Crown Ethers: Novel Permeability Enhancers for Ocular Drug Delivery?

• Published in: Molecular pharmaceutics Vol. 14; no. 10; pp. 3528 - 3538
• Main Authors: Morrison, Peter W. J, Porfiryeva, Natalia N, Chahal, Sukhmanpreet, Salakhov, Ilgiz A, Lacourt, Charlène, Semina, Irina I, Moustafine, Rouslan I, Khutoryanskiy, Vitaliy V
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 02.10.2017
• Subjects: Administration, Ophthalmic; Animals; Benzalkonium Compounds - pharmacology; Calcium - metabolism; Cattle; Corneal Opacity - chemically induced; Corneal Stroma - drug effects; Corneal Stroma - metabolism; Crown Ethers - pharmacology; Drug Compounding - methods; Epithelium, Corneal - drug effects; Epithelium, Corneal - metabolism; Keratoconus - drug therapy; Male; Ophthalmic Solutions - pharmacology; Ophthalmic Solutions - therapeutic use; Permeability - drug effects; Rats; Rats, Wistar; Riboflavin - pharmacology; Riboflavin - therapeutic use; Solubility - drug effects; Spectrophotometry, Atomic - methods; Tight Junctions - drug effects; toxicity; crown ethers; ocular drug delivery; in vitro−in vivo correlation; permeability enhancement; corneal epithelium; riboflavin
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.7b00556

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.