Ophthalmic Drug Research Articles

The Evolution of Triamcinolone Acetonide Therapeutic Use in Retinal Diseases: From Off-Label Intravitreal Injection to Advanced Nano-Drug Delivery Systems.

Ophthalmic drug delivery to the posterior segment of the eye has been challenging due to the complex ocular anatomy. Intravitreal injection of drugs was introduced to deliver therapeutic doses in the posterior segment. Different posterior segment diseases including age-related macular degeneration, diabetic macular edema, retinal vein occlusions, uveitis, and cystoid macular edema, among others, have been historically treated with intravitreal corticosteroids injections, and more recently with intravitreal corticosteroids drug implants. Triamcinolone acetonide (TA) is the most frequently used intraocular synthetic corticosteroid. Using nanoparticle-based TA delivery systems has been proposed as an alternative to intravitreal injections in the treatment of posterior segment diseases. From these novel delivery systems, topical liposomes have been the most promising strategy. This review is oriented to exhibit triamcinolone acetonide drug evolution and its results in treating posterior segment diseases using diverse delivery platforms.

Fill levels, cost comparisons, and expulsion force requirements of commonly used topical ophthalmic nonsteroidal anti-inflammatory drugs.

To determine volume fill levels, estimated costs, and force expulsion requirements per bottle of topical ophthalmic nonsteroidal anti-inflammatory drugs (NSAIDs) commonly perioperatively in the United States. Tertiary care academic medical center. Prospective laboratory investigation. 8 commercially available NSAIDs (3 branded, 5 generic) were tested: branded bromfenac 0.07%, generic bromfenac 0.09%, diclofenac 0.1%, flurbiprofen 0.03%, generic ketorolac 0.5%, branded ketorolac 0.5%, ketorolac 0.47%, and branded nepafenac 0.3%. 10 bottles of each medication were tested, with an additional bottle tested for expulsion force requirements. A double-blinded method was used to measure the actual bottle fill volume and number of drops per bottle. The total cost per drop was calculated using published cash prices. Force requirements were measured using a customized force gauge apparatus. Formulations were compared using the Kruskal-Wallis test, followed by pairwise comparisons with the Dwass, Steel, Critchlow-Fligner Method. 2 branded NSAIDs (bromfenac and nepafenac) had slightly lower-than-sticker volumes while generics other than ketorolac had higher-than-sticker volumes. Diclofenac and branded bromfenac had the highest and lowest adjusted number of drops respectively. Generic bromfenac and generic ketorolac had the highest and lowest adjusted volume compared with sticker volume respectively. Branded bromfenac was the most expensive medication, while generic diclofenac was the least expensive. Force expulsion requirements varied significantly among generic and branded NSAIDs. Volume fill levels, patient-incurred costs, and expulsion force requirements per bottle of topical NSAID medications vary significantly. Surgeons may wish to consider these factors when deciding how best to use these medications perioperatively.

Ophthalmic nano-bioconjugates: critical challenges and technological advances.

Ophthalmic disease can cause permanent loss of vision and blindness. Easy-to-administer topical and systemic treatments are preferred for treating sight-threatening disorders. Typical ocular anatomy makes topical and systemic ophthalmic drug delivery challenging. Various novel nano-drug delivery approaches are developed to attain the desired bioavailability in the eye by increasing residence time and improved permeability across the cornea. The review focuses on novel methods that are biocompatible, safeand highly therapeutic. Novelty in nanocarrier design and modification can overcome their drawbacks and make them potential drug carriers for eye disorders in both the anterior and posterior eye segments. This review briefly discussed technologies, patented developments, and clinical trial data to support nanocarriers' use in ocular drug delivery.

A biomimetic peptide–drug supramolecular hydrogel as eyedrops enables controlled release of ophthalmic drugs

The rapid clearance of instilled drugs from the ocular surface due to tear flushing and excretion results in low drug bioavailability, necessitating the development of new drug delivery routes. Here, we generated an antibiotic hydrogel eye drop that can extend the pre-corneal retention of a drug after topical instillation to address the risk of side effects (e.g., irritation and inhibition of enzymes), resulting from frequent and high-dosage administrations of antibiotics used to obtain the desired therapeutic drug concentration. The covalent conjugation of small peptides to antibiotics (e.g., chloramphenicol) first endows the self-assembly ability of peptide-drug conjugate to generate supramolecular hydrogels. Moreover, the further addition of calcium ions, which are also widely present in endogenous tears, tunes the elasticity of supramolecular hydrogels, making them ideal for ocular drug delivery. The in vitro assay revealed that the supramolecular hydrogels exhibited potent inhibitory activities against both gram-negative (e.g., Escherichia coli) and gram-positive (e.g., Staphylococcus aureus) bacteria, whereas they were innocuous toward human corneal epithelial cells. Moreover, the in vivo experiment showed that the supramolecular hydrogels remarkably increased pre-corneal retention without ocular irritation, thereby showing appreciable therapeutic efficacy for treating bacterial keratitis. This work, as a biomimetic design of antibiotic eye drops in the ocular microenvironment, addresses the current issues of ocular drug delivery in the clinic and further provides approaches to improve the bioavailability of drugs, which may eventually open new directions to resolve the difficulty of ocular drug delivery. Statement of SignificanceHerein, we present a biomimetic design for antibiotic hydrogel eye drops mediated by calcium ions (Ca2+) in the ocular microenvironment, which can extend the pre-corneal retention of antibiotics after topical instillation. The mediation of Ca2+ which is widely present in endogenous tears, tunes the elasticity of hydrogels, making them ideal for ocular drug delivery. Since increasing the ocular retention of antibiotic eye drops enhances its action and reduces its adverse effects, this work may lead to an approach of peptide–drug-based supramolecular hydrogel for ocular drug delivery in clinics to combat ocular bacterial infections.

Ophthalmic Drug Delivery System Using Contact Lens

Most of the ophthalmic drug delivery methods for treating ocular diseases are eye drops. However, topical eye drop instillation has limitations in that the bioavailability is low, side effects may occur due to systemic absorption, and patient compliance is low. Various delivery methods have been attempted to effectively deliver ophthalmic drugs, and among them, a drug delivery system using a contact lens will be reviewed.

In Vitro and Ex Vivo Models for Assessing Drug Permeation across the Cornea.

Drug permeation across the cornea remains a major challenge due to its unique and complex anatomy and physiology. Static barriers such as the different layers of the cornea, as well as dynamic aspects such as the constant renewal of the tear film and the presence of the mucin layer together with efflux pumps, all present unique challenges for effective ophthalmic drug delivery. To overcome some of the current ophthalmic drug limitations, the identification and testing of novel drug formulations such as liposomes, nanoemulsions, and nanoparticles began to be considered and widely explored. In the early stages of corneal drug development reliable in vitro and ex vivo alternatives, are required, to be in line with the principles of the 3Rs (Replacement, Reduction, and Refinement), with such methods being in addition faster and more ethical alternatives to in vivo studies. The ocular field remains limited to a handful of predictive models for ophthalmic drug permeation. In vitro cell culture models are increasingly used when it comes to transcorneal permeation studies. Ex vivo models using excised animal tissue such as porcine eyes are the model of choice to study corneal permeation and promising advancements have been reported over the years. Interspecies characteristics must be considered in detail when using such models. This review updates the current knowledge about in vitro and ex vivo corneal permeability models and evaluates their advantages and limitations.

A rapid solid form risk assessment workflow for ophthalmic drug candidates

Objective This work introduces a material-sparing process that rapidly screens the solid form landscape for ophthalmic compound candidates. Significance Crystalline form of compound candidates generated by a Form Risk Assessment (FRA) can be used to reduce their downstream development risk. Methods This workflow evaluated nine model compounds with various molecular and polymorphic profiles by using less than 350 mg of drug substances. Kinetic solubility of the model compounds in a variety of solvents was screened to support the experimental design. The FRA workflow integrated several crystallization methods such as temperature-cycled slurrying (thermocycling), cooling, and evaporation. The FRA was also applied on ten ophthalmic compound candidates for verification. X-ray powder diffractometry (XRPD) was used for form identification. Results For the nine model compounds studied, multiple crystalline forms were generated. This demonstrates the potential of the FRA workflow to reveal polymorphic tendency. In addition, thermocycling process was found to be the most effective technique to capture the thermodynamically most stable form. Satisfactory results were observed with the discovery compounds intended for ophthalmic formulations. Conclusions This work introduces a form risk assessment workflow by using sub-gram level of drug substances. The capability of this material-sparing workflow to discover polymorphs and capture the thermodynamically most stable forms within 2–3 weeks makes it suitable for discovery stage compounds, especially for ophthalmic candidates.

Therapeutic applications of contact lens-based drug delivery systems in ophthalmic diseases

Traditional ophthalmic drugs, such as eye drops, gels and ointments, are accompanied by many problems, including low bioavailability and potential drug side effects. Innovative ophthalmic drug delivery systems have been proposed to overcome the limitations associated with traditional formulations. Recently, contact lens-based drug delivery systems have gained popularity owing to their advantages of sustained drug delivery, prolonged drug retention, improved bioavailability, and few drug side effects. Various methods have been successfully applied to drug-loaded contact lenses and prolonged the drug release time, such as chemical crosslinking, material embedding, molecular imprinting, colloidal nanoparticles, vitamin E modification, drug polymer film/coating, ion ligand polymerization systems, and supercritical fluid technology. Contact lens-based drug delivery systems play an important role in the treatment of multifarious ophthalmic diseases. This review discusses the latest developments in drug-loaded contact lenses for the treatment of ophthalmic diseases, including preparation methods, application in ophthalmic diseases and future prospects.

A novel approach to achieve semi-sustained drug delivery to the eye through asymmetric loading of soft contact lenses

Soft contact lenses are increasingly being explored as a vehicle for controlled delivery of ophthalmic drugs. However, traditional methods of drug-loading by soaking have limitations such as burst delivery and the release of drugs at the front side of the lens, leading to poor drug efficacy and systemic side effects. This study introduces a new methodology, termed asymmetric drug loading, whereby the ophthalmic drug ‘Rebamipide’ is attached to and released from the post-lens (=cornea-contacting) surface exclusively. The methodology involves using polymeric microparticles that carry a lipophilic crystalline ophthalmic drug at their surface. These drug-loaded microparticles first transfer the drug to the concave surface of the contact lens, and when worn, the drug is transferred again, now from the lens to the cornea. This is achieved through the diffusion of the drug from one hydrophobic microenvironment (the silicone moieties of the contact lens polymer network) to another hydrophobic microenvironment (the corneal epithelium) over a short pathway. The second drug transfer was observed and studied in experiments using an ex vivo porcine eye model. The results show that the drug amount that was absorbed by the cornea after applying the rebamipide-loaded contact lenses is approximately 3× (10.7 ± 3.1 μg) as much as the amount of rebamipide that gets transferred after the instillation of one eye drop (1% solution (p < 0.001). The new drug-loading method offers a practical and reproducible means of delivering ophthalmic drugs to the cornea through soft contact lenses. The drug payloads achieved are comparable to dosages used during eye drop therapy.

In situ gels: The next new frontier in ophthalmic drug delivery system

AbstractRecently, the eye drug delivery system has received increasing attention. The in situ ophthalmic gel is a semisolid ophthalmic preparation that can be changed in the eyes immediately after the solution is administered, showing unique advantages as a new drug delivery system. Although there are still some problems to be solved, the in situ ophthalmic gel is a promising drug delivery system to treat ocular diseases, due to its properties in improving the bioavailability, prolonging the retention time of the drug, producing a sustained‐release effect, and possessing little toxicity and irritation. In this review, the characteristics, classification, ocular barrier, and route of administration of in situ ophthalmic gel have been introduced in detail for expanding the horizon of nanoscale technologies in the treatment of ocular diseases in the foreseeable future.

Dexamethasone-Loaded Pseudo-Protein Nanoparticles for Ocular Drug Delivery: Evaluation of Drug Encapsulation Efficiency and Drug Release

Ophthalmic drug delivery for treating various eye diseases still remains a challenge in ophthalmology. One perspective way of overcoming this problem is to use nanoscale biodegradable drug carriers that are able to safely deliver pharmaceuticals directly to the locus of disease and maintain a therapeutic concentration of drug for a long time. The goal of the present study was the preparation of drug- (dexamethasone-, DEX-) loaded pseudo-protein nanoparticles (NPs) and investigation of drug encapsulation efficiency and drug release kinetics. DEX-loaded pseudo-protein NPs (DEX-NPs) were successfully prepared by the nanoprecipitation method. DEX-NPs were characterized by size (average diameter, AD), size distribution (polydispersity index, PDI), and surface charge (zeta-potential, ZP) using the dynamic light scattering technique. DEX encapsulation characteristics were determined using the UV-spectrophotometric method, and kinetics of DEX release from DEX-NPs was studied according to the dialysis method in PBS at 37°C. The obtained results showed that size of DEX-NPs varies within 143.6–164.1 nm depending on DEX content during the preparation. DEX incorporation characteristics were determined—encapsulation efficiency (EE) and actual drug loading (DL) were high enough and reached 55.1 and 10.2%, respectively. The kinetics of DEX release from DEX-NPs showed a typical biphasic release pattern—an initial rapid (burst) release and further much more continuous slow release. Based on the obtained data, we can conclude that the elaborated DEX-NPs have potential for the application in ophthalmology as ocular drug delivery nanocarriers.

Safety of recent ophthalmic drugs and devices for wet macular degeneration.

With frequent antivascular endothelial growth factors (VEGF) injections well established as the standard of care in neovascular age-related macular degeneration (nAMD), focus has now shifted towards decreasing treatment burden without compromising safety and efficacy. This review summarizes clinical stage and recently approved drugs and devices for nAMD, with an emphasis paid to safety concerns and their implications for product adoption. Three strategies have emerged to decrease the treatment burden associated with the current standard of care: more durable intravitreal agents, sustained-release modalities and gene therapy. The appearance of biosimilars will further impact drug availability and cost. As patterns of adverse events emerge from clinical trial or postmarketing surveillance data, manufacturers have proactively responded by appointing independent review committees or issuing voluntary recalls. However, the example of one biosimilar approved outside of the USA and European Union demonstrates how early safety concerns, even when addressed by substantive data, can generate lingering uncertainty. As the number of promising new treatments in nAMD continues to grow, so too does the amount of data that providers must sift through. The perception of safety surrounding first movers in each new therapeutic area is sure to affect adoption of that modality more broadly.

Psychiatric aspects of ophthalmic disorders: A narrative review

Ophthalmic disorders have psychiatric aspects associated with them at various levels. Psychological factors have a well-documented role in the causation, aggravation, and maintenance of various ophthalmic conditions, including glaucoma, central serous retinopathy, dry eye disease, and retinitis pigmentosa. Many ophthalmic conditions, including blindness, have psychological manifestations as well, which need to be addressed, in addition to the ophthalmic pathology. There is also significant overlap in the treatment of the two disciplines in many ways. For instance, many ophthalmic drugs have psychiatric side effects. Even ophthalmological surgeries have psychiatric aspects associated with them, which primarily include black patch psychosis and anxiety in the operation theater. This review will be useful for psychiatrists and ophthalmologists, for their clinical practice and research. Future research should focus on this interface to give it its well-deserved attention.

Prophylaxis of posterior capsule opacification through autophagy activation with indomethacin-eluting intraocular lens.

Posterior capsule opacification (PCO) is the most common long-term postoperative complication of cataract surgery, leading to secondary vision loss. Optimized intraocular lens (IOL) structure and appropriate pharmacological intervention, which provides physical barriers and biological inhibition, respectively, can block the migration, proliferation, and epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs) for PCO prophylaxis. Herein, a novel indomethacin-eluting IOL (INDOM-IOL) with an optimized sharper edge and a sustained drug release behavior was developed for PCO prevention. Indomethacin (INDOM), an ophthalmic non-steroidal anti-inflammatory drug (NSAID) used for postoperative ocular inflammation, was demonstrated to not only be able to suppress cell migration and down-regulate the expression of cyclooxygenase-2 (COX-2) and EMT markers, including alpha-smooth muscle actin (α-SMA) and cyclin D1, but also promote the autophagy activation in LECs. Additionally, autophagy was also verified to be a potential therapeutic target for the down-regulation of EMT in LECs. The novel IOL, serving as a drug delivery platform, could carry an adjustable dose of hydrophobic indomethacin with sustained drug release ability for more than 28 days. In the rabbit PCO model, the indomethacin-eluting IOL showed excellent anti-inflammatory and anti-PCO effects. In summary, indomethacin is an effective pharmacological intervention in PCO prophylaxis, and the novel IOL we developed prevented PCO in vivo under its sustained indomethacin release property, which provided a promising approach for PCO prophylaxis in clinical application.

Modern Technologies in Diagnosis of Fungal Keratitis (Review).

Traumas and infectious diseases of the eye play a leading role in the development of corneal blindness responsible for 1.5-2 million cases of vision loss per year. To date, the issue of reducing the incidence of fungal keratitis is acute and needs to be solved worldwide. Trauma as a risk factor for corneal fungal disease is thought to be prevalent in developing countries due to agricultural involvement, while in developed countries the onset of the disease is predisposed by medical advances such as contact vision correction and modern ophthalmic surgery. Thorough analysis of the pathogenesis gives the possibility to describe the action of fungal enzymes, biofilm formation, and the resistance mechanism, which on the one hand explains the aggressive course of the disease and difficulties in its diagnosis, and on the other hand, it encourages searching for new methods of diagnosis and treatment. The non-specific clinical picture of fungal keratitis, the variety and availability of antibiotics nowadays become an obstacle for rapid detection of this pathology. Low public awareness and late visit to an ophthalmologist are also a barrier to successful combating the increasing incidence of fungal keratitis. Belated diagnosis, increasing resistance of fungi to antibiotics, and lack of registered antifungal ophthalmic drugs justify poor treatment efficacy resulting in decreased visual acuity or vision loss. Existing diagnostic methods need systematization and detailed comparison, identifying the advantages and disadvantages of each. This review considers causative agents and their influence on pathogenesis of the disease, describes difficulties of fungal keratitis diagnosis and possible ways of overcoming these problems using new developments, and also outlines further prospects of research in this direction.

Evaluation of model-based bioequivalence approach for single sample pharmacokinetic studies.

In a traditional pharmacokinetic (PK) bioequivalence (BE) study, a two-way crossover study is conducted, PK parameters (namely the area under the time-concentration curve [AUC] and the maximal concentration [ ]) are obtained by noncompartmental analysis (NCA), and the BE analysis is performed using the two one-sided test (TOST) method. For ophthalmic drugs, however, only one sample of aqueous humor, in one eye, per eye can be obtained in each patient, which precludes the traditional BE analysis. To circumvent this issue, the U.S. Food and Drug Administration (FDA) has proposed an approach coupling NCA with either parametric or nonparametric bootstrap (NCA bootstrap). The model-based TOST (MB-TOST) has previously been proposed and evaluated successfully for various settings of sparse PK BE studies. In this paper, we evaluate, via simulations, MB-TOST in the specific setting of single sample PK BE study and compare its performance to NCA bootstrap. We performed BE study simulations using a published PK model and parameter values and evaluated multiple scenarios, including study design (parallel or crossover), sampling times (5 or 10 spread across the dosing interval), and geometric mean ratio (of 0.8, 0.9, 1, and 1.25). Using the simulated structural PK model, MB-TOST performed similarly to NCA bootstrap for AUC. For , the latter tended to be conservative and less powerful. Our research suggests that MB-TOST may be considered as an alternative BE approach for single sample PK studies, provided that the PK model is correctly specified and the test drug has the same structural model as the reference drug.

Enhanced and Extended Ophthalmic Drug Delivery by pH-Triggered Drug-Eluting Contact Lenses with Large-Pore Mesoporous Silica Nanoparticles

Drug-eluting contact lenses (DCLs) have attracted considerable attention as potential therapeutic ophthalmic drug delivery devices. In this study, we propose, fabricate, and investigate pH-triggered DCLs that are combined with large-pore mesoporous silica nanoparticles (LPMSNs). Compared to reference DCLs, LPMSN-laden DCLs can prolong the residence time of glaucoma drugs in an artificial lacrimal fluid (ALF) environment at pH 7.4. Additionally, LPMSN-laden DCLs do not require drug preloading and are compatible with current contact lens manufacturing processes. LPMSN-laden DCLs soaked at pH 6.5 exhibit better drug loading than reference DCLs due to their specific adsorption. The sustained and extended release of glaucoma drugs by LPMSN-laden DCLs was successfully monitored in ALF, and the drug release mechanism was further explained. We also evaluated the cytotoxicity of LPMSN-laden DCLs, and qualitative and quantitative results showed no cytotoxicity. Our experimental results demonstrate that LPMSNs are excellent nanocarriers that have the potential to be used as safe and stable nanocarriers for the delivery of glaucoma drugs or other drugs. pH-triggered LPMSN-laden DCLs can significantly improve drug loading efficiency and control prolonged drug release, indicating that they have great potential for future biomedical applications.

Polymer based thermosensitive in-situ hydrogel in ophthalmic drug delivery

Polymer based thermosensitive in-situ hydrogel in ophthalmic drug delivery

Dupilumab-associated ocular surface disease in atopic dermatitis patients: clinical characteristics, ophthalmic treatment response, and conjunctival goblet cell analysis.

Dupilumab-associated ocular surface disease (DAOSD) is frequently reported as side effect in atopic dermatitis (AD) patients. Therefore, the aim of this study was to investigate the frequency and severity of DAOSD, ophthalmic treatment response, and to learn more about the effect of dupilumab on conjunctival goblet cells (GC). This prospective study included dupilumab-treated AD patients between February 2020 and June 2022 from the University Medical Centre Utrecht. Patients were examined by an ophthalmologist and a dermatologist before start (baseline), and after 4 and 28 weeks of dupilumab treatment. Ophthalmological examination was assessed by the Utrecht Ophthalmic Inflammatory and Allergic disease (UTOPIA) score. DAOSD was defined as an increase in UTOPIA score of ≥3 points from baseline. To quantify conjunctival GCs and to investigate the percentage of Cytokeratin 19 (CK19)-CD45-Mucin 5AC (MUC5AC)+ cells, conjunctival impression cytology samples were analysed. Ocular surface disease (OSD) was present in 91.3% (n=63/69) patients at baseline. DAOSD was observed in 28.9% (n=20/69) patients, in whom GC numbers remained stable and the percentage of CK19-CD45-MUC5AC+ cells decreased at onset of DAOSD compared with baseline. After 28 weeks of dupilumab treatment, DAOSD was seen in 14.5% (n=10/69) patients. Of the 85.5% (n=59/69) patients without DAOSD or with controlled DAOSD at week 28, 40.7% (n=24/59) patients received anti-inflammatory ophthalmic drugs. OSD is common in moderate-to-severe AD patients before starting dupilumab. During treatment with dupilumab DAOSD severity improves with early ophthalmic treatment. The decrease in percentage of CK19-CD45-MUC5AC+ cells during dupilumab treatment suggests an impairment of the GC function due to dupilumab treatment.

Overcoming Treatment Challenges in Posterior Segment Diseases with Biodegradable Nano-Based Drug Delivery Systems.

Posterior segment eye diseases present a challenge in treatment due to the complex structures in the eye that serve as robust static and dynamic barriers, limiting the penetration, residence time, and bioavailability of topical and intraocular medications. This hinders effective treatment and requires frequent dosing, such as the regular use of eye drops or visits to the ophthalmologist for intravitreal injections, to manage the disease. Moreover, the drugs must be biodegradable to minimize toxicity and adverse reactions, as well as small enough to not affect the visual axis. The development of biodegradable nano-based drug delivery systems (DDSs) can be the solution to these challenges. First, they can stay in ocular tissues for longer periods of time, reducing the frequency of drug administration. Second, they can pass through ocular barriers, offering higher bioavailability to targeted tissues that are otherwise inaccessible. Third, they can be made up of polymers that are biodegradable and nanosized. Hence, therapeutic innovations in biodegradable nanosized DDS have been widely explored for ophthalmic drug delivery applications. In this review, we will present a concise overview of DDSs utilized in the treatment of ocular diseases. We will then examine the current therapeutic challenges faced in the management of posterior segment diseases and explore how various types of biodegradable nanocarriers can enhance our therapeutic arsenal. A literature review of the pre-clinical and clinical studies published between 2017 and 2023 was conducted. Through the advances in biodegradable materials, combined with a better understanding of ocular pharmacology, the nano-based DDSs have rapidly evolved, showing great promise to overcome challenges currently encountered by clinicians.