Crown ethers are cyclic molecules consisting of a ring containing several ether groups. The most common and important members of this series are 12-crown-4 (12C4), 15-crown-5 (15C5), and 18-crown-6 (18C6). These container molecules have the ability to sequester metal ions, and their complexes with drugs are able to traverse cell membranes. This study investigated 12C4, 15C5, and 18C6 for their ability to increase solubility of ocular drugs and enhance their penetration into the cornea. Phase solubility analysis determined crown ethers’ ability to enhance the solubility of riboflavin, a drug used for the therapy of keratoconus, and these solutions were investigated for ocular drug permeation enhancing properties. Atomic absorption spectroscopy demonstrated crown ether solutions’ ability to sequester Ca²⁺ from corneal epithelia, and crown ether mediated adsorption of riboflavin into the stroma was investigated. Induced corneal opacity studies assessed potential toxicity of crown ethers. Crown ethers enhanced riboflavin’s aqueous solubility and its penetration into in vitro bovine corneas; the smaller sized crown ethers gave greatest enhancement. They were shown to sequester Ca²⁺ ions from corneal epithelia; doing so loosens cellular membrane tight junctions thus enhancing riboflavin penetration. Induced corneal opacity was similar to that afforded by benzalkonium chloride and less than is produced using polyaminocarboxylic acids. However, in vivo experiments performed in rats with 12C4 did not show any statistically significant permeability enhancement compared to enhancer-free formulation.

中文翻译：

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冠醚：用于眼部药物递送的新型渗透性增强剂？

冠醚是由含有几个醚基的环组成的环状分子。该系列中最常见和最重要的成员是12冠4（12C4），15冠5（15C5）和18冠6（18C6）。这些容器分子具有螯合金属离子的能力，并且它们与药物的复合物能够穿过细胞膜。这项研究调查了12C4、15C5和18C6增强眼用药物的溶解度并增强其渗透到角膜中的能力。相溶解度分析确定了冠醚增强核黄素（一种用于治疗圆锥角膜的药物）的溶解度的能力，并对这些溶液的眼药渗透增强特性进行了研究。原子吸收光谱法证明冠醚溶液螯合Ca ²⁺的能力角膜上皮细胞，冠醚介导的核黄素吸附到基质中的研究。诱导的角膜混浊研究评估了冠醚的潜在毒性。冠醚增强了核黄素的水溶性，并增强了其渗透入体外牛角膜的能力；较小的冠醚具有最大的增强作用。他们被证明可以隔离角膜上皮细胞中的Ca ²⁺离子。这样做可以放松细胞膜的紧密连接，从而增强核黄素的渗透。诱导的角膜混浊与苯扎氯铵所提供的相似，并且小于使用聚氨基羧酸产生的混浊。但是，与不含增强剂的制剂相比，在具有12C4的大鼠中进行的体内实验未显示任何统计学上显着的通透性增强。