School of Pharmacy, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
School of Pharmacy, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
Int J Pharm. 2019 Oct 30;570:118653. doi: 10.1016/j.ijpharm.2019.118653. Epub 2019 Aug 28.
Co-amorphous mixtures have been demonstrated to represent a promising approach for enhancing the dissolution of poorly water-soluble drugs. However, little is known of their permeability properties, especially through biological membranes, or about the relationship between their dissolution and permeability. In the present study, co-amorphous glibenclamide (GBC) mixtures with two amino acids, arginine (ARG) and serine (SER), in molar ratios of 1:1 were prepared by cryomilling. Their dissolution and permeability properties were studied in side-by-side diffusion chambers using cell layers containing Madine Darby kidney cells overexpressing P-glycoprotein (Pgp) transporters (MDCKII-MDR1), as Pgp may influence the absorption of GBC. Furthermore, two other compounds, the flavonoid quercetin (QRT) which is a Pgp inhibitor and the surfactant, sodium lauryl sulfate (SLS), were used as excipients to investigate if they improved either passive or active diffusion of GBC. In addition, amorphous QRT and a co-amorphous mixture of GBC and QRT (1:1) were characterized with respect to their solid-state properties and physical stability. It was demonstrated that co-amorphous GBC mixtures exhibited superior dissolution properties over the corresponding physical mixtures and amorphous GBC. Furthermore, the co-amorphous GBC-ARG-SLS mixture exhibited a 9-fold increase in permeating through the MDCKII-MDR1 cell layer as compared to the corresponding physical mixture. There was a correlation between the dissolution and permeability area under curve (AUC) values, evidence that the main mechanism behind the improved permeability of co-amorphous mixtures was their improved dissolution. The simultaneous dissolution/permeation testing with side-by-side diffusion chambers and MDCKII-MDR1 cells proved to be a feasible method for evaluating the dissolution/permeation interplay of amorphous compounds.
共无定形混合物已被证明是提高水溶性差的药物溶解的一种很有前途的方法。然而，对于它们的渗透性质，特别是通过生物膜的渗透性质，或者关于它们的溶解和渗透之间的关系，人们知之甚少。在本研究中，通过冷冻研磨制备了摩尔比为 1:1 的共无定形格列本脲（GBC）与两种氨基酸精氨酸（ARG）和丝氨酸（SER）的混合物。使用含有过表达 P 糖蛋白（Pgp）转运体的 Madine Darby 肾细胞（MDCKII-MDR1）的细胞层，在侧-侧扩散室中研究了它们的溶解和渗透性质，因为 Pgp 可能影响 GBC 的吸收。此外，还使用了两种其他化合物，黄酮类槲皮素（QRT），一种 Pgp 抑制剂和表面活性剂十二烷基硫酸钠（SLS），作为赋形剂，以研究它们是否改善 GBC 的被动或主动扩散。此外，还对无定形 QRT 和 GBC 与 QRT（1:1）的共无定形混合物的固态特性和物理稳定性进行了表征。结果表明，共无定形 GBC 混合物的溶解特性优于相应的物理混合物和无定形 GBC。此外，与相应的物理混合物相比，共无定形 GBC-ARG-SLS 混合物透过 MDCKII-MDR1 细胞层的渗透增加了 9 倍。溶解和渗透曲线下面积（AUC）值之间存在相关性，这表明共无定形混合物渗透性提高的主要机制是其溶解性的提高。使用侧-侧扩散室和 MDCKII-MDR1 细胞进行同时溶解/渗透测试被证明是评估无定形化合物溶解/渗透相互作用的一种可行方法。
