Ophthalmic Drug Research Articles

Comparative proteomic analysis of human vitreous in rhegmatogenous retinal detachment and diabetic retinopathy reveals a common pathway and potential therapeutic target

BackgroundThe vitreous humor serves as a window into the physiological and pathological processes of the eye, particularly the retina. Diabetic retinopathy (DR), a leading cause of blindness, involves hyperglycemia-induced damage to retinal cells, leading to ischemia and elevated nitric oxide levels, culminating in vascular proliferation. Rhegmatogenous retinal detachment (RD) results from a break in the neuroretina, triggering ischemia, photoreceptor death, and cellular proliferation. Proliferative vitreoretinopathy (PVR) further complicates these conditions through fibrous proliferation. Despite their prevalence and potential for blindness, our understanding of the molecular mechanisms underlying these vitreoretinal diseases is incomplete.Methods and resultsTo elucidate disease mechanisms and identify potential therapeutic targets, we conducted a comparative proteomic analysis of vitreous samples from DR, RD, and macular pucker (P) patients, which were chosen as controls. LC–MS analysis identified 988 quantifiable proteins, with distinct clustering observed among disease groups. Differential expression analysis revealed 202 proteins in RD vs. P and 167 in DR vs. P, highlighting distinct proteomic signatures. Enrichment analysis identified glucose metabolism as an altered process in both diseases, suggesting common pathways despite differing etiologies. Notably, aldo–keto reductase family 1 member B1 (AKR1B1) has emerged as a potential key player in both DR and RD, indicating its role in glucose metabolism and inflammation. In silico drug screening identified diclofenac, an approved ophthalmic non-steroidal anti-inflammatory drug (NSAID), as a potential therapeutic agent targeting AKR1B1.ConclusionOur study revealed distinct proteomic signatures and common pathways in vitreoretinal diseases, highlighting AKR1B1 as a potential therapeutic target. Using diclofenac during diagnosis and postoperative care for diabetic retinopathy or rhegmatogenous retinal detachment may reduce complications, lower costs, and improve quality of life. Future research will focus on confirming AKR1B1’s role in vitreoretinal diseases and understanding diclofenac’s mechanism of action.

Risk of ophthalmic adverse drug reactions in patients prescribed glucagon-like peptide 1 receptor agonists: a pharmacovigilance study based on the FDA adverse event reporting system database.

To investigate the association between glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and ophthalmic adverse drug reactions (OADRs) using data from the FDA Adverse Event Reporting System (FAERS). This retrospective pharmacovigilance study analyzed post-marketing FAERS data from 2018 to 2023 to identify GLP-1 RA-related OADRs. This study employed the Weibull model for time-to-onset (TTO) analysis, Bayesian Information Component analysis for disproportionality comparing GLP-1 RAs with other drugs, and the Ω shrinkage method for co-medication analysis. FAERS reported 5003 OADRs associated with GLP-1 RAs, including retinopathy and visual impairment. Disproportionality analysis identified significant signals for semaglutide, liraglutide, and exenatide, suggesting potential associations with OADRs. Co-medication analysis indicated that OADRs primarily resulted from GLP-1 RA use. TTO analysis categorized most OADRs as early failures, emphasizing the need for early monitoring. This study emphasizes the importance of ophthalmic surveillance in patients using GLP-1 RAs, particularly semaglutide, dulaglutide, and exenatide. Enhanced monitoring and patient education are essential for timely detection and management of potential OADRs. Regulatory agencies should consider updating drug labels to include comprehensive warnings about OADRs associated with GLP-1 RA therapies.

Engineered PVA-tamarind gum-based biocomposite for sustained ophthalmic delivery of moxifloxacin: Effect of nanocellulose on physicochemical, mechanoelectrical and permeation kinetics

Widely used polysaccharide-based films in ophthalmic drug delivery have major limitations of inadequate mechanical strength, poor electrical conductivity, and insufficient ocular drug permeability. Moxifloxacin (MFX) biocomposite film of adequate mechanoelectrical properties was developed for sustained ophthalmic drug delivery. Nanocellulose (NC) incorporated (2.5, 5.0, 7.5, and 10.0 %) PVA-tamarind gum-based moxifloxacin composite was prepared using solvent casting method. The addition of NC improved the mechanical properties of the film, demonstrating its ability to strengthen the structure. Stress relaxation (SR) of the film has been augmented (64.67±7.55 to 73.15±0.34 %) due to increased content of NC (0 to 10 %) respectively. Film containing 5 % NC showed the critical edge of tensile strength (11.9±0.39 MPa), and also the threshold limit of electrical conductivity (4.5*107 Ω). The same film exhibited continued drug release as well as erosion-controlled sustained ocular permeation (pH 7.4) and revealed the highest antibacterial activity (ZOI of disc diffusion, cm) with Pseudomonas aeruginosa (4.63±0.15) and Staphylococcus aureus (4.30±0.26) of MFX (≈224 μg). Notably, incorporating NC produced non-irritating and safe for corneal delivery as confirmed by the Draize model test. Our findings suggested that the NC-containing PVA-tamarind gum-based composite film holds a promising approach for sustained ophthalmic delivery of MFX.

Self-assembled latanoprost loaded soluplus nanomicelles as an ophthalmic drug delivery system for the management of glaucoma

Glaucoma, a leading cause of blindness due to elevated intraocular pressure (IOP), is managed with medications like latanoprost (LAT), a prostaglandin analogue, to enhance aqueous outflow. Despite the challenge posed by eye anatomy and tear dynamics, effective ocular bioavailability via topical administration remains elusive. This study aims to optimize self-assembled nanomicelles incorporating LAT, an anti-glaucoma drug, belonging to BCS Class II (low solubility and high permeability) via a two-level, two-factor full factorial design, the nanomicelles were formulated via direct dissolution method and validated using design of expert. The optimized nanomicelles exhibited a spherical morphology, with a size of 69 nm and encapsulation efficiency of 77.5%, demonstrating a sustained LAT release over 12 h. In normotensive rabbits, the nanomicelles elicited a substantial reduction in intraocular pressure (IOP) by up to 40% for a duration of three days, that was significantly longer than the IOP-lowering efficacy of XALATAN eye drops (24 h). These findings indicated that self-assembled nanomicelles hold promise for enhancing the ocular bioavailability and extending the therapeutic duration of LAT, while providing the physical stability.

Extended release of ciprofloxacin from commercial silicone-hydrogel and conventional hydrogel contact lenses containing vitamin E diffusion barriers.

Vitamin E could be used as a coating with commercial silicone hydrogel lenses to extend the release of various ophthalmic drugs. This concept could provide a promising approach to improve overall ocular therapeutic outcomes for topical ocular drugs. This study aimed to develop a contact lens-based ocular drug delivery system using vitamin E as a diffusion barrier to extend the release duration of ciprofloxacin. Five commercial lenses were soaked for 24 hours in various concentrations of vitamin E dissolved in ethanol (0.0125 to 0.2 g/mL). The lenses were loaded with ciprofloxacin for 24 hours in 3 mL of 3 mg/mL of ciprofloxacin/acetic acid solution. The drug release was evaluated in 3 mL of phosphate-buffered saline solution. At t = 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours, the amount of ciprofloxacin released was measured using a UV-VIS spectrophotometer at 270 nm. There was a decrease in ciprofloxacin loading with increasing amounts of vitamin E loaded into the silicone hydrogel lenses. For each lens type, there was an optimal amount of vitamin E loaded that extended the release duration of the drug from 1 hour (without vitamin E) to as long as 16 hours. In contrast, vitamin E loaded into hydrogel lenses had no effect on the amounts of drugs loaded or the release duration. Vitamin E can be used as a diffusion barrier with commercially available silicone hydrogel lenses to provide sustained release of ciprofloxacin. The results suggest that vitamin E may form blockages in channels within a silicone hydrogel lens material, thereby forcing a longer path for drugs to diffuse into and out of the lens material. There is an optimal amount of vitamin E that needs to be loaded to extend the release duration, and this is lens material dependent.

Synthesis and Ocular Hypotensive Properties 3(4)‐Alkyl‐[1,2,4]triazolo[1,5‐a]pyrimidin‐7‐amines

AbstractGlaucoma is one of the major causes of irreversible blindness worldwide. Increased intraocular pressure (IOP) is a key factor in the onset and progression of this disease. The drugs used to treat glaucoma influence a variety of biological targets. Azolopyrimidine derivatives have attracted significant attention as potential agents for the treatment of glaucoma because they presumed to be analogs of adenosine receptor (AR) agonists and antagonists. In this study, a series of novel 3(4)‐alkyl‐[1,2,4]triazolo[1,5‐a]pyrimidin‐7‐amines were synthesized to develop promising ophthalmic hypotensive drugs. The synthesized compounds demonstrated significant hypotensive activity against IOP, which opens new possibilities for glaucoma therapy.

Drug-associated glaucoma: A real-world study based on the Food and Drug Administration adverse event reporting system database.

This study aims to assess the risk of drug-associated glaucoma and track its epidemiological characteristics using real-world data. Adverse event reports from the Food and Drug Administration Adverse Event Reporting System (FAERS) from January 2004 to December 2023 were analysed. Disproportionality analysis and the Bayesian Confidence Propagation Neural Network algorithm were used. The study classified drugs associated with glaucoma, assessed risk levels, and compared drug-induced times across different categories. Eight hundred and five drugs were linked to glaucoma in the FAERS database. Disproportionality analysis identified 46 drugs with significant risk, mainly adrenergic medications (clobetasol propionate, fluocinolone acetonide), antihypertensives (hydrochlorothiazide), insulin (insulin human), anticholinergics (umeclidinium, darifenacin), VEGF inhibitors (brolucizumab, faricimab), and psychotropics (topiramate, ziprasidone). The top three high-risk drugs were clobetasol propionate, umeclidinium, and fluocinolone acetonide. The shortest drug-induced times were observed with indacaterol, salmeterol, and umeclidinium. Anticholinergic medications had the shortest drug-induced time among all categories. Females (62.5%) and the elderly (average age 63.5 ± 16.8 years) were predominantly affected. Reports of drug-associated glaucoma increased over the years. Preventing drug-associated glaucoma is more effective than treatment. Identifying the risk and drug-induced times of systemic and ophthalmic drugs can reduce occurrence risk. Clinical practitioners should be vigilant and inform patients of these risks.

From Preformulative Design to In Vivo Tests: A Complex Path of Requisites and Studies for Nanoparticle Ocular Application. Part 1: Design, Characterization, and Preliminary In Vitro Studies.

Ocular pathologies are widely diffused worldwide, and their effective treatment, combined with a high patient compliance, is sometimes challenging to achieve due to the barriers of the eye; in this context, the use of nanoparticles for topical ophthalmic application could represent a successful strategy. Aiming to develop nanoplatforms with potential clinical applications, great attention has to be paid to their features, in relation to the route of administration and to the pharmacopoeial requirements. This review (part 1) thus embraces the preliminary steps of nanoparticle development and characterization. At the beginning, the main barriers of the eye and the different administration routes are resumed, followed by a general description of the advantages of the employment of nanoparticles for ocular topical administration. Subsequently, the preformulative steps are discussed, deepening the choice of raw materials and determining the quantitative composition. Then, a detailed report of the physicochemical and technological characterization of nanoparticles is presented, analyzing the most relevant tests that should be performed on nanoparticles to verify their properties and the requisites (both mandatory and suggested) demanded by regulatory agencies. In conclusion, some preliminary noncellular in vitro evaluation methods are described. Studies from in vitro cellular assays to in vivo tests will be discussed in a separate (part 2) review paper. Hence, this overview aims to offer a comprehensive tool to guide researchers in the choice of the most relevant studies to develop a nanoplatform for ophthalmic drug administration.

Development of FK506-loaded maleimide-functionalized cationic niosomes for prolonged retention and therapeutic efficacy in dry eye disease.

Tacrolimus (FK506) is widely used in ocular diseases such as corneal transplantation-host disease, uveitis, conjunctivitis, and dry eye disease (DED). However, its low aqueous solubility and poor ocular retention pose challenges for its application in the eye diseases. This study developed a novel FK506-loaded maleimide-functionalized cationic niosomes (FK506 M-CNS), aiming to prolong the retention time of FK506 in the eye and enhance its therapeutic efficacy. FK506 M-CNS had a particle size of 87.69 ± 1.05nm and zeta potential of 22.06 ± 1.01 mV. Results of histological evaluation through H&E staining and in vitro cytotoxicity of human corneal epithelial cells consistently revealed the excellent biocompatibility of FK506 M-CNS. FK506 M-CNS exhibited superior ocular retention compared to the market product Talymus®. FK506 M-CNS significantly alleviated the symptoms of DED and promoted the recovery of corneal epithelia. FK506 M-CNS group had the lowest expression levels of inflammatory factors associated with DED. These superiorities might be due to the electrostatic interaction between cationic niosomes and negatively charged mucin in the eye, and the covalent binding of maleimide with the thiol group in the mucin. The maleimide group improved the ocular retention and efficacy of FK506, but did not increase the toxicity. Results indicated that FK506 M-CNS had great potential as a nanopharmaceutical in the treatment of ocular diseases, and M-CNS could be a promising drug carrier for ophthalmic drug delivery systems.

Formulation of Thermo-Sensitive In Situ Gels Loaded with Dual Spectrum Antibiotics of Azithromycin and Ofloxacin.

In situ gels have been developed as an innovative strategy to prolong corneal residence time and enhance drug absorption compared to traditional eye drops. Our study aimed to formulate an ophthalmic in situ gel with a combination of two thermosensitive poloxamers, P407 and P188, in an optimal ratio not only to increase the time of action but also to increase the solubility of selected antibiotics for the treatment of ophthalmic infections. Two BSC II class substances, Azithromycin and Ofloxacin, with different mechanisms of action, have been incorporated into the in situ gel system after determining their solubility. The antibiotics-loaded in situ gel formulation was evaluated for its clarity, pH, rheological properties, and gel characteristics of gelling time, temperature, and capacity. The formulation demonstrated satisfactory clarity, appropriate pH, effective gelation properties in simulated tear fluid, and suitable rheological characteristics. In addition, APIs release insight has been studied through a dissolution test, and the effectivity against sensitive and resistant bacterial strains has been proved through the antimicrobial study. Therefore, our in situ gel system based on thermosensitive poloxamers, with two hydrophobic antibiotics, AZM and OFX, can be considered a valuable approach for ophthalmic drug delivery with an enhancement of the antibiotics bioavailability through increasing the contact time with the ocular surface and enhancing patient compliance.

Hydrogel-Embedded Polydimethylsiloxane Contact Lens for Ocular Drug Delivery.

Topical administration is the commonly preferred method of administering ophthalmic formulations, with the majority of available medications in the form of eye drops or ointments. However, the topical application of ophthalmological medications has less bioavailability and a short residence time because of the physiological and anatomical constraints of the eye, making efficient ophthalmic drug delivery a challenging task. Microfluidic contact lenses have the advantage of delivering drugs into the eye in a controlled and on-demand manner. Here, we showcase the use of hydrogel-embedded microcavities on PDMS-based contact lenses for ocular drug delivery applications. The fabrication technique adopted here is the spontaneous formation of the spherical cavity by hydrogel monomer droplet, followed by the simultaneous thermal curing of hydrogel and PDMS, creating a spherical cavity as small as 150 μm. The spherical cavity is embedded with pH-responsive hydrogel for on-demand drug delivery. The drug loaded in the hydrogel matrix is released into the ocular environment by diffusion. The spherical cavity with a narrow opening restricts the diffusion to a minimum under normal ocular pH conditions(pH > 6). When the ocular pH reduces (pH < 6), the pH-responsive hydrogel inside the spherical cavity deswell and accelerates the drug release.

Innovations in Nanoemulsion Technology: Enhancing Drug Delivery for Oral, Parenteral, and Ophthalmic Applications.

Nanoemulsions (NEs) are submicron-sized heterogeneous biphasic liquid systems stabilized by surfactants. They are physically transparent or translucent, optically isotropic, and kinetically stable, with droplet sizes ranging from 20 to 500 nm. Their unique properties, such as high surface area, small droplet size, enhanced bioavailability, excellent physical stability, and rapid digestibility, make them ideal for encapsulating various active substances. This review focuses on recent advancements, future prospects, and challenges in the field of NEs, particularly in oral, parenteral, and ophthalmic delivery. It also discusses recent clinical trials and patents. Different types of in vitro and in vivo NE characterization techniques are summarized. High-energy and low-energy preparation methods are briefly described with diagrams. Formulation considerations and commonly used excipients for oral, ocular, and ophthalmic drug delivery are presented. The review emphasizes the need for new functional excipients to improve the permeation of large molecular weight unstable proteins, oligonucleotides, and hydrophilic drugs to advance drug delivery rapidly.

Sustained release of proteins from contact lenses with porous annulus.

Ophthalmic drugs are administered to the front of the eye by eyedrops. The bioavailability of drugs delivered via eye drops is low due to tear turnover. Contact lenses can address some deficiencies of eye drops by sustaining the delivery of drugs, but commercial contact lenses have small pore sizes that cannot load biologics, which are becoming more common for treating ophthalmic diseases. This study aims to investigate novel poly(hydroxyethyl methacrylate) (pHEMA) lenses with transparent center and porous annulus for sustained release of model proteins. A novel hydrogel polymerization process was used to fabricate concentric, porous layer pHEMA hydrogel rods. The hydrogels were lathe cut into contact lenses which were explored for the delivery of proteins and gold nanoparticles. Lenses were characterized by partition coefficient and diffusivity, which was estimated by fitting experimental data to an analytical model. Transmittance measurements were made to compare transparency of porous lens centers to commercial contact lenses. Porous pHEMA lenses consisting of a concentric, porous layer made from 55% water content in precursor were successfully lathe cut into lenses with transparent center and opaque porous annulus. The porous lenses could load large model proteins of bovine serum albumin and human γ-globulin and provide sustained release. The core annular pHEMA contact lenses consisting of an outer annulus of opaque, porous pHEMA and an inner, center layer of clear, nonporous pHEMA can provide sustained delivery of biologics.

Advancements in Ocular Therapy: A Review of Emerging Drug Delivery Approaches and Pharmaceutical Technologies

Eye disorders affect a substantial portion of the global population, yet the availability of efficacious ophthalmic drug products remains limited. This can be partly ascribed to a number of factors: (1) inadequate understanding of physiological barriers, treatment strategies, drug and polymer properties, and delivery systems; (2) challenges in effectively delivering drugs to the anterior and posterior segments of the eye due to anatomical and physiological constraints; and (3) manufacturing and regulatory hurdles in ocular drug product development. The present review discusses innovative ocular delivery and treatments, encompassing implants, liposomes, nanoparticles, nanomicelles, microparticles, iontophoresis, in situ gels, contact lenses, microneedles, hydrogels, bispecific antibodies, and gene delivery strategies. Furthermore, this review also introduces advanced manufacturing technologies such as 3D printing and hot-melt extrusion (HME), aimed at improving bioavailability, reducing therapeutic dosages and side effects, facilitating the design of personalized ophthalmic dosage forms, as well as enhancing patient compliance. This comprehensive review lastly offers insights into digital healthcare, market trends, and industry and regulatory perspectives pertaining to ocular product development.

Green Voltammetric Detection of Ophthalmic Drug Nepafenac Using Pencil Graphite Electrode as a Responsive Disposable Electrochemical Sensor

AbstractIn this study, the electrochemical properties of nepafenac, used after eye surgery operations, were investigated on a disposable pencil graphite electrode. Cyclic and square wave voltammetry techniques were used to investigate the electrochemical properties of nepafenac. Two peaks at potentials of approximately +0.33 V and +1.03 V in the anodic direction and two peaks at potentials of approximately +0.29 V and +0.08 V in the cathodic direction were observed on the surface of the disposable pencil electrode in acetate (pH 4.8) medium with the cyclic voltammetry technique. The analytical performance of the developed voltammetric technique had good linearity in the concentration range of 0.30 µM to 3.5 µM at pH 4.8. The LOD value of this voltammetric method in acetate (pH 4.8) medium was calculated as 0.035 µM (8.90 ng mL−1). For reproducibility, the relative standard deviation (RSD) values for Ia and IIa anodic peak current/potential were found to be 1.45%/0.43% and 1.28%/0.25%, respectively. The voltammetric method was successfully applied to urine and pharmaceutical preparations and the results were compared with the spectrophotometric method.

Oxidative stress-induced degradation of Brinzolamide: Isolation and in-depth characterization of unique hydroxylamine and oxime degradation products

Since the safety and efficacy of therapeutic products are strongly related to their stability and purity, impurities including the unavoidable degradation products may affect the pharmacological effect. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines Q3A requires the identification of process impurities and as well as degradation products in any drug substance to assess the inherent stability of the drug. The present work involves an ICH-guided degradation study for the Brinzolamide (BRZ), a topical ophthalmic drug which is generally used to lower the intraocular pressure (IOP) during glaucoma. Under oxidative stress at room temperature for 20 h, four degradation products (namely BRZ-Pk1, BRZ-PK2, BRZ-Pk3, and BRZ-Pk4) are isolated using advanced chromatographic techniques. Upon confirming the masses of the compounds using High-resolution mass spectrometry (HRMS), functional groups are identified with the help of Fourier-transform infrared spectroscopy (FT-IR). Extensive 1-dimensional (1D) and 2-dimensional (2D) Nuclear Magnetic Resonance spectroscopic (NMR) experiments especially 1D nOe, 1H-13C-HSQC and 1H-13C-HMBC unequivocally confirm the structures. Among the four compounds analyzed, three (BRZ-Pk1, BRZ-Pk2, and BRZ-Pk4) are novel, while BRZ-Pk3 was previously reported solely with mass spectrometric data. Nitrogen-based 2D NMR experiments are crucial for determining the oxidation state of hydroxylamine and oxime products within the molecules, and 1D nOe measurements help confirming E/Z isomerism (geometrical isomerism) for BRZ-Pk2 and BRZ-Pk4. All the proposed structures are justified with appropriate analytical data. The proposed mechanisms are expected to help in identifying the possible degradation pathways for similar pharmaceutical candidates.

Mathematical Models of Drug Delivery via a Contact Lens During Wear

AbstractIn this work we develop and investigate mathematical and computational models that describe drug delivery from a contact lens during wear. Our models are designed to predict the dynamics of drug release from the contact lens and subsequent transport into the adjacent pre-lens tear film and post-lens tear film as well as into the ocular tissue (e.g. cornea), into the eyelid, and out of these regions. These processes are modeled by one dimensional diffusion out of the lens coupled to compartment-type models for drug concentrations in the various accompanying regions. In addition to numerical solutions that are compared with experimental data on drug release in an in vitro eye model, we also identify a large diffusion limit model for which analytical solutions can be written down for all quantities of interest, such as cumulative release of the drug from the contact lens. We use our models to make assessments about possible mechanisms and drug transport pathways through the pre-lens and post-lens tear films and provide interpretation of experimental observations. We discuss successes and limitations of our models as well as their potential to guide further research to help understand the dynamics of ophthalmic drug delivery via drug-eluting contact lenses.

Injectable and 3D Extrusion Printable Hydrophilic Silicone-Based Hydrogels for Controlled Ocular Delivery of Ophthalmic Drugs.

While silicone elastomers have found widespread use in the biomedical industry, 3D printing them has proven to be difficult due to the material's slow drying time, low viscosity, and hydrophobicity. Herein, we arrested the hydrophilic silicone (HS) macrochains into a semi-interpenetrating polymer network (semi-IPN) via an in situ photogelation-assisted 3D microextrusion printing technique. The flow behavior of the pregel solutions and the mechanical properties of the printed HS hydrogels were tested, showing a high elastic modulus (approximately 15 kPa), a low tan δ, high elasticity, and delayed network rupturing. The uniaxial compression tests demonstrated a nearly negligible permanent deformation, suggesting that the printed hybrid hydrogel maintained its elastic properties. Drug loading and diffusion in the microporous hydrogel are shown via the non-Fickian anomalous transport mechanism, leading to highly tunable loading/releasing profiles (approximately 20% cumulative release) depending on the HS concentration. The drug encapsulation exhibits exceptional stability, remaining intact without any degradation even after a storage period of 1 month. As far as we know, this is the first soft biomaterial based on HS that functions as an exceptional controlled drug delivery device.

Investigating Flow-Induced Corrosion of Magnesium in Ophthalmological Milieu.

Although the impact of local fluid dynamics in the biodegradation of magnesium is well known, currently no studies in the literature address the degradation effects of ocular vitreous on bioresorbable devices made of magnesium, which could be developed as drug delivery carriers. The aim of this study was to investigate the flow-induced corrosion mechanism of magnesium in an ophthalmological environment for future applications in ophthalmic drug delivery. To achieve this, experimental and computational methods were combined. Specifically, a CFD model was employed to design experimental conditions that replicate the ocular flow-induced shear stress (FISS) on manufactured magnesium samples. Pure Mg samples were tested in a bioreactor system capable of imposing the ocular CFD calculated values of FISS on the Mg samples' surface by varying the pump flow rate. Optimal flow rates for a range of different FISS values specific to the ophthalmological fluid dynamics affecting the device were indeed determined before running the experiments. After conducting customized corrosion tests, morphological observations and profilometric maps of the eroded surfaces of Mg samples were obtained using scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). These maps were then post-processed for the parametric evaluation of corrosion rates. Pre-existing localized superficial defects did affect the final corrosion pattern. SEM images and CLSM data confirmed a uniform corrosion mechanism, with corrosion rates of 1.9, 2.7, and 3.4 μm/day under different shear stress conditions (0, 0.01, and 0.032 Pa, respectively). More generally, uniform corrosion on pure Mg samples increased with higher FISS values, and at higher shear stress values (FISS = 0.032 Pa), a notable washing-out effect of the corrosion products was observed. The removal of corrosion products at higher shear stresses suggests that the dynamic ocular environment, influenced by saccadic movements, plays a significant role in the corrosion mechanism of pure magnesium. The corrosion rates determined in this study, in conjunction with clinical drug release requirements, are crucial for designing potential drug-release devices for ocular applications.

Enhancement of therapeutic efficacy of Brinzolamide for Glaucoma by nanocrystallization and tyloxapol addition

BackgroundBrinzolamide (BRI) suspensions are used for the treatment of glaucoma; however, sufficient drug delivery to the target tissue after eye drop administration is hampered by poor solubility. To address this issue, we focused on nanocrystal technology, which is expected to improve the bioavailability of poor-solubility drugs, and investigated the effect of BRI nanocrystal formulations on corneal permeability and intraocular pressure (IOP)-reducing effect.MethodsBRI nanocrystal formulations were prepared by the wet-milling method with beads and additives. The particle size was measured by NANOSIGHT LM10, and the morphology was determined using a scanning probe microscope (SPM-9700) and a scanning electron microscope (SEM). Corneal permeability was evaluated in vitro using a Franz diffusion cell with rat corneas and in vivo using rabbits, and the IOP-reducing effect was investigated using a rabbit hypertensive model.ResultsThe particle size range for prepared BRI nanocrystal formulation was from 50 to 300 nm and the mean particle size was 135 ± 4 nm. The morphology was crystalline, and the nanoparticles were uniformly dispersed. In the corneal permeability study, BRI nanocrystallization exhibited higher corneal permeability than non-milled formulations. This result may be attributed to the increased solubility of BRI by nanocrystallization and the induction of energy-dependent endocytosis by the attachment of BRI nanoparticles to the cell membrane. Furthermore, the addition of tyloxapol to BRI nanocrystal formulation further improved the intraocular penetration of BRI and showed a stronger IOP-reducing effect than the commercial product.ConclusionsThe combination of BRI nanocrystallization and tyloxapol is expected to be highly effective in glaucoma treatment and a useful tool for new ophthalmic drug delivery.