Pharmaceutical Research Group, Department of Health Sciences, Luleå University of Technology, Luleå, Sweden.
School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; Faculty of Pharmacy, University of Kufa, Al-Najaf, Iraq.
Eur J Pharm Sci. 2018 May 30;117:147-153. doi: 10.1016/j.ejps.2018.01.047. Epub 2018 Feb 2.
The interplay between supersaturation, precipitation and permeation characteristics of the poorly water-soluble drug ezetimibe (EZ) was investigated. Supersaturation and precipitation characteristics of EZ in the presence of Caco-2 cells were compared to those in a cell-free environment. The effect of the water-soluble polymer polyvinyl pyrrolidone (PVP-K30) on the supersaturation, precipitation and transport of EZ was also investigated and the amount of drug taken up by Caco-2 cells was quantified. A one-compartment setup without Caco-2 cells (i.e. in the wells of cell-culture plates) was used to mimic a non-sink in vitro dissolution chamber. The two-compartment Caco-2 cell monolayer setup (with apical and basolateral compartments) was used to investigate how the absorption of EZ affects supersaturation. EZ in varying degrees of supersaturation (DS; 10, 20, 30 and 40) was introduced into the one-compartment setup or the apical chamber of the two-compartment setup. Samples were collected at specific times to determine supersaturation, precipitation and permeation. At the end of the study, Caco-2 cells were lysed and the intracellular amount of EZ was quantified. In the one-compartment setup, a high DS was associated with rapid precipitation. Supersaturation was maintained for longer time periods and precipitation was lower in the presence of Caco-2 cells. There were no significant differences in the absorption rate of the drug, even at high concentrations on the apical side. Permeability coefficients for all supersaturated solutions (i.e. DS 10-40) were significantly (p < 0.05) different from those when EZ was present in crystalline form. Both concentrations of PVP-K30 (i.e. 0.05% and 0.1% w/v) improved solubility and supersaturation of EZ when added to the apical side, however, the increase in absorption at the higher concentration was not proportional. The amount of intracellular EZ increased with increasing DS in the apical side, until the saturation limit was reached in the cells (i.e. at DS 30 and higher). This study demonstrated that precipitation of EZ could be overestimated when supersaturation was investigated without the implementation of an absorption compartment in vitro, both in the absence and in the presence of polymer.
研究了低水溶解度药物依泽替米贝（EZ）的过饱和度、沉淀和渗透特性之间的相互作用。比较了 Caco-2 细胞存在下 EZ 的过饱和度和沉淀特性与无细胞环境下的过饱和度和沉淀特性。还研究了水溶性聚合物聚乙烯吡咯烷酮（PVP-K30）对 EZ 的过饱和度、沉淀和转运的影响，并定量了 Caco-2 细胞摄取的药物量。使用没有 Caco-2 细胞的一室装置（即在细胞培养板的孔中）模拟非溶出度室中的非饱和状态。使用两室 Caco-2 细胞单层装置（具有顶侧和基底外侧隔室）来研究 EZ 的吸收如何影响过饱和度。将不同程度过饱和度（DS；10、20、30 和 40）的 EZ 引入一室装置或两室装置的顶侧隔室。在特定时间收集样品以确定过饱和度、沉淀和渗透。在研究结束时，裂解 Caco-2 细胞并定量细胞内 EZ 的含量。在一室装置中，高 DS 与快速沉淀相关。在存在 Caco-2 细胞的情况下，过饱和度保持更长时间，沉淀较低。即使在顶侧的高浓度下，药物的吸收速率也没有显著差异。所有过饱和溶液（即 DS 10-40）的渗透系数均显著（p < 0.05）不同于晶体形式存在的 EZ 时的渗透系数。当添加到顶侧时，两种浓度的 PVP-K30（即 0.05%和 0.1%w/v）均提高了 EZ 的溶解度和过饱和度，但是在较高浓度下吸收的增加不成比例。随着顶侧 DS 的增加，细胞内 EZ 的量增加，直到细胞达到饱和极限（即在 DS 30 及以上）。本研究表明，在没有体外吸收隔室的情况下研究过饱和度时，EZ 的沉淀可能被高估，无论是在没有聚合物的情况下还是在存在聚合物的情况下都是如此。
