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

Deadline for manuscript submissions: closed (31 October 2025) | Viewed by 23176

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Prof. Dr. Francisco Javier Otero-Espinar

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Guest Editor

Department of Pharmaceutical Technology, Faculty of Pharmacy, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Interests: ocular drug delivery
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Dr. Anxo Fernández Ferreiro

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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
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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 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 the knowledge of ocular pharmacokinetics that allow 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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Related Special Issues

Ophthalmic Drug Delivery in Pharmaceutics (16 articles)
Ophthalmic Drug Delivery, 2nd Edition in Pharmaceutics (18 articles)

Published Papers (9 papers)

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Research

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20 pages, 1978 KB

Open AccessArticle

Antibiofilm and Immunomodulatory Effects of Cinnamaldehyde in Corneal Epithelial Infection Models: Ocular Treatments Approach

by Ashraf Khalifa, Muthukumar Thangavelu, Krishnaraj Thirugnanasambantham and Hairul-Islam M. Ibrahim

Pharmaceutics 2026, 18(1), 5; https://doi.org/10.3390/pharmaceutics18010005 - 19 Dec 2025

Viewed by 201

Abstract

Background: Bacterial keratitis, a major cause of corneal blindness, is frequently associated with biofilm-forming pathogens such as Klebsiella pneumoniae. Cyclic-di-GMP (c-di-GMP) controls biofilm development, which increases antibiotic resistance and makes treatment more difficult, highlighting the need for innovative therapeutic approaches. Methods: This study investigated cinnamaldehyde as a potential ocular therapeutic using combined computational and experimental approaches. Molecular docking and in vitro assays (XTT, resazurin reduction, crystal violet staining, qRT-PCR, and fluorescence microscopy) were used to evaluate the anti-biofilm and immunomodulatory activities of cinnamaldehyde (CA) against Klebsiella pneumoniae. Results: CA inhibited biofilm formation in a dose-dependent manner (≈89% at 1000 µM; >50% at 250 µM), reduced bacterial attachment to contact lenses, and downregulated key biofilm genes (mrkA, mrkC, ybtS, bolA). Docking analysis revealed strong binding affinity to the mrkH regulator (−5.46 kcal/mol. CA maintained more than 80% corneal cell viability by increasing IL-10, suppressing inflammatory mediators (IL-1β, IL-6, and TNF-α), and improving bacterial clearance. Conclusions: This study combines computational docking, biofilm quantification, immune cell assays, and functional gene expression analyses to reveal the ability of cinnamaldehyde not only to suppress biofilm formation but also to enhance macrophage-mediated clearance and modulate corneal immune responses, a multi-target approach not previously described in the context of bacterial keratitis. Such effects highlight its potential as a novel ocular drug candidate for protecting corneal integrity in infectious keratitis. Full article

(This article belongs to the Special Issue Ophthalmic Drug Delivery, 3rd Edition)

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20 pages, 2563 KB

Open AccessArticle

Enhanced Ocular Delivery of Epalrestat Using Nanostructured Lipid Carrier Laden Soft Contact Lens

by Ketan Ranch, Yashkumar Patel, Esha Acharya, Paras Gupta, Anil Kumar Singh and Sudarshan Singh

Pharmaceutics 2025, 17(12), 1515; https://doi.org/10.3390/pharmaceutics17121515 - 24 Nov 2025

Viewed by 461

Abstract

Background/Objectives: Epalrestat (EPL), an aldose reductase inhibitor, exhibits poor aqueous solubility and limited ocular bioavailability, which significantly restricts its therapeutic efficacy in the treatment of diabetic retinopathy. To overcome these limitations, a novel nanostructured lipid carrier (NLCs)-laden contact lens system was developed to achieve sustained and enhanced ocular delivery of EPL. Methods: In this study EPL-loaded NLCs were prepared using Compritol^® 888 ATO (solid lipid), Labrafac™ WL 1349 (liquid lipid), and Solutol^® HS 15 (surfactant) using high-speed homogenization method. The formulations were statistically optimized using a D-optimal mixture design, considering globule size (Y₁), swelling index (Y₂), and drug release at 6 h (Y₃) as key responses. The optimized NLCs were incorporated into contact lenses via the soaking technique and evaluated for physicochemical properties, drug content, in vitro release, ex vivo corneal permeability, and in vivo ocular tolerance. Results: The optimized NLCs formulation showed a globule size of 41.85 ± 2.14 nm, zeta potential of −20.3 ± 1.8 mV, and entrapment efficiency of 93.32 ± 1.27%, indicating excellent physical stability with high drug encapsulation. The swelling index of the optimized NLCs-laden contact lens was 140.69 ± 4.32%, and the optical transmittance was 80.54 ± 1.12%, confirming adequate hydration and transparency for ocular use. The drug content was 96.32 ± 0.84%, ensuring uniform distribution throughout the hydrogel matrix. In vitro release studies demonstrated a sustained drug release of 98.12 ± 2.08% over 24 h, whereas ex vivo corneal permeation indicated significantly higher permeation (97.26 ± 1.95% at 6 h) compared with the control contact lens (38.14 ± 2.41% at 5 h). The in vivo Draize test confirmed that both blank and drug-loaded contact lenses were non-irritating and biocompatible. Conclusions: Thus, the optimized EPL NLCs-laden contact lens demonstrated enhanced corneal permeation, prolonged drug retention, and excellent ocular safety, offering a promising advancement in the management of diabetic retinopathy by improving bioavailability, reducing dosing frequency, and enhancing therapeutic efficacy. Full article

(This article belongs to the Special Issue Ophthalmic Drug Delivery, 3rd Edition)

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14 pages, 982 KB

Open AccessArticle

Development of Practical Low-Volume Screening Method and Pharmacokinetic Simulation of Levofloxacin-Loaded Nanofiber Inserts for Sustained Ocular Therapy

by Houssam Aaref Abboud, Romána Zelkó and Adrienn Kazsoki

Pharmaceutics 2025, 17(10), 1343; https://doi.org/10.3390/pharmaceutics17101343 - 17 Oct 2025

Viewed by 916

Abstract

Background/Objectives: Ocular drug delivery faces significant challenges due to anatomical and physiological barriers that limit drug bioavailability, particularly with conventional eye drops. Levofloxacin (LEVO), a broad-spectrum antibiotic, is widely used in the treatment of bacterial conjunctivitis, but its therapeutic efficacy is hindered by rapid precorneal clearance and short residence time. Methods: This study introduces a biorelevant 2 mL dissolution model to simulate ocular conditions better and evaluate the release kinetics of LEVO-loaded nanofibrous ophthalmic inserts. Compared to the conventional 40 mL setup, the 2 mL system demonstrated a slower and more sustained drug release profile, with kinetic modeling confirming a more controlled release behavior. Difference and similarity factor analysis further validated the distinct release profiles, highlighting the impact of dissolution volume on release dynamics. Results: Preliminary pharmacokinetic modeling suggested that the nanofiber inserts, particularly when applied twice daily, maintained levofloxacin concentrations above minimum inhibitory and bactericidal levels for extended durations across three bacterial strains (Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus), potentially outperforming traditional eye drops. Conclusions: These findings suggest that small-volume dissolution testing may provide a more realistic method for evaluating ophthalmic insert formulations, though in vivo validation is needed. Moreover, the nanofibrous inserts show potential as a sustained-release alternative that warrants further investigation to improve patient compliance and therapeutic outcomes in ocular disease management. Full article

(This article belongs to the Special Issue Ophthalmic Drug Delivery, 3rd Edition)

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16 pages, 3822 KB

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Enhanced Ocular Drug Delivery of Dexamethasone Using a Chitosan-Coated Soluplus^®-Based Mixed Micellar System

by Samer Adwan, Faisal Al-Akayleh, Madeiha Qasmieh and Teiba Obeidi

Pharmaceutics 2024, 16(11), 1390; https://doi.org/10.3390/pharmaceutics16111390 - 29 Oct 2024

Cited by 6 | Viewed by 2437

Abstract

Background: This study introduces a novel dexamethasone (DEX) mixed micellar system (DEX-MM) using Soluplus^® and Pluronic F-127 (PF127) to enhance ocular drug delivery. The enhancement of ocular application properties was achieved by creating a chitosan-coated DEX-MM (DEX-CMM), which promotes better adherence to the ocular surface, thereby improving drug absorption. Methods: Using the solvent evaporation method, a formulation was developed with a Soluplus^®-to-drug ratio of 1:10, enhanced with 0.25% PF127. After dispersing in water, 1% chitosan (CS) was added. The stability and integrity of DEX within the micelles were verified using attenuated total reflection–Fourier transform infrared spectroscopy (ATR-FTIR) and differential scanning calorimetry (DSC). Additionally, in vitro and ex vivo drug release studies were conducted. Results: DEX-CMM (F6) demonstrated a particle size of 151.9 ± 1 nm and a polydispersity index (PDI) of 0.168 ± 0.003, suggesting uniformity and high electrostatic stability with a zeta potential of +35.96 ± 2.13 mV. The non-Fickian drug release mechanism indicated prolonged drug retention. Comparative analyses showed DEX-CMM outperforming a standard DEX suspension in drug release and ocular tissue permeation, with flux measurements significantly higher than the DEX suspension. Conclusion: The study confirmed the efficacy of DEX-CMM in enhancing drug delivery to ocular tissues, evidenced by improved permeability. Safety evaluations using the HET-CAM test demonstrated that DEX-CMM was non-irritant, supporting its potential for effective ocular drug delivery. Full article

(This article belongs to the Special Issue Ophthalmic Drug Delivery, 3rd Edition)

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15 pages, 6029 KB

Open AccessArticle

Cysteamine Eye Drops in Hyaluronic Acid Packaged in Innovative Single-Dose Systems, Part II: Long-Term Stability and Clinical Ocular Biopermanence

by Ana Castro-Balado, Andrea Cuartero-Martínez, Hugo Pena-Verdeal, Gonzalo Hermelo-Vidal, Anja Schmidt, Belén Montero, Manuela Hernández-Blanco, Irene Zarra-Ferro, Miguel González-Barcia, Cristina Mondelo-García, María Jesús Giráldez, Eva Yebra-Pimentel, Francisco J. Otero-Espinar and Anxo Fernández-Ferreiro

Pharmaceutics 2023, 15(11), 2589; https://doi.org/10.3390/pharmaceutics15112589 - 5 Nov 2023

Cited by 3 | Viewed by 2845

Abstract

Background: Cystinosis is a rare genetic disorder characterized by the accumulation of cystine crystals in several tissues and organs causing, among others, severe eye symptoms. The high instability of cysteamine eye drops makes it difficult to develop formulations with an acceptable shelf life to be prepared in hospital pharmacy departments. Previously, a new compounded formulation of cysteamine eye drops in hyaluronic acid (HA) packaged in innovative single-dose systems was developed. Methods: Long-term stability at −20 °C of this formulation was studied considering the content of cysteamine, pH, osmolality, viscosity, and microbiological analysis. The oxygen permeability of single-dose containers was also studied and an ocular biopermanence study was conducted in healthy volunteers measuring lacrimal stability and volume parameters. Results: Data confirm that cysteamine concentration remained above 90% for 120 days, all parameters remaining within the accepted range for ophthalmic formulations. The permeability of the containers was reduced over time, while ocular biopermanence was maintained despite the freezing process and storage time. Conclusions: 0.55% cysteamine hydrochloride formulation in HA and packaged in single-dose containers preserved at −20 °C is stable for 120 days protected from light, presenting high potential for its translation into clinical practice when commercial presentations are not available. Full article

(This article belongs to the Special Issue Ophthalmic Drug Delivery, 3rd Edition)

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13 pages, 10673 KB

Open AccessArticle

Ex Vivo Visualization of Distribution of Intravitreal Injections in the Porcine Vitreous and Hydrogels Simulating the Vitreous

by Tobias Auel, Lara Paula Scherke, Stefan Hadlich, Susan Mouchantat, Michael Grimm, Werner Weitschies and Anne Seidlitz

Pharmaceutics 2023, 15(3), 786; https://doi.org/10.3390/pharmaceutics15030786 - 27 Feb 2023

Cited by 7 | Viewed by 2615

Abstract

The characterization of intravitreal dosage forms with regard to their behavior in vivo is usually explored in preclinical development through animal studies. In vitro vitreous substitutes (VS) to simulate the vitreous body for preclinical investigations have so far been insufficiently studied. To determine a distribution or concentration in the mostly gel-like VS, extraction of the gels is required in many cases. This destroys the gels, which makes a continuous investigation of the distribution impossible. In this work, the distribution of a contrast agent in hyaluronic acid agar gels and polyacrylamide gels was studied by magnetic resonance imaging and compared with the distribution in ex vivo porcine vitreous. The porcine vitreous served as a surrogate for human vitreous since both are similar in their physicochemical properties. It was shown that both gels do not completely represent the porcine vitreous body, but the distribution in the polyacrylamide gel is similar to that in the porcine vitreous body. In contrast, the distribution throughout the hyaluronic acid agar gel is much faster. It was also shown that anatomical features such as the lens and the interfacial tension to the anterior eye chamber could have an influence on the distribution that is difficult to reproduce using in vitro VS. However, with the presented method, new in vitro VS can be investigated continuously without destruction in the future, and thus their suitability as a substitute for the human vitreous can be verified. Full article

(This article belongs to the Special Issue Ophthalmic Drug Delivery, 3rd Edition)

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26 pages, 5357 KB

Open AccessArticle

Antifungal Combination Eye Drops for Fungal Keratitis Treatment

by Victoria Díaz-Tomé, Carlos Bendicho-Lavilla, Xurxo García-Otero, Rubén Varela-Fernández, Manuel Martín-Pastor, José Llovo-Taboada, Pilar Alonso-Alonso, Pablo Aguiar, Miguel González-Barcia, Anxo Fernández-Ferreiro and Francisco J. Otero-Espinar

Pharmaceutics 2023, 15(1), 35; https://doi.org/10.3390/pharmaceutics15010035 - 22 Dec 2022

Cited by 11 | Viewed by 3949

Abstract

Fungal keratitis (FK) is a corneal mycotic infection that can lead to vision loss. Furthermore, the severity of FK is aggravated by the emergence of resistant fungal species. There is currently only one FDA-approved formulation for FK treatment forcing hospital pharmacy departments to reformulate intravenous drug preparations with unknown ocular bioavailability and toxicity. In the present study, natamycin/voriconazole formulations were developed and characterized to improve natamycin solubility, permanence, and safety. The solubility of natamycin was studied in the presence of two cyclodextrins: HPβCD and HPγCD. The HPβCD was chosen based on the solubility results. Natamycin/cyclodextrin (HPβCD) inclusion complexes characterization and a competition study between natamycin and voriconazole were conducted by NMR (Nuclear Magnetic Resonance). Based on these results, several eye drops with different polymer compositions were developed and subsequently characterized. Permeability studies suggested that the formulations improved the passage of natamycin through the cornea compared to the commercial formulation Natacyn^®. The ocular safety of the formulations was determined by BCOP and HET-CAM. The antifungal activity assay demonstrated the ability of our formulations to inhibit the in vitro growth of different fungal species. All these results concluded that the formulations developed in the present study could significantly improve the treatment of FK. Full article

(This article belongs to the Special Issue Ophthalmic Drug Delivery, 3rd Edition)

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Review

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47 pages, 1332 KB

Open AccessReview

Base and Prime Editing for Inherited Retinal Diseases: Delivery Platforms, Safety, Efficacy, and Translational Perspectives

by Haoliang Zhang, Yuxuan Li, Jiajie Li, Xiaosa Li and Tong Li

Pharmaceutics 2025, 17(11), 1405; https://doi.org/10.3390/pharmaceutics17111405 - 30 Oct 2025

Viewed by 2601

Abstract

Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous spectrum of disorders that lead to progressive and irreversible vision loss. Gene therapy is the most promising emerging treatment for IRDs. While gene augmentation strategies have demonstrated clinical benefit and results within the first approved ocular gene therapy, their application is restricted by adeno-associated virus (AAV) packaging capacity and limited efficacy for dominant mutations. Recent breakthroughs in precision genome editing, particularly base editing (BE) and prime editing (PE), have provided alternatives capable of directly correcting pathogenic variants. BE enables targeted single-nucleotide conversions, whereas PE further allows for precise insertions and deletions, both circumventing the double-strand DNA cleavage or repair processes typically induced by conventional CRISPR–Cas editing systems, thereby offering advantages in post-mitotic retinal cells. Preclinical investigations across murine and non-human primate models have demonstrated the feasibility, molecular accuracy, and preliminary safety profiles of these platforms in targeting IRD-associated mutations. However, critical challenges remain before clinical application can be realized, including limited editing efficiency in photoreceptors, interspecies variability in therapeutic response, potential risks of off-target effects, and barriers in large-scale vector manufacturing. Moreover, the delivery of genome editors to the outer retina remains suboptimal, prompting intensive efforts in capsid engineering and the development of non-viral delivery systems. This review synthesizes the current progress in BE and PE optimization, highlights innovations in delivery platforms that encompass viral and emerging non-viral systems and summarizes the major barriers to clinical translation. We further discuss AI-driven strategies for the rational design of BE/PE systems, thereby outlining their future potential and perspectives in the treatment of IRDs. Full article

(This article belongs to the Special Issue Ophthalmic Drug Delivery, 3rd Edition)

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28 pages, 3876 KB

Open AccessReview

Ocular Drug Delivery: Emerging Approaches and Advances

by Shilpkala Gade, Yin So, Deepakkumar Mishra, Shubhamkumar M. Baviskar, Ahmad A. Assiri, Katie Glover, Ravi Sheshala, Lalitkumar K. Vora and Raghu Raj Singh Thakur

Pharmaceutics 2025, 17(5), 599; https://doi.org/10.3390/pharmaceutics17050599 - 1 May 2025

Cited by 4 | Viewed by 5969

Abstract

Complex anatomical and physiological barriers make the eye a challenging organ to treat from a drug delivery perspective. Currently available treatment methods (topical eyedrops) for anterior segment diseases pose several limitations in terms of bioavailability and patient compliance. Conventional drug delivery methods to treat posterior segment ocular diseases are primarily intravitreal injection (IVT) of solutions. IVT is highly invasive and leads to retinal toxicity, endophthalmitis, and intraocular inflammation, frequently requiring professional administration and frequent clinical visits. Advanced drug delivery treatment strategies could improve patient compliance and convenience. Long-acting drug delivery platforms (biodegradable or nonbiodegradable) provide sustained/controlled release of drugs for at least four to six months. Smart drug delivery alternatives, for instance, in situ forming implants, are injectable formulations that form semisolid-to-solid implants in response to the various stimuli of pH, light, osmolarity, and temperature. Additionally, nanoparticulate drug delivery systems, contact lenses, electrospun patches, and microneedle-based drug delivery systems provide minimally invasive treatment options for ocular disorders. This comprehensive review focuses on advanced drug delivery options for the management of ocular disorders. Full article

(This article belongs to the Special Issue Ophthalmic Drug Delivery, 3rd Edition)

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