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Pharmaceutics
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Ophthalmic Drug Delivery
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Ophthalmic Drug Delivery

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Biopharmaceutics".

Deadline for manuscript submissions: closed (10 July 2020) | Viewed by 72990

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Prof. Dr. Francisco Javier Otero-Espinar

E-Mail Website
Guest Editor
Department of Pharmaceutical Technology, Faculty of Pharmacy, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Interests: ocular drug delivery
Special Issues, Collections and Topics in MDPI journals
Dr. Anxo Fernández Ferreiro

E-Mail Website
Guest Editor
Clinical Pharmacology Group, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
Interests: ocular drug delivery; ocular pharmacokinetic; drug development; pharmacogenetics; clinical and translational research
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Research in ophthalmic drug delivery has developed significant advances in the last years, and efforts have been made to develop more effective topical formulations to increase the drug bioavailability, efficiency, and safety. Drug delivery to the posterior segment of the eye remains a great challenge in the pharmaceutical industry due to the complexity and particularity of the anatomy and physiology of the eye. Some advances have been made with the purpose of maintaining constant drug levels in the site of action. The anatomical ocular barriers have a great impact on drug pharmacokinetics and, subsequently, on the pharmacological effect.

Despite the increasing interest in efficiently reaching the posterior segment of the eye with reduced adverse effects, there is still a need to expand knowledge of ocular pharmacokinetics that allows the development of safer and more innovative drug delivery systems. These novel approaches may greatly help to improve the lives of patients with ocular pathologies.

In this Special Issue, our goal is to highlight papers describing the advances in ophthalmic drug delivery systems for topical and specialized ocular administration.

Prof. Dr. Francisco Javier Otero-Espinar
Dr. Anxo Fernández Ferreiro
Guest Editors

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Keywords

  • ocular pharmacokinetics
  • ocular drug delivery systems
  • ocular routs of drug administration
  • intravitreal administration
  • topical administration

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Published Papers (16 papers)

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14 pages, 4368 KiB  
Article
The EyeFlowCell: Development of a 3D-Printed Dissolution Test Setup for Intravitreal Dosage Forms
by Tobias Auel, Linus Großmann, Lukas Schulig, Werner Weitschies and Anne Seidlitz
Pharmaceutics 2021, 13(9), 1394; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13091394 - 03 Sep 2021
Cited by 8 | Viewed by 2353
Abstract
An in vitro dissolution model, the so-called EyeFlowCell (EFC), was developed to test intravitreal dosage forms, simulating parameters such as the gel-like consistency of the vitreous body. The developed model consists of a stereolithography 3D-printed flow-through cell with a polyacrylamide (PAA) gel as [...] Read more.
An in vitro dissolution model, the so-called EyeFlowCell (EFC), was developed to test intravitreal dosage forms, simulating parameters such as the gel-like consistency of the vitreous body. The developed model consists of a stereolithography 3D-printed flow-through cell with a polyacrylamide (PAA) gel as its core. This gel needed to be coated with an agarose sheath because of its low viscosity. Drug release from hydroxypropyl methylcellulose-based implants containing either triamcinolone acetonide or fluorescein sodium was studied in the EFC using a schematic eye movement by the EyeMovementSystem (EyeMoS). For comparison, studies were performed in USP apparatus 4 and USP apparatus 7. Significantly slower drug release was observed in the PAA gel for both model drugs compared with the compendial methods. Drug release from fluorescein sodium-containing model implants was completed after 40 min in USP apparatus 4, whereas drug release in the gel-based EFC lasted 72 h. Drug release from triamcinolone acetonide-containing model implants was completed after 35 min in USP apparatus 4 and after 150 min in USP apparatus 7, whereas this was delayed until 96 h in the EFC. These results suggest that compendial release methods may overestimate the drug release rate in the human vitreous body. Using a gel-based in vitro release system such as the EFC may better predict drug release. Full article
(This article belongs to the Special Issue Ophthalmic Drug Delivery)
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21 pages, 3457 KiB  
Article
Dexamethasone PLGA Microspheres for Sub-Tenon Administration: Influence of Sterilization and Tolerance Studies
by Deyanira Barbosa-Alfaro, Vanessa Andrés-Guerrero, Ivan Fernandez-Bueno, María Teresa García-Gutiérrez, Esther Gil-Alegre, Irene Teresa Molina-Martínez, José Carlos Pastor-Jimeno, Rocío Herrero-Vanrell and Irene Bravo-Osuna
Pharmaceutics 2021, 13(2), 228; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13020228 - 06 Feb 2021
Cited by 17 | Viewed by 2667
Abstract
Many diseases affecting the posterior segment of the eye require repeated intravitreal injections with corticosteroids in chronic treatments. The periocular administration is a less invasive route attracting considerable attention for long-term therapies. In the present work, dexamethasone-loaded poly(lactic-co-glycolic) acid (PLGA) microspheres [...] Read more.
Many diseases affecting the posterior segment of the eye require repeated intravitreal injections with corticosteroids in chronic treatments. The periocular administration is a less invasive route attracting considerable attention for long-term therapies. In the present work, dexamethasone-loaded poly(lactic-co-glycolic) acid (PLGA) microspheres (Dx-MS) were prepared using the oil-in-water (O/W) emulsion solvent evaporation technique. MS were characterized in terms of mean particle size and particle size distribution, external morphology, polymer integrity, drug content, and in vitro release profiles. MS were sterilized by gamma irradiation (25 kGy), and dexamethasone release profiles from sterilized and non-sterilized microspheres were compared by means of the similarity factor (f2). The mechanism of drug release before and after irradiation exposure of Dx-MS was identified using appropriate mathematical models. Dexamethasone release was sustained in vitro for 9 weeks. The evaluation of the in vivo tolerance was carried out in rabbit eyes, which received a sub-Tenon injection of 5 mg of sterilized Dx-MS (20–53 µm size containing 165.6 ± 3.6 µg Dx/mg MS) equivalent to 828 µg of Dx. No detectable increase in intraocular pressure was reported, and clinical and histological analysis of the ocular tissues showed no adverse events up to 6 weeks after the administration. According to the data presented in this work, the sub-Tenon administration of Dx-MS could be a promising alternative to successive intravitreal injections for the treatment of chronic diseases of the back of the eye. Full article
(This article belongs to the Special Issue Ophthalmic Drug Delivery)
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22 pages, 4838 KiB  
Article
Transferrin Non-Viral Gene Therapy for Treatment of Retinal Degeneration
by Karine Bigot, Pauline Gondouin, Romain Bénard, Pierrick Montagne, Jenny Youale, Marie Piazza, Emilie Picard, Thierry Bordet and Francine Behar-Cohen
Pharmaceutics 2020, 12(9), 836; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12090836 - 01 Sep 2020
Cited by 11 | Viewed by 3567
Abstract
Dysregulation of iron metabolism is observed in animal models of retinitis pigmentosa (RP) and in patients with age-related macular degeneration (AMD), possibly contributing to oxidative damage of the retina. Transferrin (TF), an endogenous iron chelator, was proposed as a therapeutic candidate. Here, the [...] Read more.
Dysregulation of iron metabolism is observed in animal models of retinitis pigmentosa (RP) and in patients with age-related macular degeneration (AMD), possibly contributing to oxidative damage of the retina. Transferrin (TF), an endogenous iron chelator, was proposed as a therapeutic candidate. Here, the efficacy of TF non-viral gene therapy based on the electrotransfection of pEYS611, a plasmid encoding human TF, into the ciliary muscle was evaluated in several rat models of retinal degeneration. pEYS611 administration allowed for the sustained intraocular production of TF for at least 3 and 6 months in rats and rabbits, respectively. In the photo-oxidative damage model, pEYS611 protected both retinal structure and function more efficiently than carnosic acid, a natural antioxidant, reduced microglial infiltration in the outer retina and preserved the integrity of the outer retinal barrier. pEYS611 also protected photoreceptors from N-methyl-N-nitrosourea-induced apoptosis. Finally, pEYS611 delayed structural and functional degeneration in the RCS rat model of RP while malondialdehyde (MDA) ocular content, a biomarker of oxidative stress, was decreased. The neuroprotective benefits of TF non-viral gene delivery in retinal degenerative disease models further validates iron overload as a therapeutic target and supports the continued development of pEY611 for treatment of RP and dry AMD. Full article
(This article belongs to the Special Issue Ophthalmic Drug Delivery)
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18 pages, 3738 KiB  
Article
Understanding the Half-Life Extension of Intravitreally Administered Antibodies Binding to Ocular Albumin
by Simon Hauri, Paulina Jakubiak, Matthias Fueth, Stefan Dengl, Sara Belli, Rubén Alvarez-Sánchez and Antonello Caruso
Pharmaceutics 2020, 12(9), 810; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12090810 - 26 Aug 2020
Cited by 6 | Viewed by 3481
Abstract
The burden associated with frequent injections of current intravitreal (IVT) therapeutics may be reduced by long-acting delivery strategies. Binding to serum albumin has been shown to extend the ocular half-life in rabbits, however, the underlying molecular mechanisms and translational relevance remain unclear. The [...] Read more.
The burden associated with frequent injections of current intravitreal (IVT) therapeutics may be reduced by long-acting delivery strategies. Binding to serum albumin has been shown to extend the ocular half-life in rabbits, however, the underlying molecular mechanisms and translational relevance remain unclear. The aim of this work was to characterize the in vitro and in vivo formation of complexes between human serum albumin (HSA) and an antigen-binding fragment of a rabbit antibody linked to an anti-HSA nanobody (FabA). The ocular and systemic pharmacokinetics of 3H-labeled FabA (0.05 mg/eye IVT) co-formulated with HSA (1 and 15 nmol/eye) were assessed in Dutch belted rabbits. Next, FabA was incubated in vitreous samples from cynomolgus monkeys and human donors (healthy and diseased) supplemented with species-specific serum albumin. Finally, the FabA-albumin complexes formed in vitro and in vivo were analyzed by radio-size exclusion chromatography. A 3-fold increase in FabA vitreal exposure and half-life was observed in rabbits co-administered with 15 nmol HSA compared to 1 nmol and a control arm. The different pharmacokinetic behavior was explained with the formation of higher molecular weight FabA–albumin complexes. The analysis of vitreous samples revealed the existence of predominantly 1:1 complexes at endogenous or low concentrations of supplemented albumin. A shift towards 1:2 complexes was observed with increasing albumin concentrations. Overall, these results suggest that endogenous vitreal albumin concentrations are insufficient for half-life extension and warrant supplementation in the dosing formulation. Full article
(This article belongs to the Special Issue Ophthalmic Drug Delivery)
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17 pages, 14355 KiB  
Article
Lutein-Loaded, Biotin-Decorated Polymeric Nanoparticles Enhance Lutein Uptake in Retinal Cells
by Pradeep Kumar Bolla, Vrinda Gote, Mahima Singh, Manan Patel, Bradley A. Clark and Jwala Renukuntla
Pharmaceutics 2020, 12(9), 798; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12090798 - 24 Aug 2020
Cited by 32 | Viewed by 4866
Abstract
Age related macular degeneration (AMD) is one of the leading causes of visual loss and is responsible for approximately 9% of global blindness. It is a progressive eye disorder seen in elderly people (>65 years) mainly affecting the macula. Lutein, a carotenoid, is [...] Read more.
Age related macular degeneration (AMD) is one of the leading causes of visual loss and is responsible for approximately 9% of global blindness. It is a progressive eye disorder seen in elderly people (>65 years) mainly affecting the macula. Lutein, a carotenoid, is an antioxidant, and has shown neuroprotective properties in the retina. However, lutein has poor bioavailability owing to poor aqueous solubility. Drug delivery to the posterior segment of the eye is challenging due to the blood–retina barrier. Retinal pigment epithelium (RPE) expresses the sodium-dependent multivitamin transporter (SMVT) transport system which selectively uptakes biotin by active transport. In this study, we aimed to enhance lutein uptake into retinal cells using PLGA–PEG–biotin nanoparticles. Lutein loaded polymeric nanoparticles were prepared using O/W solvent-evaporation method. Particle size and zeta potential (ZP) were determined using Malvern Zetasizer. Other characterizations included differential scanning calorimetry, FTIR, and in-vitro release studies. In-vitro uptake and cytotoxicity studies were conducted in ARPE-19 cells using flow cytometry and confocal microscopy. Lutein was successfully encapsulated into PLGA and PLGA–PEG–biotin nanoparticles (<250 nm) with uniform size distribution and high ZP. The entrapment efficiency of lutein was ≈56% and ≈75% for lutein-loaded PLGA and PLGA–PEG–biotin nanoparticles, respectively. FTIR and DSC confirmed encapsulation of lutein into nanoparticles. Cellular uptake studies in ARPE-19 cells confirmed a higher uptake of lutein with PLGA–PEG–biotin nanoparticles compared to PLGA nanoparticles and lutein alone. In vitro cytotoxicity results confirmed that the nanoparticles were safe, effective, and non-toxic. Findings from this study suggest that lutein-loaded PLGA–PEG–biotin nanoparticles can be potentially used for treatment of AMD for higher lutein uptake. Full article
(This article belongs to the Special Issue Ophthalmic Drug Delivery)
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17 pages, 2491 KiB  
Article
Do Ophthalmic Solutions of Amphotericin B Solubilised in 2-Hydroxypropyl-γ-Cyclodextrins Possess an Extended Physicochemical Stability?
by Philip Chennell, Mouloud Yessaad, Florence Abd El Kader, Mireille Jouannet, Mathieu Wasiak, Yassine Bouattour and Valérie Sautou
Pharmaceutics 2020, 12(9), 786; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12090786 - 19 Aug 2020
Cited by 7 | Viewed by 3595
Abstract
Fungal keratitis is a sight-threatening disease for which amphotericin B eye drops is one of the front-line treatments. Unfortunately, there are currently no commercial forms available, and there is little data concerning the long-term stability of compounded formulations based on intravenous dosages forms. [...] Read more.
Fungal keratitis is a sight-threatening disease for which amphotericin B eye drops is one of the front-line treatments. Unfortunately, there are currently no commercial forms available, and there is little data concerning the long-term stability of compounded formulations based on intravenous dosages forms. New formulations of amphotericin B ophthalmic solutions solubilised with γ-cyclodextrins have shown promising in-vitro results, but stability data is also lacking. The objective of this study was therefore to investigate the stability of a formulation of ready-to-use amphotericin B solubilised in 2-hydroxypropyl-γ-cyclodextrins (AB-HP-γ-CD), for 350 days. An amphotericin B deoxycholate (ABDC) formulation was used as a comparator. Analyses used were the following: visual inspection, turbidity, osmolality and pH measurements, amphotericin B quantification by a stability-indicating liquid chromatography method, breakdown product research, and sterility assay. AB-HP-γ-CD formulation showed signs of chemical instability (loss of amphotericin B) after 28 and 56 days at 25 °C and 5 °C. Adding an antioxidant (ascorbic acid) to the formulation did not improve stability. ABDC formulation showed signs of physical instability (increased turbidy and amphotericin B precipitation) after 28 days and 168 days at 25 °C and 5 °C. As such, AB-HP-γ-CD formulation does not provide long-term stability for ophthalmic amphotericin B solutions. Full article
(This article belongs to the Special Issue Ophthalmic Drug Delivery)
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18 pages, 2070 KiB  
Article
Stability of Ophthalmic Atropine Solutions for Child Myopia Control
by Baptiste Berton, Philip Chennell, Mouloud Yessaad, Yassine Bouattour, Mireille Jouannet, Mathieu Wasiak and Valérie Sautou
Pharmaceutics 2020, 12(8), 781; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12080781 - 17 Aug 2020
Cited by 19 | Viewed by 7404
Abstract
Myopia is an ophthalmic condition affecting more than 1/5th of the world population, especially children. Low-dose atropine eyedrops have been shown to limit myopia evolution during treatment. However, there are currently no commercial industrial forms available and there is little data published concerning [...] Read more.
Myopia is an ophthalmic condition affecting more than 1/5th of the world population, especially children. Low-dose atropine eyedrops have been shown to limit myopia evolution during treatment. However, there are currently no commercial industrial forms available and there is little data published concerning the stability of medications prepared by compounding pharmacies. The objective of this study was to evaluate the stability of two 0.1 mg/mL atropine formulations (with and without antimicrobiobial preservatives) for 6 months in two different low-density polyethylene (LDPE) multidose eyedroppers. Analyses used were the following: visual inspection, turbidity, chromaticity measurements, osmolality and pH measurements, atropine quantification by a stability-indicating liquid chromatography method, breakdown product research, and sterility assay. In an in-use study, atropine quantification was also performed on the drops emitted from the multidose eyedroppers. All tested parameters remained stable during the 6 months period, with atropine concentrations above 94.7% of initial concentration. A breakdown product (tropic acid) did increase slowly over time but remained well below usually admitted concentrations. Atropine concentrations remained stable during the in-use study. Both formulations of 0.1 mg/mL of atropine (with and without antimicrobial preservative) were proved to be physicochemically stable for 6 months at 25 °C when stored in LDPE bottles, with an identical microbial shelf-life. Full article
(This article belongs to the Special Issue Ophthalmic Drug Delivery)
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12 pages, 1011 KiB  
Article
Uptake Study in Lysosome-Enriched Fraction: Critical Involvement of Lysosomal Trapping in Quinacrine Uptake but Not Fluorescence-Labeled Verapamil Transport at Blood-Retinal Barrier
by Yoshiyuki Kubo, Miki Yamada, Saki Konakawa, Shin-ichi Akanuma and Ken-ichi Hosoya
Pharmaceutics 2020, 12(8), 747; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12080747 - 08 Aug 2020
Cited by 8 | Viewed by 2473
Abstract
Lysosomal trapping at the blood–retinal barrier (BRB) was investigated through quinacrine and fluorescence-labeled verapamil (EFV) uptake. Quinacrine uptake by conditionally immortalized rat retinal capillary endothelial (TR-iBRB2) cells suggested saturable and non-saturable transport processes in the inner BRB. The reduction of quinacrine uptake by [...] Read more.
Lysosomal trapping at the blood–retinal barrier (BRB) was investigated through quinacrine and fluorescence-labeled verapamil (EFV) uptake. Quinacrine uptake by conditionally immortalized rat retinal capillary endothelial (TR-iBRB2) cells suggested saturable and non-saturable transport processes in the inner BRB. The reduction of quinacrine uptake by bafilomycin A1 suggested quinacrine distribution to the acidic intracellular compartments of the inner BRB, and this notion was also supported in confocal microscopy. In the study using the lysosome-enriched fraction of TR-iBRB2 cells, quinacrine uptake was inhibited by bafilomycin A1, suggesting the lysosomal trapping of quinacrine in the inner BRB. Pyrilamine, clonidine, and nicotine had no effect on quinacrine uptake, suggesting the minor role of lysosomal trapping in their transport across the inner BRB. Bafilomycin A1 had no effect on EFV uptake, and lysosomal trapping driven by the acidic interior pH was suggested as a minor mechanism for EFV transport in the inner BRB. The minor contribution of lysosomal trapping was supported by the difference in inhibitory profiles between EFV and quinacrine uptakes. Similar findings were observed in the outer BRB study with the fraction of conditionally immortalized rat retinal pigment epithelial (RPE-J) cells. These results suggest the usefulness of lysosome-enriched fractions in studying lysosomal trapping at the BRB. Full article
(This article belongs to the Special Issue Ophthalmic Drug Delivery)
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19 pages, 2909 KiB  
Article
Biopharmaceutical Assessment of Dexamethasone Acetate-Based Hydrogels Combining Hydroxypropyl Cyclodextrins and Polysaccharides for Ocular Delivery
by Roseline Mazet, Xurxo García-Otero, Luc Choisnard, Denis Wouessidjewe, Vincent Verdoot, Frédéric Bossard, Victoria Díaz-Tomé, Véronique Blanc-Marquis, Francisco-Javier Otero-Espinar, Anxo Fernandez-Ferreiro and Annabelle Gèze
Pharmaceutics 2020, 12(8), 717; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12080717 - 30 Jul 2020
Cited by 5 | Viewed by 3531
Abstract
We previously developed two optimized formulations of dexamethasone acetate (DXMa) hydrogels by means of special cubic mixture designs for topical ocular administration. These gels were elaborated with hydroxypropyl-β-CD (HPβCD) and hydroxypropyl-γ-CD (HPγCD) and commercial hydrogels in order to enhance DXMa water solubility and [...] Read more.
We previously developed two optimized formulations of dexamethasone acetate (DXMa) hydrogels by means of special cubic mixture designs for topical ocular administration. These gels were elaborated with hydroxypropyl-β-CD (HPβCD) and hydroxypropyl-γ-CD (HPγCD) and commercial hydrogels in order to enhance DXMa water solubility and finally DXMa’s ocular bioavailability and transcorneal penetration. The main objective of this study was to characterize them and to evaluate in vitro, ex vivo, and in vivo their safety, biopermanence, and transcorneal permeation. Gels A and B are Newtonian fluids and display a viscosity of 13.2 mPa.s and 18.6 mPa.s, respectively, which increases their ocular retention, according to the in vivo biopermanence study by PET/CT. These hydrogels could act as corneal absorption promoters as they allow a higher transcorneal permeation of DXMa through porcine excised cornea, compared to DEXAFREE® and MAXIDEX®. Cytotoxicity assays showed no cytotoxic effects on human primary corneal epithelial cells (HCE). Furthermore, Gel B is clearly safe for the eye, but the effect of Gel A on the human eye cannot be predicted. Both gels were also stable 12 months at 25 °C after sterilization by filtration. These results demonstrate that the developed formulations present a high potential for the topical ocular administration of dexamethasone acetate. Full article
(This article belongs to the Special Issue Ophthalmic Drug Delivery)
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22 pages, 4627 KiB  
Article
Fasudil Loaded PLGA Microspheres as Potential Intravitreal Depot Formulation for Glaucoma Therapy
by Raphael Mietzner, Christian Kade, Franziska Froemel, Diana Pauly, W. Daniel Stamer, Andreas Ohlmann, Joachim Wegener, Rudolf Fuchshofer and Miriam Breunig
Pharmaceutics 2020, 12(8), 706; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12080706 - 27 Jul 2020
Cited by 22 | Viewed by 4371
Abstract
Rho-associated protein kinase (ROCK) inhibitors allow for causative glaucoma therapy. Unfortunately, topically applied ROCK inhibitors suffer from high incidence of hyperemia and low intraocular bioavailability. Therefore, we propose the use of poly (lactide-co-glycolide) (PLGA) microspheres as a depot formulation for intravitreal injection to [...] Read more.
Rho-associated protein kinase (ROCK) inhibitors allow for causative glaucoma therapy. Unfortunately, topically applied ROCK inhibitors suffer from high incidence of hyperemia and low intraocular bioavailability. Therefore, we propose the use of poly (lactide-co-glycolide) (PLGA) microspheres as a depot formulation for intravitreal injection to supply outflow tissues with the ROCK inhibitor fasudil over a prolonged time. Fasudil-loaded microspheres were prepared by double emulsion solvent evaporation technique. The chemical integrity of released fasudil was confirmed by mass spectrometry. The biological activity was measured in cell-based assays using trabecular meshwork cells (TM cells), Schlemm’s canal cells (SC cells), fibroblasts and adult retinal pigment epithelium cells (ARPE-19). Cellular response to fasudil after its diffusion through vitreous humor was investigated by electric cell-substrate impedance sensing. Microspheres ranged in size from 3 to 67 µm. The release of fasudil from microspheres was controllable and sustained for up to 45 days. Released fasudil reduced actin stress fibers in TM cells, SC cells and fibroblasts. Decreased collagen gel contraction provoked by fasudil was detected in TM cells (~2.4-fold), SC cells (~1.4-fold) and fibroblasts (~1.3-fold). In addition, fasudil readily diffused through vitreous humor reaching its target compartment and eliciting effects on TM cells. No negative effects on ARPE-19 cells were observed. Since fasudil readily diffuses through the vitreous humor, we suggest that an intravitreal drug depot of ROCK inhibitors could significantly improve current glaucoma therapy particularly for patients with comorbid retinal diseases. Full article
(This article belongs to the Special Issue Ophthalmic Drug Delivery)
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31 pages, 7169 KiB  
Article
Characterization, Stability, and In Vivo Efficacy Studies of Recombinant Human CNTF and Its Permeation into the Neural Retina in Ex Vivo Organotypic Retinal Explant Culture Models
by Jaakko Itkonen, Ada Annala, Shirin Tavakoli, Blanca Arango-Gonzalez, Marius Ueffing, Elisa Toropainen, Marika Ruponen, Marco G. Casteleijn and Arto Urtti
Pharmaceutics 2020, 12(7), 611; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12070611 - 30 Jun 2020
Cited by 8 | Viewed by 3902
Abstract
Ciliary neurotrophic factor (CNTF) is one of the most studied neuroprotective agents with acknowledged potential in treating diseases of the posterior eye segment. Although its efficacy and mechanisms of action in the retina have been studied extensively, it is still not comprehensively understood [...] Read more.
Ciliary neurotrophic factor (CNTF) is one of the most studied neuroprotective agents with acknowledged potential in treating diseases of the posterior eye segment. Although its efficacy and mechanisms of action in the retina have been studied extensively, it is still not comprehensively understood which retinal cells mediate the therapeutic effects of CNTF. As with therapeutic proteins in general, it is poorly elucidated whether exogenous CNTF administered into the vitreous can enter and distribute into the retina and hence reach potentially responsive target cells. Here, we have characterized our purified recombinant human CNTF (rhCNTF), studied the protein’s in vitro bioactivity in a cell-based assay, and evaluated the thermodynamic and oligomeric status of the protein during storage. Biological activity of rhCNTF was further evaluated in vivo in an animal model of retinal degeneration. The retinal penetration and distribution of rhCNTF after 24 h was studied utilizing two ex vivo retina models. Based on our characterization findings, our rhCNTF is correctly folded and biologically active. Moreover, based on initial screening and subsequent follow-up, we identified two buffers in which rhCNTF retains its stability during storage. Whereas rhCNTF did not show photoreceptor preservative effect or improve the function of photoreceptors in vivo, this could possibly be due to the used disease model or the short duration of action with a single intravitreal injection of rhCNTF. On the other hand, the lack of in vivo efficacy was shown to not be due to distribution limitations; permeation into the retina was observed in both retinal explant models as in 24 h rhCNTF penetrated the inner limiting membrane, and being mostly observed in the ganglion cell layer, distributed to different layers of the neural retina. As rhCNTF can reach deeper retinal layers, in general, having direct effects on resident CNTF-responsive target cells is plausible. Full article
(This article belongs to the Special Issue Ophthalmic Drug Delivery)
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17 pages, 4192 KiB  
Article
Topical Application of Hyaluronic Acid-RGD Peptide-Coated Gelatin/Epigallocatechin-3 Gallate (EGCG) Nanoparticles Inhibits Corneal Neovascularization via Inhibition of VEGF Production
by Takuya Miyagawa, Zhi-Yu Chen, Che-Yi Chang, Ko-Hua Chen, Yang-Kao Wang, Guei-Sheung Liu and Ching-Li Tseng
Pharmaceutics 2020, 12(5), 404; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12050404 - 28 Apr 2020
Cited by 18 | Viewed by 3721
Abstract
Neovascularization (NV) of the cornea disrupts vision which leads to blindness. Investigation of antiangiogenic, slow-release and biocompatible approaches for treating corneal NV is of great importance. We designed an eye drop formulation containing gelatin/epigallocatechin-3-gallate (EGCG) nanoparticles (NPs) for targeted therapy in corneal NV. [...] Read more.
Neovascularization (NV) of the cornea disrupts vision which leads to blindness. Investigation of antiangiogenic, slow-release and biocompatible approaches for treating corneal NV is of great importance. We designed an eye drop formulation containing gelatin/epigallocatechin-3-gallate (EGCG) nanoparticles (NPs) for targeted therapy in corneal NV. Gelatin-EGCG self-assembled NPs with hyaluronic acid (HA) coating on its surface (named GEH) and hyaluronic acid conjugated with arginine-glycine-aspartic acid (RGD) (GEH-RGD) were synthesized. Human umbilical vein endothelial cells (HUVECs) were used to evaluate the antiangiogenic effect of GEH-RGD NPs in vitro. Moreover, a mouse model of chemical corneal cauterization was employed to evaluate the antiangiogenic effects of GEH-RGD NPs in vivo. GEH-RGD NP treatment significantly reduced endothelial cell tube formation and inhibited metalloproteinase (MMP)-2 and MMP-9 activity in HUVECs in vitro. Topical application of GEH-RGD NPs (once daily for a week) significantly attenuated the formation of pathological vessels in the mouse cornea after chemical cauterization. Reduction in both vascular endothelial growth factor (VEGF) and MMP-9 protein in the GEH-RGD NP-treated cauterized corneas was observed. These results confirm the molecular mechanism of the antiangiogenic effect of GEH-RGD NPs in suppressing pathological corneal NV. Full article
(This article belongs to the Special Issue Ophthalmic Drug Delivery)
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11 pages, 2493 KiB  
Article
Novel Sustained-Release Drug Delivery System for Dry Eye Therapy by Rebamipide Nanoparticles
by Noriaki Nagai, Miyu Ishii, Ryotaro Seiriki, Fumihiko Ogata, Hiroko Otake, Yosuke Nakazawa, Norio Okamoto, Kazutaka Kanai and Naohito Kawasaki
Pharmaceutics 2020, 12(2), 155; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12020155 - 14 Feb 2020
Cited by 22 | Viewed by 5173
Abstract
The commercially available rebamipide ophthalmic suspension (CA-REB) was approved for clinical use in patients with dry eye; however, the residence time on the ocular surface for the traditional formulations is short, since the drug is removed from the ocular surface through the nasolacrimal [...] Read more.
The commercially available rebamipide ophthalmic suspension (CA-REB) was approved for clinical use in patients with dry eye; however, the residence time on the ocular surface for the traditional formulations is short, since the drug is removed from the ocular surface through the nasolacrimal duct. In this study, we designed a novel sustained-release drug delivery system (DDS) for dry eye therapy by rebamipide nanoparticles. The rebamipide solid nanoparticle-based ophthalmic formulation (REB-NPs) was prepared by a bead mill using additives (2-hydroxypropyl-β-cyclodextrin and methylcellulose) and a gel base (carbopol). The rebamipide particles formed are ellipsoid, with a particle size in the range of 40–200 nm. The rebamipide in the REB-NPs applied to eyelids was delivered into the lacrimal fluid through the meibomian glands, and sustained drug release was observed in comparison with CA-REB. Moreover, the REB-NPs increased the mucin levels in the lacrimal fluid and healed tear film breakup levels in an N-acetylcysteine-treated rabbit model. The information about this novel DDS route and creation of a nano-formulation can be used to design further studies aimed at therapy for dry eye. Full article
(This article belongs to the Special Issue Ophthalmic Drug Delivery)
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26 pages, 693 KiB  
Review
Intravitreal Dexamethasone Implant as a Sustained Release Drug Delivery Device for the Treatment of Ocular Diseases: A Comprehensive Review of the Literature
by Claudio Iovino, Rodolfo Mastropasqua, Marco Lupidi, Daniela Bacherini, Marco Pellegrini, Federico Bernabei, Enrico Borrelli, Riccardo Sacconi, Adriano Carnevali, Rossella D’Aloisio, Alessio Cerquaglia, Lucia Finocchio, Andrea Govetto, Stefano Erba, Giacinto Triolo, Antonio Di Zazzo, Matteo Forlini, Aldo Vagge and Giuseppe Giannaccare
Pharmaceutics 2020, 12(8), 703; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12080703 - 26 Jul 2020
Cited by 26 | Viewed by 5281
Abstract
Drug delivery into the vitreous chamber remains a great challenge in the pharmaceutical industry due to the complex anatomy and physiology of the eye. Intravitreal injection is the mainstream route of drug administration to the posterior segment of the eye. The purpose of [...] Read more.
Drug delivery into the vitreous chamber remains a great challenge in the pharmaceutical industry due to the complex anatomy and physiology of the eye. Intravitreal injection is the mainstream route of drug administration to the posterior segment of the eye. The purpose of this review is to assess the current literature about the widening use of the intravitreal 0.7 mg dexamethasone (Dex) implant, and to provide a comprehensive collection of all the ocular disorders that benefit from Dex administration. Although anti-vascular endothelial growth-factors (VEGFs) have been largely indicated as a first-choice level, the Dex implant represents an important treatment option, especially in selected cases, such as vitrectomized eyes or patients in whom anti-VEGF failed or are contraindicated. In this article, the safety profile as well as the list of the possible complications related to intravitreal Dex injection are also discussed. Full article
(This article belongs to the Special Issue Ophthalmic Drug Delivery)
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39 pages, 2422 KiB  
Review
Drug Delivery to the Posterior Segment of the Eye: Biopharmaceutic and Pharmacokinetic Considerations
by Rubén Varela-Fernández, Victoria Díaz-Tomé, Andrea Luaces-Rodríguez, Andrea Conde-Penedo, Xurxo García-Otero, Asteria Luzardo-Álvarez, Anxo Fernández-Ferreiro and Francisco J. Otero-Espinar
Pharmaceutics 2020, 12(3), 269; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12030269 - 16 Mar 2020
Cited by 187 | Viewed by 12088
Abstract
The treatment of the posterior-segment ocular diseases, such as age-related eye diseases (AMD) or diabetic retinopathy (DR), present a challenge for ophthalmologists due to the complex anatomy and physiology of the eye. This specialized organ is composed of various static and dynamic barriers [...] Read more.
The treatment of the posterior-segment ocular diseases, such as age-related eye diseases (AMD) or diabetic retinopathy (DR), present a challenge for ophthalmologists due to the complex anatomy and physiology of the eye. This specialized organ is composed of various static and dynamic barriers that restrict drug delivery into the target site of action. Despite numerous efforts, effective intraocular drug delivery remains unresolved and, therefore, it is highly desirable to improve the current treatments of diseases affecting the posterior cavity. This review article gives an overview of pharmacokinetic and biopharmaceutics aspects for the most commonly-used ocular administration routes (intravitreal, topical, systemic, and periocular), including information of the absorption, distribution, and elimination, as well as the benefits and limitations of each one. This article also encompasses different conventional and novel drug delivery systems designed and developed to improve drug pharmacokinetics intended for the posterior ocular segment treatment. Full article
(This article belongs to the Special Issue Ophthalmic Drug Delivery)
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18 pages, 1728 KiB  
Review
Retinal Cell Protection in Ocular Excitotoxicity Diseases. Possible Alternatives Offered by Microparticulate Drug Delivery Systems and Future Prospects
by Javier Rodríguez Villanueva, Jorge Martín Esteban and Laura J. Rodríguez Villanueva
Pharmaceutics 2020, 12(2), 94; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12020094 - 24 Jan 2020
Cited by 13 | Viewed by 3317
Abstract
Excitotoxicity seems to play a critical role in ocular neurodegeneration. Excess-glutamate-mediated retinal ganglion cells death is the principal cause of cell loss. Uncontrolled glutamate in the synapsis has significant implications in the pathogenesis of neurodegenerative disorders. The exploitation of various approaches of controlled [...] Read more.
Excitotoxicity seems to play a critical role in ocular neurodegeneration. Excess-glutamate-mediated retinal ganglion cells death is the principal cause of cell loss. Uncontrolled glutamate in the synapsis has significant implications in the pathogenesis of neurodegenerative disorders. The exploitation of various approaches of controlled release systems enhances the pharmacokinetic and pharmacodynamic activity of drugs. In particular, microparticles are secure, can maintain therapeutic drug concentrations in the eye for prolonged periods, and make intimate contact by improving drug bioavailability. According to the promising results reported, possible new investigations will focus intense attention on microparticulate formulations and can be expected to open the field to new alternatives for doctors, as currently required by patients. Full article
(This article belongs to the Special Issue Ophthalmic Drug Delivery)
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