Law D, Krill S L, Schmitt E A, Fort J J, Qiu Y, Wang W, Porter W R
Pharmaceutical and Analytical Research and Development, Pharmaceutical Products Division, Abbott Laboratories, D4P3, AP9, 100 Abbott Park Road, Abbott Park, IL 60064, USA.
J Pharm Sci. 2001 Aug;90(8):1015-25. doi: 10.1002/jps.1054.
A systematic study of the properties of ritonavir and the influence of polyethylene glycol 8000 (PEG) on ritonavir revealed that amorphous ritonavir dispersions in PEG would have an improved dissolution profile and could exhibit long-term stability. Ritonavir, a human immunodeficiency virus (HIV) protease inhibitor, is highly lipophilic [distribution coefficient (log D)= 4.3, 25 degrees C, pH 6.8], poorly water soluble (400 microg/mL in 0.1 N HCl, 1 microg/mL at pH 6.8, 37 degrees C), and exhibits an exceedingly slow dissolution rate (0.03 mg/cm(2)-min in 0.1 N HCl at 37 degrees C). These properties indicated that a solid dispersion containing ritonavir might be useful for overcoming problems associated with slow dissolution. In addition, ritonavir is a good glass former [glass-transition temperature (T(g))/melting point (T(m)) > 0.7]. Amorphous ritonavir has an apparent solubility of 4 mg/mL in 0.1 N HCl at 37 degrees C and shows reasonable stability at 25 degrees C. Amorphous ritonavir, therefore, has properties desirable for preparing a solid dispersion containing this phase. Since PEG, a commonly used polymer, improved the aqueous solubility of crystalline ritonavir, it was expected to have a positive influence on the dissolution rate of ritonavir. Moreover, PEG was found to have negligible plasticizing effect on amorphous ritonavir, which was beneficial for the stability of the dispersion. Finally, solid dispersions of amorphous ritonavir in PEG were prepared, and these dispersions had improved in vitro dissolution rate and were physically stable for > 1.5 years at 25 degrees C when protected from moisture. The performance of this solid dispersion has been attributed to the physicochemical properties of amorphous ritonavir.
一项关于利托那韦性质以及聚乙二醇8000（PEG）对利托那韦影响的系统性研究表明，利托那韦在PEG中的无定形分散体具有改善的溶出曲线，并且能够展现出长期稳定性。利托那韦是一种人类免疫缺陷病毒（HIV）蛋白酶抑制剂，具有高度亲脂性[分配系数（log D）= 4.3，25℃，pH 6.8]，水溶性差（在0.1 N HCl中为400 μg/mL，在pH 6.8、37℃时为1 μg/mL），并且溶出速率极慢（在37℃的0.1 N HCl中为0.03 mg/cm² - min）。这些性质表明，含有利托那韦的固体分散体可能有助于克服与溶出缓慢相关的问题。此外，利托那韦是一种良好的玻璃形成体[玻璃化转变温度（T(g)）/熔点（T(m)）> 0.7]。无定形利托那韦在37℃的0.1 N HCl中的表观溶解度为4 mg/mL，并且在25℃时显示出合理的稳定性。因此，无定形利托那韦具有制备包含该相的固体分散体所需的性质。由于PEG是一种常用聚合物，它提高了结晶利托那韦的水溶性，预计其对利托那韦的溶出速率有积极影响。此外，发现PEG对无定形利托那韦的增塑作用可忽略不计，这有利于分散体的稳定性。最后，制备了无定形利托那韦在PEG中的固体分散体，这些分散体具有改善的体外溶出速率，并且在25℃下防潮时物理稳定性超过1.5年。这种固体分散体的性能归因于无定形利托那韦的物理化学性质。
