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      Penetration Enhancers in Ocular Drug Delivery

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          Abstract

          There are more than 100 recognized disorders of the eye. This makes the development of advanced ocular formulations an important topic in pharmaceutical science. One of the ways to improve drug delivery to the eye is the use of penetration enhancers. These are defined as compounds capable of enhancing drug permeability across ocular membranes. This review paper provides an overview of anatomical and physiological features of the eye and discusses some common ophthalmological conditions and permeability of ocular membranes. The review also presents the analysis of literature on the use of penetration-enhancing compounds (cyclodextrins, chelating agents, crown ethers, bile acids and bile salts, cell-penetrating peptides, and other amphiphilic compounds) in ocular drug delivery, describing their properties and modes of action.

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          Bile acids: regulation of synthesis.

          John Chiang (2009)
          Bile acids are physiological detergents that generate bile flow and facilitate intestinal absorption and transport of lipids, nutrients, and vitamins. Bile acids also are signaling molecules and inflammatory agents that rapidly activate nuclear receptors and cell signaling pathways that regulate lipid, glucose, and energy metabolism. The enterohepatic circulation of bile acids exerts important physiological functions not only in feedback inhibition of bile acid synthesis but also in control of whole-body lipid homeostasis. In the liver, bile acids activate a nuclear receptor, farnesoid X receptor (FXR), that induces an atypical nuclear receptor small heterodimer partner, which subsequently inhibits nuclear receptors, liver-related homolog-1, and hepatocyte nuclear factor 4alpha and results in inhibiting transcription of the critical regulatory gene in bile acid synthesis, cholesterol 7alpha-hydroxylase (CYP7A1). In the intestine, FXR induces an intestinal hormone, fibroblast growth factor 15 (FGF15; or FGF19 in human), which activates hepatic FGF receptor 4 (FGFR4) signaling to inhibit bile acid synthesis. However, the mechanism by which FXR/FGF19/FGFR4 signaling inhibits CYP7A1 remains unknown. Bile acids are able to induce FGF19 in human hepatocytes, and the FGF19 autocrine pathway may exist in the human livers. Bile acids and bile acid receptors are therapeutic targets for development of drugs for treatment of cholestatic liver diseases, fatty liver diseases, diabetes, obesity, and metabolic syndrome.
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            Cyclic polyethers and their complexes with metal salts

            Charles J. Pedersen (1967)
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              Lanosterol reverses protein aggregation in cataracts.

              Ling Zhao, Xiang-Jun Chen, Jie Zhu … (2015)
              The human lens is comprised largely of crystallin proteins assembled into a highly ordered, interactive macro-structure essential for lens transparency and refractive index. Any disruption of intra- or inter-protein interactions will alter this delicate structure, exposing hydrophobic surfaces, with consequent protein aggregation and cataract formation. Cataracts are the most common cause of blindness worldwide, affecting tens of millions of people, and currently the only treatment is surgical removal of cataractous lenses. The precise mechanisms by which lens proteins both prevent aggregation and maintain lens transparency are largely unknown. Lanosterol is an amphipathic molecule enriched in the lens. It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of a cholesterol synthesis pathway. Here we identify two distinct homozygous LSS missense mutations (W581R and G588S) in two families with extensive congenital cataracts. Both of these mutations affect highly conserved amino acid residues and impair key catalytic functions of LSS. Engineered expression of wild-type, but not mutant, LSS prevents intracellular protein aggregation of various cataract-causing mutant crystallins. Treatment by lanosterol, but not cholesterol, significantly decreased preformed protein aggregates both in vitro and in cell-transfection experiments. We further show that lanosterol treatment could reduce cataract severity and increase transparency in dissected rabbit cataractous lenses in vitro and cataract severity in vivo in dogs. Our study identifies lanosterol as a key molecule in the prevention of lens protein aggregation and points to a novel strategy for cataract prevention and treatment.
              Article 0 comments Cited 132 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Pharmaceutics
                Journal ID (iso-abbrev): Pharmaceutics
                Journal ID (publisher-id): pharmaceutics
                Title: Pharmaceutics
                Publisher: MDPI
                ISSN (Electronic): 1999-4923
                Publication date (Electronic): 09 July 2019
                Publication date Collection: July 2019
                Volume: 11
                Issue: 7
                Electronic Location Identifier: 321
                Affiliations
                [1 ]Reading School of Pharmacy, University of Reading, Whiteknights, P.O. Box 224, Reading RG66AD, UK
                [2 ]MC2 Therapeutics, James House, Emlyn Lane, Leatherhead KT22 7EP, UK
                Author notes
                [* ]Correspondence: v.khutoryanskiy@ 123456reading.ac.uk ; Tel.: +44-(0)-118-378-6119
                Author information
                https://orcid.org/0000-0002-4358-9981
                https://orcid.org/0000-0002-3712-7908
                https://orcid.org/0000-0003-4501-1451
                https://orcid.org/0000-0002-7221-2630
                Article
                Publisher ID: pharmaceutics-11-00321
                DOI: 10.3390/pharmaceutics11070321
                PMC ID: 6681039
                PubMed ID: 31324063
                SO-VID: 16815134-0ce9-4b43-9c80-42c7466b29ce
                Copyright © © 2019 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 30 May 2019
                Date accepted : 03 July 2019
                Categories
                Subject: Review

                Keywords: ocular drug delivery,cornea,penetration enhancers,ocular conditions,ophthalmology
                Data availability:
                Keywords: ocular drug delivery, cornea, penetration enhancers, ocular conditions, ophthalmology

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