Crown Ethers: Novel Permeability Enhancers for Ocular Drug Delivery

Aug 21, 2017 - School of Pharmacy, University of Reading, Whiteknights, PO Box 224, Reading, RG6 6AD, United Kingdom. § Department of Pharmaceutical,...
1 downloads 11 Views 1MB Size
Subscriber access provided by PEPPERDINE UNIV

Article

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

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Molecular Pharmaceutics is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 40

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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).

1

ACS Paragon Plus Environment

Molecular Pharmaceutics

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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.

2

ACS Paragon Plus Environment

Page 2 of 40

Page 3 of 40

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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