Crown Ethers: Novel Permeability Enhancers for Ocular Drug Delivery?

被引:48
作者
Morrison, Peter W. J. [1 ,6 ,7 ]
Porfiryeva, Natalia N. [2 ]
Chahal, Sukhmanpreet [1 ]
Salakhov, Ilgiz A. [3 ]
Lacourt, Charlene [4 ]
Semina, Irina I. [5 ]
Moustafine, Rouslan I. [2 ,5 ]
Khutoryanskiy, Vitaliy V. [1 ]
机构
[1] Univ Reading, Sch Pharm, POB 224, Reading RG6 6AD, Berks, England
[2] Kazan State Med Univ, Dept Pharmaceut Analyt & Toxicol Chem, 49 Butlerov St, Kazan 420012, Russia
[3] Nanopharma Dev Ltd, 100 Vosstaniya St, Kazan 420095, Russia
[4] EBI, 32,Blvd Port, F-95094 Cergy 95094, France
[5] Kazan State Med Univ, Cent Res Lab, 6-30 Tolstogo St, Kazan 420012, Russia
[6] Cardiff Univ, Sch Pharm & Pharmaceut Sci, Cardiff CF10 3NB, S Glam, Wales
[7] Cardiff Univ, Sch Optometry & Vis Sci, Cardiff CF10 3NB, S Glam, Wales
基金
英国生物技术与生命科学研究理事会;
关键词
crown ethers; corneal epithelium; ocular drug delivery; riboflavin; permeability enhancement; toxicity; in vitro-in vivo correlation; COLLAGEN CROSS-LINKING; CORNEAL PERMEABILITY; CHELATING-AGENTS; AQUEOUS-SOLUTION; ION SELECTIVITY; IN-VITRO; RIBOFLAVIN; SOLUBILITY; COMPLEXES; SYSTEMS;
D O I
10.1021/acs.molpharmaceut.7b00556
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
引用
收藏
页码:3528 / 3538
页数:11
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