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Crown Ethers: novel permeability enhancers for ocular drug delivery? Peter W.J. Morrison, Natalia N Porfiryeva, Sukhmanpreet Chahal, Ilgiz A. Salakhov, Charlene Lacourt, Irina I Semina, Rouslan I. Moustafine, and Vitaliy V. Khutoryanskiy Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.7b00556 • Publication Date (Web): 21 Aug 2017 Downloaded from http://pubs.acs.org on August 23, 2017
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Molecular Pharmaceutics
Crown Ethers: novel permeability enhancers for ocular drug delivery? Peter W. J. Morrison, a, f Natalia N. Porfiryeva,b Sukhmanpreet Chahal,a Ilgiz A. Salakhov,с Charlène Lacourt,d Irina I. Semina,e Rouslan I. Moustafine,b,e Vitaliy V. Khutoryanskiy a,*
a
School of Pharmacy, University of Reading, Whiteknights, PO Box 224, Reading, RG6 6AD,
United Kingdom. *Author for correspondence: Tel.: +44(0)118 378 6119. Fax: +44(0)118 378 4644. E-mail:
[email protected] b
Department of Pharmaceutical, Analytical and Toxicological Chemistry, Kazan State Medical
University, 49 Butlerov Street, 420012 Kazan, Russian Federation c
Nanopharma Development Ltd, 100 Vosstaniya Street, 420095, Kazan, Russian Federation
d
E.B.I. (École de Biologie Industrielle), 32, Boulevard du Port, 95094 Cergy Cedex, France
e
Central Research Laboratory, Kazan State Medical University, 6/30 Tolstogo Street, 420012
Kazan, Russian Federation
f
School of Pharmacy and Pharmaceutical Sciences & School of Optometry and Vision Sciences,
Cardiff University, CF10 3NB (Current address).
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Molecular Pharmaceutics
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Abstract: 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), 15crown-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.
Keywords: Crown ethers, corneal epithelium, ocular drug delivery, riboflavin, permeability enhancement, toxicity, in vitro-in vivo correlation.
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Molecular Pharmaceutics
Introduction Eye drops are generally the preferred means to apply medication when treating ocular disorders; they are convenient and easy to use for most patients. However, this has difficulties despite the fact that the eye is easily accessible since effective drug delivery requires several barriers to be overcome. With aqueous formulations, delivering lipophilic or poorly water soluble drugs at an effective concentration is problematic as is blinking, tear washout and nasolacrimal drainage mechanisms. Up to 90% of the instilled dose is lost almost immediately; more is absorbed systemically to be eliminated by metabolic processes. It is estimated that
