Search Results (62)

Background/Objectives: This study aimed to repurpose aripiprazole (AR), an antipsychotic clinically approved by the FDA, as a novel antifungal drug and to potentiate its therapeutic efficacy through PEGylated terpesomes (PEG-TERs). Methods: PEG-TERs were prepared by thin-film hydration and optimized using a central composite design. The optimum PEG-TER formulation was characterized for entrapment efficiency (EE%), particle size (PS), polydispersity index (PDI), and zeta potential (ZP), and subsequently integrated into polylactic acid (PLA)-based 3D-printed ocuserts. Results: The optimized formulation exhibited spherical vesicles with high EE%, nanoscale PS, narrow PDI, and favorable ZP, alongside excellent stability and mucoadhesive properties. Ex vivo permeation demonstrated a sustained release profile of AR from PEG-TERs compared with an AR suspension, while confocal microscopy confirmed efficient corneal deposition of fluorescein-labeled PEG-TERs. In vivo, the optimum AR-loaded PEG-TERs ocusert exhibited a substantial therapeutic effect in a rabbit model of Candida albicans keratitis, while histopathological assessment confirmed its ocular safety and biocompatibility. Conclusions: In conclusion, AR-loaded PEG-TERs embedded in PLA-based 3D-printed ocuserts represent a promising, safe, and innovative therapeutic platform for the management of Candida albicans-induced corneal infections, offering both drug repurposing and emerging opportunities in advanced ocular drug delivery. Full article

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

Background: Amlodipine besylate (AML) is recognized as a calcium channel blocker curative for hypertension. However, the drug emerged recently as an antibacterial cure that competently prevails over resistant strains. Methods: Incorporating amlodipine into zein nanoparticles was employed to innovate a suitable carrier for loading and targeting deep corneal infection. The Box–Behnken design was adopted to produce various formulations of amlodipine-loaded zein nanoparticles (AML-ZNs) with diversity in composition concentration (% w/v), comprising zein, Labrafac, and poloxamer 407. Results: Relying on the optimization criterion, the chosen preference formulation concentration (% w/v) consists of 2.068 for zein, 0.75 for Labrafac, and 1.0 for Poloxamer. Morphological micrography of AML-ZNs showed regular spherical particles in the nanometric scale, and physicochemical characterization procedures confirmed system suitability. While tracking eyedrop optimum features, sodium alginate was selected for coating nanoparticles to improve stability and system viscosity. Both pH and sterility were also considered and maintained. Comparative studies were conducted pre- and post-coating, and the assessed features for the final selected formulation were 349.9 ± 5.8 nm, 0.2186 ± 0.0271, −55.45 ± 1.84 mV, 81.293 ± 0.9%, and 19.3 ± 0.19 cp for size, PDI, surface charge, entrapment, and viscosity, respectively. The AML-ZNs-Alg formulation demonstrates a more controlled pattern of release of roughly 40% of the drug released after 48 h, while the permeation profile shows 37 ± 3.52% permeated after 24 h, confirmed visually. In vitro microbial assay alongside the corneal in vivo microbial and histological pathology evaluation proved the efficacy of amlodipine as an antibacterial agent. Conclusions: These findings highlighted that the prepared AML-ZNs-Alg eyedrop can be a promising system as an antibacterial therapy. Full article

Objectives: This study was designed to optimize a ceftazidime (CTZ)-loaded nanocarrier that could efficiently permeate across corneal tissues. Moreover, N-acetylcysteine (NAC) was combined with an optimized CTZ-loaded formula to augment the antimicrobial activity and facilitate the efficient healing of Pseudomonas aeruginosa-induced keratitis. Methods: Different CTZ-loaded invasomes (INVs) and CTZ-loaded nanostructured lipid carriers (NLC) were fabricated and fully characterized via the determination of the entrapment efficiency (EE%), particle size (PS), surface charge, and percentage of CTZ release. Next, NAC was added to the optimized formulae from each nanocarrier, which were further assessed through ex vivo corneal permeation and in vitro antimicrobial activity studies. Finally, an in vivo evaluation of the optimal nanocarrier in the presence of NAC was performed. Results: Both nanocarriers showed nanoscale PS with sufficient surface charges. CTZ-loaded NLC formulae showed a higher EE% range with a sustained drug release profile. Both optimized formulae showed a spherical shape and excellent stability. Moreover, the antibacterial activity and biofilm inhibition assessments confirmed the synergistic effects of NAC when combined with different CTZ-loaded nanocarriers. However, the optimized CTZ-loaded INV formula achieved higher corneal permeation and deposition compared to the optimized CTZ-loaded NLC formula. Finally, the in vivo assessment confirmed the dominance of the optimized CTZ-loaded INV formula combined with NAC, where the microbiological, histopathological, and immunohistopathological examinations showed the rapid eradication of keratitis. Conclusions: Recent strategies for the incorporation of antibiotics into nanocarriers, combined with mucolytic agents, can offer a promising platform to boost the therapeutic efficiency of antibiotics and prevent antimicrobial resistance. Full article

Effective ocular drug delivery is still a challenge for pharmaceutical technologists due to the complex elimination mechanisms of the eye. In situ gels and polymeric micelles are among the pharmaceutical technologies that may enable us to overcome these challenges. Therefore, the objective of this study was to evaluate the ocular applicability of in situ gels and polymeric micelles, as well as their combinations, containing a steroidal anti-inflammatory drug, dexamethasone. The developed formulations were compared on the basis of their physicochemical characteristics, rheological behavior, mucoadhesion, in vitro drug release profile, and in vitro and ex vivo permeability. The developed formulations exhibited moderate stability according to the zeta potential measurements; however, they demonstrated appropriate mucoadhesion and sustained drug release. Furthermore, the results of the permeability studies suggest that combining thermoresponsive in situ gels and polymeric micelles represents a promising strategy for enhancing the therapeutic efficacy of ocular drug delivery. Full article

The latest advancements in nanomedicine have led to increased therapeutic efficacy and reduced complications. However, nanoparticle penetration is significantly influenced by biological hydrogels, such as mucus, the extracellular matrix, biofilms, and nucleoporins. Solely modifying well-studied physicochemical properties like size, charge, and surface chemistry is insufficient to fully elucidate or overcome these barriers. Recent studies have investigated the impact of particle elasticity, a relatively unexplored yet crucial physicochemical property influencing many biological processes. Hence, it is important to explore the impact of particle elasticity on penetrating biological hydrogels. This review examines biological hydrogels’ structural and functional features as diffusion barriers, provides an overview of particle elasticity, key elasticity measurement techniques, and explores strategies for elasticity modulation in nanoparticles, such as composition, crosslinking density, and structural design. Furthermore, nanoparticle penetration mechanisms, influenced by particle deformability, hydrogel mesh size, and adhesive interactions, are investigated by integrating theoretical and experimental findings. The evaluation of experimental data reveals the commonly observed particle elasticity trends in mucus penetration, extracellular matrix permeation, and corneal penetration of nanoparticles. Overall, this review offers valuable insights into designing next-generation nanomedicines capable of overcoming biological barriers. Full article

Background/Objectives: Dry eye disease (DED), also known as “keratoconjunctivitis sicca”, is a common chronic ocular surface disease accompanied by inflammation and diminished tear production. Bovine Lactoferrin (BLF), a multi-functional iron-binding glycoprotein found in tears, decreased significantly in patients with DED, used for the treatment of dry eye, conjunctivitis, and ocular inflammation. BLF has limited therapeutic efficacy due to poor ocular bioavailability. Methods: This study developed and optimized a BLF-loaded nanosuspension (BLF-NS) using the Box–Behnken Design (BBD). Optimized BLF-NS was then incorporated with polyvinyl pyrrolidone (PVP) and hydroxypropyl methyl cellulose (HPMC) dissolving microneedles (MNs). The formulations were characterized by Scanning and transmission microscopy, DSC, FTIR, ex vivo studies in corneal tissue from sheep and tested for its antibacterial and antifungal efficacy against Methicillin-Resistant Staphylococcus aureus (MRSA), Staphylococcus aureus, and Aspergillus niger, respectively. Moreover, they were tested for their Benzalkonium chloride (BCL) dry eye in a rabbit model. Results: The optimized nanosuspension showed a vesicle size of (215 ± 0.45) nm, a Z.P (zeta potential) of (−28 ± 0.34) mV, and an Entrapment Efficiency (EE%) of (90 ± 0.66) %. The MNs were fabricated using a ratio of biodegradable polymers, PVP/HPMC. The resulting BLF-NS-MNs exhibited sharp pyramidal geometry with high mechanical strength, ensuring ocular insertion. In vitro release showed 95% lactoferrin release over 24 h, while ex vivo permeation achieved 93% trans-corneal delivery. In vivo, BLF-NS-MNs significantly reduced pro-inflammatory cytokines (TNF-α, IL-6, MMP-9, IL-1β, MCP-1) and upregulated antioxidant and anti-inflammatory genes (PPARA, SOD 1), restoring their levels to near-normal (p < 0.001). Conclusions: The nanosuspension combined with MNs has shown higher ocular tolerance against DED ensured by the Draize and Schirmer Tear Test. Full article

Background: Folic acid (FA) is essential for cellular functions but has limited ocular bioavailability, restricting its therapeutic effectiveness. Objective: To develop chitosan (CS)-based nanogels (NGs) for FA transport and release, with corneal permeation evaluation. Methods: NGs’ hydrodynamic diameter (Ho) and polydispersity index (PdI) were determined using dynamic light scattering (DLS). CS-FA interaction was confirmed by Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA) was applied for the dehydrated material characterization. Scanning electron microscopy (SEM) was used to evaluate the NGs ultraestructure. In vitro drug release studies were performed using a modified Franz diffusion cell, and the release profile was fitted to obtain kinetics parameters. Mucoadhesion properties were evaluated through ζ-potential measurements. Ex vivo corneal permeation studies were conducted in rabbit corneas to compare the permeability of FA contained in NGs. Results: NGs presented a Ho of 312.4 ± 8.2 nm and a PdI of 0.28 ± 0.04. SEM imaging revealed spherical morphologies with minor variations in size and shape induced by FA. Lyophilized and resuspended NGs exhibited a 6.8% increase in Ho and a PdI rise to 0.42, indicating slight aggregation. In vitro drug release studies demonstrated sustained FA release, as determined by the Higuchi model. Mucoadhesion studies showed a decrease in ζ-potential from +36.9 to +18.1 mV, confirming electrostatic interactions with mucin. Ex vivo corneal permeation studies indicated that encapsulated FA permeated 2.6 times slower than free FA, suggesting sustained release. Conclusions: our findings demonstrate the potential of nanostructures in the form of NGs to enhance FA-loaded ocular delivery and bioavailability. Full article

Background Despite many studies on polymer-incorporated nanocarriers for ophthalmic drug delivery, few have thoroughly explored the relationship between coating composition and performance. This study aimed to evaluate the effects of three commonly used cationic polymers—distearoyl phosphatidylethanolamine-polyethylene glycol 1000-poly(amidoamine) (DSPE-PEG1000-PAMAM), trimethyl chitosan (TMC), and (2,3-dioleoyloxypropyl) trimethylammonium chloride (DOTAP)—on the corneal behaviors and anti-cataract efficacy of diosmetin (DIO)-loaded micelles (D-M-P, D-M-T, and D-M-D, respectively). Methods The DIO-loaded micelles were prepared using the thin-film dispersion method and incorporated with the three polymers through hydrophobic interactions and electrostatic adsorption. Structural characterization was demonstrated by TEM imaging and particle size analyzer. In vitro release behavior was detected by the dialysis method. Cell viability of D-M-P, D-M-T, and D-M-D on L929 cells was detected by CCK-8 assays, with cellular uptake performed using coumarin 6 as the fluorescence indicator. Precorneal retention behaviors of these three vesicles were observed by In Vivo Imaging System. Transcorneal permeability was determined by modified Franz diffusion method and the permeation routes of the vesicles are investigated. Selenite-induced cataract model was established. The anti-cataract effects of three different DIO-loaded micelles were evaluated by the observation of lens opacity and antioxidant enzyme activities. Eye Irritation of the DIO in different preparations was estimated using the Draize test, along with H&E staining of the corneas. Results Structural characterization of DIO-loaded micelles revealed that the vesicles were spherical, with a uniform size distribution of around 28 nm, a similar surface potential of approximately 6.0 mV, and a high DIO entrapment efficiency of about 95%. Compared to the DIO suspension, all three formulations exhibited a significant sustained-release effect. They showed no signs of irritation and demonstrated increased IC50 values in L929 cells, indicating improved biocompatibility. Cellular uptake in human lens epithelial cells (HLECs) was assessed using confocal laser scanning microscopy. C-M-T displayed the highest fluorescence signals, with a cellular internalization 3.2 times greater than that of the solution group. Both C-M-T and C-M-P enhanced vesicle retention on the corneal surface by at least 47.8% compared to the Cou-6 solution. Furthermore, TMC facilitated the paracellular transport of vesicles into the deepest layers of the cornea and delivered DIO across the cornea, with a P_app value 3.11 times and 1.49 times those of D-M-D and D-M-P, respectively. In terms of therapeutic efficacy, D-M-T demonstrated the most significant attenuation of lens opacity, along with enhanced antioxidant enzyme activities and inhibition of lipid peroxidation. Conclusion The modification of micelle vesicles with different cationic polymers significantly influences their performance in ocular drug delivery. Among the tested formulations, D-M-T stands out due to its multiple advantages, including enhanced transcorneal drug delivery, therapeutic efficacy for DIO, and safety, making it the most promising candidate for ophthalmic applications. Full article

Formulations designed to address ocular conditions and diseases are predominantly administered topically. While in vitro test systems have been developed to assess corneal permeation under extended contact conditions, methods focusing on determining the penetration depth and kinetics of a substance within the cornea itself rather than through it, are scarce. This study introduces a method for time-dependent penetration depth analysis (10 and 60 min) by means of a semiquantitative imaging method in comparison with a quantitative corneal depth-cut technique, employing fluorescein sodium at concentrations of 0.2 and 0.4 mg/mL as a small molecule model substance and sheep cornea as a human surrogate. Excised tissues exhibited sustained viability in modified artificial aqueous humor and maintained thickness (746 ± 43 µm) and integrity (electrical resistance 488 ± 218 Ω∙cm²) under the experimental conditions. Both methods effectively demonstrated the expected concentration- and time-dependent depth of penetration of fluorescein sodium, displaying a significantly strong correlation. The traceability of the kinetic processes was validated with polysorbate 80, which acted as a penetration enhancer. Furthermore, the imaging-based method enabled detecting the retention of larger structures, such as hyaluronic acid and nanoemulsions from the commercial eyedrop formulation NEOVIS^® TOTAL multi, inside the lacrimal layer. Full article

Rho-kinase (ROCK) inhibitors represent a new category of anti-glaucoma medications. Among them, Fasudil hydrochloride, a selective ROCK inhibitor, has demonstrated promising outcomes in glaucoma treatment. It works by inhibiting the ROCK pathway, which plays a crucial role in regulating the trabecular meshwork and canal of Schlemm’s aqueous humor outflow. This study aims to investigate the ocular absorption pathway of Fasudil hydrochloride and, subsequently, develop a nanoparticle-based delivery system for enhanced corneal absorption. Employing the ionic gelation method and statistical experimental design, the factors influencing chitosan nanoparticle (Cs NP) characteristics and performance were explored. Fasudil in vitro release and ex vivo permeation studies were performed, and Cs NP ocular tolerability and cytotoxicity on human lens epithelial cells were evaluated. Permeation studies on excised bovine eyes revealed significantly higher Fasudil permeation through the sclera compared to the cornea (370.0 μg/cm² vs. 96.8 μg/cm², respectively). The nanoparticle size (144.0 ± 15.6 nm to 835.9 ± 23.4 nm) and entrapment efficiency range achieved (17.2% to 41.4%) were predominantly influenced by chitosan quantity. Cs NPs showed a substantial improvement in the permeation of Fasudil via the cornea, along with slower release compared to the Fasudil aqueous solution. The results from the Hen’s Egg Test Chorioallantoic Membrane (HET-CAM) and Bovine Corneal Opacity and Permeability (BCOP) tests indicated good conjunctival and corneal biocompatibility of the formulated chitosan nanoparticles, respectively. Lens epithelial cells displayed excellent tolerance to low concentrations of these nanoparticles (>94% cell viability). To the best of our knowledge, this is the first report on the ocular absorption pathway of topically applied Fasudil hydrochloride where the cornea has been identified as a potential barrier that could be overcome using Cs NPs. Full article

Glaucoma is a progressive optic neuropathy characterized by a rise in the intraocular pressure (IOP) leading to optic nerve damage. Bimatoprost is a prostaglandin analogue used to reduce the elevated IOP in patients with glaucoma. The currently available dosage forms for Bimatoprost suffer from relatively low ocular bioavailability. The objective of this study was to fabricate and optimize solid lipid nanoparticles (SLNs) containing Bimatoprost for ocular administration for the management of glaucoma. Bimatoprost-loaded SLNs were fabricated by solvent evaporation/ultrasonication technique. Glyceryl Monostearate (GMS) was adopted as solid lipid and poloxamer 407 as surfactant. Optimization of SLNs was conducted by central composite design. The optimized formulation was assessed for average particle size, entrapment efficiency (%), zeta potential, surface morphology, drug release study, sterility test, isotonicity test, Hen’s egg test-chorioallantoic membrane (HET-CAM) test and histopathology studies. The optimized Bimatoprost-loaded SLNs formulation had an average size of 183.3 ± 13.3 nm, zeta potential of −9.96 ± 1.2 mV, and encapsulation efficiency percentage of 71.8 ± 1.1%. Transmission electron microscopy (TEM) study revealed the nearly smooth surface of formulated particles with a nano-scale size range. In addition, SLNs significantly sustained Bimatoprost release for up to 12 h, compared to free drug (p < 005). Most importantly, HET-CAM test nullified the irritancy of the formulation was verified its tolerability upon ocular use, as manifested by a significant reduction in mean irritation score, compared to positive control (1% sodium dodecyl sulfate; p < 0.001). Histopathology study inferred the absence of any signs of cornea tissue damage upon treatment with Bimatoprost optimized formulation. Collectively, it was concluded that SLNs might represent a viable vehicle for enhancing the corneal permeation and ocular bioavailability of Bimatoprost for the management of glaucoma. Full article

Innovative hybrid chitosan–sodium alginate (Ch–Ag) microparticles (MPs) were fabricated using both the ionic gelation method as well as the pre-gelation technique. The hybrid Ch–Ag MPs were studied for size, zeta potential, morphology, mucoadhesion, in-vitro release, corneal permeation, and ocular irritation using lens and corneal epithelial cell lines. The average particle size ranged from 1322 nm to 396 nm. The zeta potential for the prepared formulations showed an increase with increasing Ch concentrations up to a value of >35 mV; the polydispersity index (PDI) of some optimized MPs was around 0.1. Compared to drug-free MPs, ketorolac-loaded Ch–Ag MPs demonstrated a drug proportion-dependent increase in their size. SEM, as well as TEM of KT-loaded MPs, confirmed that the formed particles were quasi-spherical to elliptical in shape. The KT release from the MPs demonstrated a prolonged release profile in comparison to the control KT solution. Further, mucoadhesion studies with porcine mucin revealed that the KT-loaded MPs had effective mucoadhesive properties, and polymeric particles were stable in the presence of mucin. Corneal permeation was studied on bovine eyes, and the results revealed that Ch-based MPs were capable of showing more sustained KT release across the cornea compared with that for the control drug solution. Conclusively, the cytotoxicity assay confirmed that the investigated MPs were non-irritant and could confer protection from direct drug irritation of KT on the ocular surface. The MTT cytotoxicity assay confirmed that KT-loaded MPs showed acceptable and reasonable tolerability with both human lens and corneal epithelial cell lines compared to the control samples. Full article

Fungal keratitis causes corneal blindness worldwide. The treatment includes antibiotics, with Natamycin being the most commonly used; however, fungal keratitis is difficult to treat, so alternative therapies are needed. In situ gelling formulations are a promising alternative; this type of formulation has the advantages of eye drops combined with the advantages of ointments. This study was designed to develop and characterize three formulations containing 0.5% CSP: CSP-O1, CSP-O2, and CSP-O3. CSP is an antifungal drug that acts against a diverse variety of fungi, and Poloxamer 407 (P407) is a polymer of synthetic origin that is able to produce biocompatible, biodegradable, highly permeable gels and is known to be thermoreversible. Short-term stability showed that formulations are best stored at 4 °C, and rheological analysis showed that the only formulation able to gel in situ was CSP-O3. In vitro release studies indicated that CSP-O1 releases CSP most rapidly, while in vitro permeation studies showed that CSP-O3 permeated the most. The ocular tolerance study showed that none of the formulations caused eye irritation. However, CSP-O1 decreased the cornea’s transparency. Histological results indicate that the formulations are suitable for use, with the exception of CSP-O3, which induced slight structural changes in the scleral structure. All formulations were shown to have antifungal activity. In view of the results obtained, these formulations could be promising candidates for use in the treatment of fungal keratitis. Full article

The aim of this work was to develop niosomes for the ocular delivery of epalrestat, a drug that inhibits the polyol pathway and protects diabetic eyes from damage linked to sorbitol production and accumulation. Cationic niosomes were made using polysorbate 60, cholesterol, and 1,2-di-O-octadecenyl-3-trimethylammonium propane. The niosomes were characterized using dynamic light scattering, zeta-potential, and transmission electron microscopy to determine their size (80 nm; polydispersity index 0.3 to 0.5), charge (−23 to +40 mV), and shape (spherical). The encapsulation efficiency (99.76%) and the release (75% drug release over 20 days) were measured with dialysis. The ocular irritability potential (non-irritating) was measured using the Hen’s Egg Test on the Chorioallantoic Membrane model, and the blood glucose levels (on par with positive control) were measured using the gluc-HET model. The toxicity of the niosomes (non-toxic) was monitored using a zebrafish embryo model. Finally, corneal and scleral permeation was assessed with the help of Franz diffusion cells and confirmed with Raman spectroscopy. Niosomal permeation was higher than an unencapsulated drug in the sclera, and accumulation in tissues was confirmed with Raman. The prepared niosomes show promise to encapsulate and carry epalrestat through the eye to meet the need for controlled drug systems to treat the diabetic eye. Full article