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Innovative Technologies to Treat Diseases of the Back of the Eye

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 44338

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Special Issue Editors

Prof. Dr. Rocio Herrero-Vanrell

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Guest Editor

Department of Pharmaceutics and Food Technology, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain
Interests: drug delivery; ophthalmic; ocular drug delivery; nanomedicine; microparticles; controlled release

Dr. Laurence Fitzhenry

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Guest Editor

Ocular Therapeutics Research Group, Pharmaceutical and Molecular Biotechnology Research Centre (PMBRC), Department of Science, Waterford Institute of Technology, Waterford, Ireland
Interests: drug delivery; ophthalmic; ocular drug delivery; nanomaterials; controlled release; biomaterials
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Delivering drugs targeted for posterior segment diseases of the eye in a safe, patient-friendly, and controlled manner has long been the focus of drug delivery researchers. With an aim to develop smart materials capable of the controlled release of ophthalmic drugs relevant in the treatment and management of back of the eye diseases, such research hopes to meet the challenges associated with the global rise in such diseases. Much of the focus has worked towards the development of both nanomaterial delivery carriers and extended-release platforms, such as nano- and micro-devices, implants and contact lenses, as effective means to bypass the ocular barriers and deliver drug efficiently to the posterior segment of the eye. All these innovative technologies are emerging as efficient therapeutic tools in the personalized treatment of back of the eye diseases. The development of animal models of posterior segment diseases is also a critical issue as most of these pathologies are chronic and multifactorial.

Prof. Dr. Rocio Herrero-Vanrell
Dr. Laurence Fitzhenry
Guest Editors

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Keywords

drug delivery
ophthalmic
ocular controlled release
posterior segment
biomaterials
nanotechnology
microtechnology
implants
contact lenses

Published Papers (11 papers)

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Research

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19 pages, 4803 KiB

Open AccessArticle

Validation of a Rapid and Easy-to-Apply Method to Simultaneously Quantify Co-Loaded Dexamethasone and Melatonin PLGA Microspheres by HPLC-UV: Encapsulation Efficiency and In Vitro Release

by Marco Brugnera, Marta Vicario-de-la-Torre, Vanessa Andrés-Guerrero, Irene Bravo-Osuna, Irene Teresa Molina-Martínez and Rocío Herrero-Vanrell

Pharmaceutics 2022, 14(2), 288; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14020288 - 26 Jan 2022

Cited by 8 | Viewed by 3385

Abstract

This paper discusses the development and validation of a rapid method for the reversed phase HPLC-UV quantification of biodegradable poly(D,L-lactic-co-glycolic) acid (PLGA) microspheres co-loaded with two neuroprotective agents (dexamethasone and melatonin) (DX-MEL-MSs) to be intravitreally administered as a promising glaucoma treatment. The study was performed to validate two procedures that quantify the content of the two active substances entrapped into the polymer matrix during an encapsulation efficiency assay and the amount of drugs liberated over time during the in vitro release assay. The reversed-phase method allowed for the simultaneous determination of dexamethasone and melatonin, which were respectively detected at 240.5 and 222.7 nm. Chromatographic separation was performed using an Ascentis^® C18 HPLC Column (25 cm × 4.6 mm, 5 µm) with an isocratic mobile phase composed of methanol-water (70:30, v/v) with 1.0 mL min⁻¹ flow rate. The two procedures were validated analytically in terms of system suitability testing, specificity, linearity, precision, accuracy, sensitivity, and robustness. Both the validated procedures were applied to characterize DX-MEL-MSs and were found appropriate to quantify the drug quantities encapsulated and estimate their release profile over 10 days. The validation study designed in this work can be helpful for planning any other protocols that refer to the quantification of PLGA based drug delivery systems. Full article

(This article belongs to the Special Issue Innovative Technologies to Treat Diseases of the Back of the Eye)

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20 pages, 4559 KiB

Open AccessArticle

Chitosan-Coated PLGA Nanoparticles Encapsulating Triamcinolone Acetonide as a Potential Candidate for Sustained Ocular Drug Delivery

by Madhuri Dandamudi, Peter McLoughlin, Gautam Behl, Sweta Rani, Lee Coffey, Anuj Chauhan, David Kent and Laurence Fitzhenry

Pharmaceutics 2021, 13(10), 1590; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13101590 - 30 Sep 2021

Cited by 41 | Viewed by 4442

Abstract

The current treatment for the acquired retinal vasculopathies involves lifelong repeated intravitreal injections of either anti-vascular endothelial growth factor (VEGF) therapy or modulation of inflammation with steroids. Consequently, any treatment modification that decreases this treatment burden for patients and doctors alike would be a welcome intervention. To that end, this research aims to develop a topically applied nanoparticulate system encapsulating a corticosteroid for extended drug release. Poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) supports the controlled release of the encapsulated drug, while surface modification of these NPs with chitosan might prolong the mucoadhesion ability leading to improved bioavailability of the drug. Triamcinolone acetonide (TA)-loaded chitosan-coated PLGA NPs were fabricated using the oil-in-water emulsion technique. The optimized surface-modified NPs obtained using Box-Behnken response surface statistical design were reproducible with a particle diameter of 334 ± 67.95 to 386 ± 15.14 nm and PDI between 0.09 and 0.15. These NPs encapsulated 55–57% of TA and displayed a controlled release of the drug reaching a plateau in 27 h. Fourier-transform infrared spectroscopic (FTIR) analysis demonstrated characteristic peaks for chitosan (C-H, CONH2 and C-O at 2935, 1631 and 1087 cm⁻¹, respectively) in chitosan-coated PLGA NPs. This result data, coupled with positive zeta potential values (ranged between +26 and +33 mV), suggests the successful coating of chitosan onto PLGA NPs. Upon coating of the NPs, the thermal stability of the drug, polymer, surfactant and PLGA NPs have been enhanced. The characteristics of the surface-modified NPs supports their use as potential candidates for topical ocular drug delivery for acquired retinal vasculopathies. Full article

(This article belongs to the Special Issue Innovative Technologies to Treat Diseases of the Back of the Eye)

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20 pages, 2872 KiB

Open AccessArticle

Drug-Loaded Hydrogels for Intraocular Lenses with Prophylactic Action against Pseudophakic Cystoid Macular Edema

by Nadia Toffoletto, Madalena Salema-Oom, Soledad Anguiano Igea, Carmen Alvarez-Lorenzo, Benilde Saramago and Ana Paula Serro

Pharmaceutics 2021, 13(7), 976; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13070976 - 28 Jun 2021

Cited by 9 | Viewed by 3438

Abstract

Pseudophakic cystoid macular edema (PCME), caused by chronic inflammation, is the most common cause of visual impairment in the medium-term after cataract surgery. Therefore, the prophylactic topical administration of combined steroidal and non-steroidal anti-inflammatory drugs is commonly done. Drug-eluting intraocular lenses (IOLs) gained interest as an efficient way to overcome the compliance issues related to the use of ocular drops without the need for additional surgical steps. The incorporation of functional monomers and molecular imprinting were herein applied to design hydrogels suitable as IOLs and able to co-deliver steroidal (dexamethasone sodium phosphate) and non-steroidal (bromfenac sodium) drugs. The incorporation of N-(2-aminopropyl) methacrylamide (APMA) increased the drug uptake and improved the in vitro release kinetics. Imprinting with bromfenac resulted in a decreased drug release due to permanent drug bonding, while imprinting with dexamethasone increased the amount of dexamethasone released after dual-drug loading. The application of a mathematical model to predict the in vivo drug release behavior suggests the feasibility of achieving therapeutic drug concentrations of bromfenac and dexamethasone in the aqueous humor for about 2 and 8 weeks, respectively, which is compatible with the current topical prophylaxis after cataract surgery. Full article

(This article belongs to the Special Issue Innovative Technologies to Treat Diseases of the Back of the Eye)

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Graphical abstract

16 pages, 14883 KiB

Open AccessArticle

Systemic Treatment with Nicotinamide Riboside Is Protective in Two Mouse Models of Retinal Ganglion Cell Damage

by Xian Zhang, Nan Zhang, Micah A. Chrenek, Preston E. Girardot, Jiaxing Wang, Jana T. Sellers, Eldon E. Geisert, Charles Brenner, John M. Nickerson, Jeffrey H. Boatright and Ying Li

Pharmaceutics 2021, 13(6), 893; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13060893 - 16 Jun 2021

Cited by 19 | Viewed by 3297

Abstract

Glaucoma etiology often includes retinal ganglion cell (RGC) death associated with elevated intraocular pressure (IOP). However, even when IOP is managed well, disease can progress. It is thus important to develop therapeutic approaches that directly protect RGCs in an IOP-independent manner. Compromised nicotinamide adenine dinucleotide (NAD⁺) metabolism occurs in neurodegenerative diseases, including models of glaucoma. Here we report testing the protective effects of prophylactically systemically administered nicotinamide riboside (NR), a NAD⁺ precursor, in a mouse model of acute RGC damage (optic nerve crush (ONC)), and in a chronic model of RGC degeneration (ocular hypertension induced by intracameral injection of microbeads). For both models, treatment enhanced RGC survival, assessed by counting cells in retinal flatmounts immunostained for Brn3a+. In the ONC model, treatment preserved RGC function, as assessed by pattern electroretinogram, and suppressed retinal inflammation, as assessed by immunofluorescence staining of retinal fixed sections for glial fibrillary acidic protein (GFAP). This is the first study to demonstrate that systemic treatment with NR is protective in acute and chronic models of RGC damage. The protection is significant and, considering that NR is highly bioavailable in and well-tolerated by humans, may support the proposition of prospective human subject studies. Full article

(This article belongs to the Special Issue Innovative Technologies to Treat Diseases of the Back of the Eye)

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15 pages, 1519 KiB

Open AccessArticle

Preliminary Investigation on Simvastatin-Loaded Polymeric Micelles in View of the Treatment of the Back of the Eye

by Silvia Pescina, Fabio Sonvico, Adryana Clementino, Cristina Padula, Patrizia Santi and Sara Nicoli

Pharmaceutics 2021, 13(6), 855; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13060855 - 09 Jun 2021

Cited by 9 | Viewed by 2630

Abstract

There is increasing consensus in considering statins beneficial for age-related macular degeneration and in general, for immune and inflammatory mediated diseases affecting the posterior segment of the eye. However, all available data relate to oral administration, and safety and effectiveness of statins directly administered to the eye are not yet known, despite their ophthalmic administration could be beneficial. The aim was the development and the characterization of polymeric micelles based on TPGS or TPGS/poloxamer 407 to increase simvastatin solubility and stability and to enhance the delivery of the drug to the posterior segment of the eye via trans-scleral permeation. Simvastatin was chosen as a model statin and its active hydroxy acid metabolite was investigated as well. Results demonstrated that polymeric micelles increased simvastatin solubility at least 30-fold and particularly TPGS/poloxamer 407 mixed micelles, successfully stabilized simvastatin over time, preventing the hydrolysis when stored for 1 month at 4 °C. Furthermore, both TPGS (1.3 mPas) and mixed micelles (33.2 mPas) showed low viscosity, suitable for periocular administration. TPGS micelles resulted the best performing in delivery simvastatin either across conjunctiva or sclera in ex vivo porcine models. The data pave the way for a future viable ocular administration of statins. Full article

(This article belongs to the Special Issue Innovative Technologies to Treat Diseases of the Back of the Eye)

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22 pages, 2605 KiB

Open AccessArticle

Atorvastatin-Eluting Contact Lenses: Effects of Molecular Imprinting and Sterilization on Drug Loading and Release

by Ana F. Pereira-da-Mota, María Vivero-Lopez, Ana Topete, Ana Paula Serro, Angel Concheiro and Carmen Alvarez-Lorenzo

Pharmaceutics 2021, 13(5), 606; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13050606 - 22 Apr 2021

Cited by 20 | Viewed by 4770

Abstract

Statins are receiving increasing attention in the ophthalmic field. Their activity as 3-hydroxy-3-methylglutaryl–CoA (HMG–CoA) reductase inhibitors is clinically used to regulate cholesterol levels and leads to pleiotropic effects, which may help in the management of diabetes-related ocular pathologies. This work aims to design bioinspired contact lenses (CLs) with an affinity for atorvastatin by mimicking the active site of HMG–CoA reductase. Sets of imprinted and nonimprinted 2-hydroxyethyl methacrylate (HEMA) hydrogels were synthesized, varying the contents in functional monomers that bear chemical groups that resemble those present in HMG–CoA reductase, namely, ethylene glycol phenyl ether methacrylate (EGPEM), 2-aminoethyl methacrylate hydrochloride (AEMA), and N-(3-aminopropyl) methacrylamide hydrochloride (APMA). The hydrogels were characterized in terms of suitability as CLs (solvent uptake, light transmission, mechanical properties, and biocompatibility) and capability to load and release atorvastatin. Three sterilization protocols (steam heat, gamma radiation, and high hydrostatic pressure) were implemented and their effects on hydrogel properties were evaluated. Copolymerization of AEMA and, particularly, APMA endowed the hydrogels with a high affinity for atorvastatin (up to 11 mg/g; K_N/W > 200). Only high hydrostatic pressure sterilization preserved atorvastatin stability and hydrogel performance. Permeability studies through the porcine cornea and sclera tissues revealed that the amount of atorvastatin accumulated in the cornea and sclera could be effective to treat ocular surface diseases. Full article

(This article belongs to the Special Issue Innovative Technologies to Treat Diseases of the Back of the Eye)

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20 pages, 7624 KiB

Open AccessArticle

Novel Use of PLGA Microspheres to Create an Animal Model of Glaucoma with Progressive Neuroretinal Degeneration

by David Garcia-Herranz, Maria Jesus Rodrigo, Manuel Subias, Teresa Martinez-Rincon, Silvia Mendez-Martinez, Irene Bravo-Osuna, Aina Bonet, Jesus Ruberte, Julian Garcia-Feijoo, Luis Pablo, Elena Garcia-Martin and Rocío Herrero-Vanrell

Pharmaceutics 2021, 13(2), 237; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13020237 - 08 Feb 2021

Cited by 12 | Viewed by 3094

Abstract

Progressive degeneration of neuroretinal tissue with maintained elevated intraocular pressure (IOP) to simulate chronic glaucoma was produced by intracameral injections of poly (lactic-co-glycolic) acid (PLGA) microspheres (Ms) in rat eyes. The right eye of 39 rats received different sizes of PLGA-Ms (2 µL suspension; 10% w/v): 14 with 38–20 µm Ms (Ms38/20 model) and 25 with 20–10 µm particles (Ms20/10 model). This novel glaucoma animal model was compared to the episcleral vein sclerosis (EPI) model (25 eyes). Injections were performed at baseline, two, four and six weeks. Clinical signs, IOP, retina and optic nerve thicknesses (using in vivo optical coherence tomography; OCT), and histological studies were performed. An IOP increment was observed in all three groups, however, the values obtained from the PLGA-Ms injection resulted lower with a better preservation of the ocular surface. In fact, the injection of Ms20/10 created a gentler, more progressive, and more sustained increase in IOP. This IOP alteration was correlated with a significant decrease in most OCT parameters and in histological ganglion-cell count for the three conditions throughout the eight-week follow-up. In all cases, progressive degeneration of the retina, retinal ganglion cells and optic nerve, simulating chronic glaucoma, was detected by OCT and corroborated by histological study. Results showed an alternative glaucoma model to the well-known episcleral vein model, which was simpler to perform, more reproducible and easier to monitor in vivo. Full article

(This article belongs to the Special Issue Innovative Technologies to Treat Diseases of the Back of the Eye)

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Review

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40 pages, 7759 KiB

Open AccessReview

Hyaluronic Acid: Its Versatile Use in Ocular Drug Delivery with a Specific Focus on Hyaluronic Acid-Based Polyelectrolyte Complexes

by Saoirse Casey-Power, Richie Ryan, Gautam Behl, Peter McLoughlin, Mark E. Byrne and Laurence Fitzhenry

Pharmaceutics 2022, 14(7), 1479; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14071479 - 15 Jul 2022

Cited by 13 | Viewed by 4124

Abstract

Extensive research is currently being conducted into novel ocular drug delivery systems (ODDS) that are capable of surpassing the limitations associated with conventional intraocular anterior and posterior segment treatments. Nanoformulations, including those synthesised from the natural, hydrophilic glycosaminoglycan, hyaluronic acid (HA), have gained significant traction due to their enhanced intraocular permeation, longer retention times, high physiological stability, inherent biocompatibility, and biodegradability. However, conventional nanoformulation preparation methods often require large volumes of organic solvent, chemical cross-linkers, and surfactants, which can pose significant toxicity risks. We present a comprehensive, critical review of the use of HA in the field of ophthalmology and ocular drug delivery, with a discussion of the physicochemical and biological properties of HA that render it a suitable excipient for drug delivery to both the anterior and posterior segments of the eye. The pivotal focus of this review is a discussion of the formation of HA-based nanoparticles via polyelectrolyte complexation, a mild method of preparation driven primarily by electrostatic interaction between opposing polyelectrolytes. To the best of our knowledge, despite the growing number of publications centred around the development of HA-based polyelectrolyte complexes (HA-PECs) for ocular drug delivery, no review articles have been published in this area. This review aims to bridge the identified gap in the literature by (1) reviewing recent advances in the area of HA-PECs for anterior and posterior ODD, (2) describing the mechanism and thermodynamics of polyelectrolyte complexation, and (3) critically evaluating the intrinsic and extrinsic formulation parameters that must be considered when designing HA-PECs for ocular application. Full article

(This article belongs to the Special Issue Innovative Technologies to Treat Diseases of the Back of the Eye)

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43 pages, 5083 KiB

Open AccessReview

Posterior Segment Ophthalmic Drug Delivery: Role of Muco-Adhesion with a Special Focus on Chitosan

by Ayah Mohammad Burhan, Butsabarat Klahan, Wayne Cummins, Vanessa Andrés-Guerrero, Mark E. Byrne, Niall J. O’Reilly, Anuj Chauhan, Laurence Fitzhenry and Helen Hughes

Pharmaceutics 2021, 13(10), 1685; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13101685 - 14 Oct 2021

Cited by 26 | Viewed by 3897

Abstract

Posterior segment eye diseases (PSEDs) including age macular degeneration (AMD) and diabetic retinopathy (DR) are amongst the major causes of irreversible blindness worldwide. Due to the numerous barriers encountered, highly invasive intravitreal (IVT) injections represent the primary route to deliver drugs to the posterior eye tissues. Thus, the potential of a more patient friendly topical route has been widely investigated. Mucoadhesive formulations can decrease precorneal clearance while prolonging precorneal residence. Thus, they are expected to enhance the chances of adherence to corneal and conjunctival surfaces and as such, enable increased delivery to the posterior eye segment. Among the mucoadhesive polymers available, chitosan is the most widely explored due to its outstanding mucoadhesive characteristics. In this review, the major PSEDs, their treatments, barriers to topical delivery, and routes of topical drug absorption to the posterior eye are presented. To enable the successful design of mucoadhesive ophthalmic drug delivery systems (DDSs), an overview of mucoadhesion, its theory, characterization, and considerations for ocular mucoadhesion is given. Furthermore, chitosan-based DDs that have been explored to promote topical drug delivery to the posterior eye segment are reviewed. Finally, challenges of successful preclinical to clinical translation of these DDSs for posterior eye drug delivery are discussed. Full article

(This article belongs to the Special Issue Innovative Technologies to Treat Diseases of the Back of the Eye)

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29 pages, 998 KiB

Open AccessReview

From Oxidative Stress to Inflammation in the Posterior Ocular Diseases: Diagnosis and Treatment

by Azza Dammak, Fernando Huete-Toral, Carlos Carpena-Torres, Alba Martin-Gil, Cristina Pastrana and Gonzalo Carracedo

Pharmaceutics 2021, 13(9), 1376; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13091376 - 31 Aug 2021

Cited by 35 | Viewed by 4816

Abstract

Most irreversible blindness observed with glaucoma and retina-related ocular diseases, including age-related macular degeneration and diabetic retinopathy, have their origin in the posterior segment of the eye, making their physiopathology both complex and interconnected. In addition to the age factor, these diseases share the same mechanism disorder based essentially on oxidative stress. In this context, the imbalance between the production of reactive oxygen species (ROS) mainly by mitochondria and their elimination by protective mechanisms leads to chronic inflammation. Oxidative stress and inflammation share a close pathophysiological process, appearing simultaneously and suggesting a relationship between both mechanisms. The biochemical end point of these two biological alarming systems is the release of different biomarkers that can be used in the diagnosis. Furthermore, oxidative stress, initiating in the vulnerable tissue of the posterior segment, is closely related to mitochondrial dysfunction, apoptosis, autophagy dysfunction, and inflammation, which are involved in each disease progression. In this review, we have analyzed (1) the oxidative stress and inflammatory processes in the back of the eye, (2) the importance of biomarkers, detected in systemic or ocular fluids, for the diagnosis of eye diseases based on recent studies, and (3) the treatment of posterior ocular diseases, based on long-term clinical studies. Full article

(This article belongs to the Special Issue Innovative Technologies to Treat Diseases of the Back of the Eye)

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18 pages, 1778 KiB

Open AccessReview

Penetration Enhancers for Topical Drug Delivery to the Ocular Posterior Segment—A Systematic Review

by Abhinav Thareja, Helen Hughes, Carmen Alvarez-Lorenzo, Jenni J. Hakkarainen and Zubair Ahmed

Pharmaceutics 2021, 13(2), 276; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13020276 - 18 Feb 2021

Cited by 22 | Viewed by 4448

Abstract

There is an unmet clinical need for eye drop formulations to efficiently treat the diseases of the posterior ocular segment by non-invasive topical administration. Here, we systematically reviewed the literature on ocular penetration enhancers and their ability to transfer drugs to the posterior segment of the eye in experimental studies. Our aim was to assess which penetration enhancer is the most efficient at delivering drugs to the posterior segment of the eye, when topically applied. We conducted a comprehensive search in three electronic databases (Ovid Embase, Ovid MEDLINE, and PubMed) to identify all the relevant manuscripts reported on ocular penetration enhancers based on the PRISMA guidelines. We identified 6540 records from our primary database search and filtered them per our inclusion/exclusion criteria to select a final list of 14 articles for qualitative synthesis. Of these, 11 studies used cell penetrating peptides (CPPs), 2 used chitosan, and 1 used benzalkonium chloride (BAC) as the penetration enhancer. Cationic and amphipathic CPPs, transactivator of transcription (TAT), and penetratin can be inferred to be the best among all the identified penetration enhancers for drug delivery to the fundus oculi via topical eye drop instillation. Further high-quality experimental studies are required to ascertain their quantitative efficacy. Full article

(This article belongs to the Special Issue Innovative Technologies to Treat Diseases of the Back of the Eye)

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