Department of Veterinary Sciences, The University of Melbourne , Werribee, Victoria 3030, Australia.
Pfizer Global Research and Development , Groton, Connecticut 06340, United States.
Mol Pharm. 2017 Dec 4;14(12):4525-4538. doi: 10.1021/acs.molpharmaceut.7b00660. Epub 2017 Nov 9.
Lipid based formulations (LBFs) are a promising formulation strategy for many poorly water-soluble drugs and have been shown previously to enhance the oral exposure of CP-532,623, an oral cholesteryl ester transfer protein inhibitor. In the current study, an in vitro lipid digestion model was used to probe the relationship between drug solubilization and supersaturation on in vitro dispersion and digestion of LBF containing long chain (LC) lipids and drug absorption in vivo. After in vitro digestion of LBF based on LC lipids, the proportion of CP-532,623 maintained in the solubilized state in the aqueous phase of the digest was highest in formulations containing Kolliphor RH 40, and in most cases outperformed equivalent formulations based on MC lipids. Subsequent administration of the LC-LBFs to beagle dogs resulted in reasonable correlation between concentrations of CP-532,623 measured in the aqueous phase of the in vitro digest after 30 min digestion and in vivo exposure (AUC); however, the LC-LBFs required greater in vitro drug solubilization to elicit similar in vivo exposure when compared to previous studies with MC-LBF. Although post digestion solubilization was enhanced in LC-LBF compared to MC-LBF, equilibrium solubility studies of CP-532,623 in the aqueous phase isolated from blank lipid digestion experiments revealed that equilibrium solubility was also higher, and therefore supersaturation lower. A revised correlation based on supersaturation in the digest aqueous phase and drug absorption was therefore generated. A single, linear correlation was evident for both LC- and MC-LBF containing Kolliphor RH 40, but this did not extend to formulations based on other surfactants. The data suggest that solubilization and supersaturation are significant drivers of drug absorption in vivo, and that across formulations with similar formulation composition good correlation is evident between in vitro and in vivo measures. However, across dissimilar formulations, solubilization and supersaturation alone are not sufficient to explain drug exposure and other factors also likely play a role.
基于脂质的制剂（LBFs）是许多水溶性差的药物的有前途的制剂策略，先前已经证明，它们可以提高口服胆固醇酯转移蛋白抑制剂 CP-532,623 的口服暴露。在本研究中，使用体外脂质消化模型来探究药物增溶作用与超饱和度之间的关系，以研究含有长链（LC）脂质的 LBF 在体外分散和消化以及体内药物吸收中的作用。在基于 LC 脂质的 LBF 体外消化后，在消化物水相中保持溶解状态的 CP-532,623 的比例在含有 Kolliphor RH 40 的制剂中最高，在大多数情况下，优于基于 MC 脂质的等效制剂。随后将 LC-LBF 施用于比格犬，结果表明，在 30 分钟消化后，在体外消化物的水相中和体内暴露（AUC）中测量的 CP-532,623 浓度之间存在合理的相关性；然而，与之前基于 MC-LBF 的研究相比，LC-LBF 增加了体外药物增溶作用以产生相似的体内暴露。尽管与 MC-LBF 相比，LC-LBF 增加了消化后的增溶作用，但 CP-532,623 在空白脂质消化实验分离出的水相中的平衡溶解度研究表明，平衡溶解度也更高，因此超饱和度更低。因此，生成了基于消化物水相中的超饱和度和药物吸收的修订相关性。对于含有 Kolliphor RH 40 的 LC-LBF 和 MC-LBF，都存在明显的单一线性相关性，但这并不扩展到基于其他表面活性剂的制剂。数据表明，增溶作用和超饱和度是体内药物吸收的重要驱动因素，并且在具有相似制剂组成的制剂中，体外和体内测量之间存在良好的相关性。然而，在不同的制剂中，增溶作用和超饱和度本身不足以解释药物暴露，其他因素也可能起作用。
