rate for amorphous ritonavir compared with the crystalline counterpart. In vitro dissolution of ritonavir depended on the solid phase as well as drug loading of the dispersion. In vivo study results indicate that amorphous solid dispersions containing 10-30% drug exhibited significant increases in area under the curve of concentration versus time (AUC) and maximum concentration (C(max)) over crystalline drug. For example, 10% amorphous dispersion exhibited increases of 22- and 13.7-fold in AUC and C(max), respectively. However, both in vitro dissolution and bioavailability decreased with increasing drug load, which led to the construction of a multiple Level C in vitro-in vivo relationship for this Class IV compound. The established relationship between in vitro dissolution and in vivo absorption can help guide formulation development.
利托那韦是一种大分子亲脂性分子，几乎不溶于水介质，其固有溶出速率极慢。尽管它具有良好的亲脂性，但体外渗透性研究表明利托那韦是P-糖蛋白的底物。因此，利托那韦的口服吸收可能受到溶出和渗透性的限制，从而使其在生物药剂学分类系统中属于IV类化合物。由于制剂很少对局部肠道渗透性产生直接影响，因此研究了提高溶出速率对口服吸收的影响。更具体地说，制备了具有不同载药量的聚乙二醇（PEG）-无定形利托那韦固体分散体，并评估了这些分散体的体外和体内性能。在0.1N盐酸中使用美国药典装置I进行体外溶出试验。采用交叉设计评估无定形分散体相对于比格犬体内结晶药物的口服生物利用度。两种固相的固有溶出度测量表明，无定形利托那韦的固有溶出速率比结晶型利托那韦提高了10倍。利托那韦的体外溶出取决于分散体的固相以及载药量。体内研究结果表明，含10%-30%药物的无定形固体分散体相对于结晶药物，其浓度-时间曲线下面积（AUC）和最大浓度（C(max)）显著增加。例如，10%的无定形分散体的AUC和C(max)分别增加了22倍和13.7倍。然而，体外溶出度和生物利用度均随载药量的增加而降低，这为该IV类化合物建立了多级体外-体内关系。所建立的体外溶出与体内吸收之间的关系有助于指导制剂开发。
