Ocular Delivery Research Articles

Development of ion-triggered in situ gel containing ketoconazole/hydroxypropyl-β-cyclodextrin for ocular delivery: in vitro and in vivo evaluation

The application of ketoconazole (KET) in ocular drug delivery is restricted by its poor aqueous solubility though its broad-spectrum antifungal activity. The aim of this study is to develop an ion-sensitive in situ gel (ISG) of KET to promote its ocular bioavailability in topical application. The solubility of KET in water was increased by complexation with hydroxypropyl-β-cyclodextrin (HPβCD), then KET-HPβCD inclusion complex (KET-IC) was fabricated into an ion-sensitive ISG triggered by sodium alginate (SA). The in vitro drug release and antifungal activities investigations demonstrated that the KET-IC-ISG formulation increased drug release and anti-fungal activities compared to pure KET. The ex vivo rabbit corneal permeation studied demonstrated higher permeability of KET-IC-ISG formulation (Papp of (6.34 ± 0.21) × 10−4 cm/h) than pure KET (Papp of (3.09 ± 0.09) × 10−4 cm/h). The cytotoxicity assay and the ocular irritation study in rabbits confirmed the KET-IC-ISG safety and well tolerance. The ocular pharmacokinetics of KET in rabbits was investigated and the results showed that the KET-IC-ISG increased its bioavailability in cornea by 47-fold. In conclusion, the KET-IC-ISG system promoted the precorneal retention, the ocular drug bioavailability and the developed formulation is a potential strategy to treat mycotic keratitis.

Development of puerarin-loaded poly(lactic acid) microspheres for sustained ocular delivery: In vitro/vivo evaluation

Diabetic retinopathy, an ocular complication of diabetes, is an important cause of blindness in adults. Puerarin is considered to have promising potential for clinical use in treating diabetic retinopathy. In this study, we designed a novel puerarin-loaded poly(lactic acid) sustained-release microspheres suitable for ocular administration, and we assessed itsin vitro and in vivo properties. The preparation of puerarin-loaded microspheres was optimized by Box-Behnken response surface design. The encapsulation efficiency and drug loading of microspheres were 35.71% and 3.85%, respectively. The microspheres exhibited good dispersion and high safety, making it suitable for ocular drug delivery. In vitro release demonstrated that microspheres had a well-sustained release effectiveness, and its release behavior complied with the zero-order kinetic characteristics. The results of ocular tissue distribution revealed that the CmaxandAUC0-∞ of the microspheres group in the retina and choroid were considerably higher than those of the solution group and the intravenous injection group. This research revealed that intravitreal injection of microspheres can significantly prolong the half-life of puerarin in eye tissues and achieve sustained drug release. Therefore, intravitreal injection of microspheres has positive implications for the treatment of diabetic retinopathy.

Preparation of a thermosensitive and antibacterial in situ gel using poloxamer-quaternized chitosan for sustained ocular delivery of Levofloxacin hydrochloride

In this study, a thermosensitive in situ gel with porous structure was developed using poloxamer (Po) and N-(2-hydroxy-3-trimethyl ammonium) propyl chitosan chloride (HTCC). The poloxamer-quaternized chitosan (Po-HTCC) in situ gel exhibited superior rheological property, water absorption capacity and antibacterial activity against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Streptococcus pyogenes, making it well-suited for ocular applications. Scanning electron microscope revealed a macroporous architecture with pore sizes ranging from 1 to 2 μm, suggesting that the gel has desirable breathability, corneal adhesion capability, and overall conformability. In vitro drug release assay was conducted with levofloxacin hydrochloride, demonstrating that sustained release over 48 h could be achieved at 34 °C, with approximately 80 % of the drug released within this timeframe. Computational simulations revealed substantial binding affinity between the material and the Escherichia coli outer membrane lipopolysaccharide-associated protein and corneal mucin. The protein showing the strongest binding energy to N-(2-hydroxy-3-trimethyl ammonium) propyl chitosan chloride (HTCC), as calculated by the Molecular Mechanics Generalized Born Surface Area Method (MM-GBSA), was LptD-LptE, with a binding energy of −61.14 ± 4.72 kcal/mol. These results underscore the potential of this system for effective and convenient ocular delivery with sustained drug release.

In Situ Gelling Eye Drops of Tacrolimus with Improved Ocular Delivery and Therapeutic Efficacy.

In situ gelling eye drops of tacrolimus (FK506 Gel) were developed to address the formulation challenge of tacrolimus for anterior ocular inflammatory diseases. Both in silico and in vitro investigations were conducted to screen a suitable cyclodextrin species to increase the drug solubility. Guanosine was employed as the gelator and combined with inclusion complexes of tacrolimus in the presence of borate anions to obtain FK506 Gel, which gelated when came into contact with cations in tear fluid and led to the formation of a nanofibrous hydrogel. The versatility of our design to improve the solubility and ocular retention of the hydrophobic drug was demonstrated in vivo with coumarin 6 as a model drug. A mouse dry eye model was used to evaluate the therapeutic effects of FK506 Gel, which, in combination with the biocompatibility study, suggested that FK506 Gel served as a superior treatment for anterior ocular inflammatory diseases.

Fluconazole-loaded Hyaluronic Acid-modified Transfersomal Hydrogels Containing D-panthenol for Ocular Delivery in Fungal Keratitis Management.

Fungal keratitis (mycotic keratitis) is an eye infection in which the cornea is infected by fungi and such fungal keratitis management can be effectively possible by ocular administration of antifungal drugs. The main objectives of the present research were to develop and evaluate fluconazoleloaded transfersomal hydrogels for ocular delivery in the effective management of fungal keratitis. A 23 factorial design-based approach was used for statistical optimization, where (A) the ratio of lipid to edge activators, (B) the amount of hyaluronic acid (% HA), and (C) the ratio of edge activators (sodium deoxycholate to Span 80) were taken as three factors. The average vesicle diameter (Z, nm) of transfersomes was taken as a response. Further, fluconazole-loaded transfersomes (FTO) were incorporated into 1% Carbopol 940-based hydrogel (OF1) and 2% HMPC K4M-based hydrogel (OF2) containing D-panthenol (5% w/w). The optimal variable setting for the optimized formulations of FTO was (A) = 9.15, (B) = 0.30%, and (C) = 3.00. FTO exhibited 66.39 nm Z, 0.247 polydispersity index, - 33.10 mV zeta potential, and 65.38 ± 1.77 % DEE, and desirable elasticity. TEM image of FTO demonstrated a unilamellar vesicular structure. The ex vivo ocular permeation of fluconazole from transfersomal hydrogels was sustained over 24 h. All the transfersomal hydrogels showed good bioadhesion and excellent antifungal activity with respect to the zone of inhibition against Candida albicans than Aspergillus fumigates, in vitro. HET-CAM study results demonstrated that both the hydrogels were nonirritant and safe for ocular. Short-term physical stability study suggested the stability of the developed formulation. The current research demonstrated a new way to enhance the ocular penetration of fluconazole via transfersomal hydrogel formulations for ocular delivery in the effective management of fungal keratitis.

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.

Development and evaluation of locust bean gum based in situ gel for ocular delivery of ofloxacin for treatment of bacterial keratitis

One of the drawbacks of conventional ocular dosage forms is their short residence time in the eye. To address this, we propose an ocular in situ gel that adheres to the eye surface for a prolonged period. Locust bean gum (LBG), a galactomannan polysaccharide, exhibits the desired characteristics to serve as a drug carrier for ocular application. However, the gum has not yet been investigated for ocular drug delivery. In this work, we have developed an LBG based in situ gel loaded with ofloxacin and evaluated its drug delivery efficacy through in vitro and ex vivo tests. To confer temperature sensitivity, LBG was grafted with N-isopropyl acrylamide (NIPAAm), and a series of solutions were made with ofloxacin (0.03 % w/v). The solution turned into a gel when the temperature was raised to 37 °C. The safety and efficacy of the developed in situ gels were validated through experiments on rat eyes infected with clinical strains of bacteria. The developed keratitis was completely healed indicating that the grafted LBG can be used as a potential candidate for the development of ocular in situ gel.

Role of Natural Polymers in Novel Drug Delivery Systems

Natural polymers have gained significant attention in the field of drug delivery due to their inherent biocompatibility, biodegradability, and low toxicity. This review article aims to provide a comprehensive overview of the diverse roles that natural polymers play in the development of novel drug delivery systems. Beginning with a classification of natural polymers based on their origin (plant, animal, microbial), we explore their unique characteristics and advantages over synthetic counterparts. The review discusses the pivotal role of natural polymers in formulating various drug delivery systems, including sustained/controlled release formulations, targeted delivery platforms, mucoadhesive systems, and nanotechnology-based approaches. Techniques such as emulsification, ionotropic gelation, coacervation, and electrospinning for natural polymer-based drug delivery are elucidated, highlighting their versatility and applicability across different administration routes. Furthermore, we delve into the diverse applications of natural polymers in drug delivery, encompassing oral, transdermal, ocular, injectable, nasal, buccal, and vaginal delivery routes. Recent advances and innovations in combining natural polymers with synthetic counterparts, incorporating stimuli-responsive properties, and personalized medicine approaches are also explored. Despite the numerous advantages offered by natural polymers, challenges such as variability in polymer properties, standardization issues, scale-up challenges, and regulatory considerations are discussed. The review concludes with future perspectives, highlighting emerging trends and opportunities for further research and development in the field of natural polymer-based drug delivery systems. Overall, this review provides valuable insights into the pivotal role of natural polymers in advancing drug delivery technology, paving the way for safer, more efficient, and patient-friendly therapeutic interventions.

Development of transferosomes for topical ocular drug delivery of curcumin

BackgroundTransferosomes (TFS) are ultra-deformable elastic bilayer vesicles that have previously been used to enhance gradient driven penetration through the skin. This study aimed to evaluate the potential of TFS for topical ocular drug delivery and to compare their penetration enhancing properties in different ocular tissues. MethodsCurcumin-loaded TFS were prepared using Tween 80 as the edge activator. Drug release and precorneal retention of the TFS were evaluated in vitro, while their ocular biocompatibility and bioavailability were evaluated ex vivo using a curcumin solution in medium chain triglycerides as the oily control. ResultsThe TFS had a narrow size distribution with a particle size less than 150 nm and an entrapment efficiency greater than 99.96 %. Burst release from the TFS was minimal and the formulation showed good corneal biocompatibility. Moreover, enhanced corneal and conjunctival drug penetration with significantly greater and deeper drug delivery was observed with TFS. ConclusionTFS offer a promising platform for ocular delivery of hydrophobic drugs. This study, for the first time, elucidates the effect of tissue morphology and osmotic gradients on drug penetration in different ocular tissues.

Design, pharmacokinetic, and pharmacodynamic evaluation of a lecithin-chitosan hybrid nanoparticle-loaded dual-responsive in situ gel of nebivolol for effective treatment of glaucoma

In this research work, optimized nebivolol-loaded lecithin-chitosan hybrid nanoparticles (NEB-LCNPs) were prepared using sequential screening and optimization designs. The design of experiments software (DoE) was used to obtain a robust formulation that can improve ocular delivery of the NEB in the treatment of glaucoma. The optimized NEB-LCNPs had a mean particle size of 170.5 ± 5.3 nm and drug loading of 10.5 ± 1.2%. These were further loaded in a dual-responsive in situ gel, designed and reported previously by our group. The NEB-LCNPs loaded in situ gel (NEB-LCNPs-ISG) was characterized for physicochemical properties, rheological behavior, stability, in vitro dissolution, and ocular in vivo studies. The ocular pharmacokinetics showed that NEB-LCNPs-ISG had two-fold higher aqueous humor exposure with AUC0–tlast of 375.4 ng × h/mL and sustained drug concentrations for longer durations (1.7-folds higher duration with a mean residence time of 10.6 h) in comparison to a conventional aqueous suspension of NEB (NEB-Susp). Similarly, the pharmacodynamic study showed that NEB-LCNPs-ISG resulted in a higher percentage reduction in intraocular pressure (% ΔIOP) of 28.1 ± 1.8% × h, which was 2.2-times higher reduction compared to NEB-Susp (74.2 ± 3.2% × h). In addition, the pharmacodynamic effect was more sustained with a mean response time of 11.3 ± 0.2 h, a 2.8-times higher response time compared to NEB-Susp (4.06 ± 0.3 h). These results suggest that NEB-LCNPs-ISG was more effective than the conventional aqueous suspension of NEB in the treatment of glaucoma.

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.

Exploring Hydrogel Nanoparticle Systems for Enhanced Ocular Drug Delivery.

Drug delivery to the ocular system is affected by anatomical factors like the corneal epithelium, blinking reflex, aqueous blood barrier, and retinal blood barrier, which lead to quick removal from the site and inefficient drug delivery. Developing a drug delivery mechanism that targets specific eye tissue is a major hurdle for researchers. Our study examines the challenges of drug absorption in these pathways. Hydrogels have been researched as a suitable delivery method to overcome some obstacles. These are developed alone or in conjunction with other technologies, such as nanoparticles. Many polymer hydrogel nanoparticle systems utilizing both natural and synthetic polymers have been created and investigated; each has pros and cons. The complex release mechanism of encapsulated agents from hydrogel nanoparticles depends on three key factors: hydrogel matrix swelling, drug-matrix chemical interactions, and drug diffusion. This mechanism exists regardless of the type of polymer. This study provides an overview of the classification of hydrogels, release mechanisms, and the role of controlled release systems in pharmaceutical applications. Additionally, it highlights the integration of nanotechnology in ocular disease therapy, focusing on different types of nanoparticles, including nanosuspensions, nanoemulsions, and pharmaceutical nanoparticles. Finally, the review discusses current commercial formulations for ocular drug delivery and recent advancements in non-invasive techniques. The objective is to present a comprehensive overview of the possibilities for enhancing ocular medication delivery through hydrogel nanoparticle systems.

Macrolide-loaded nanofibrous inserts with polycaprolactone and cellulose acetate base for sustained ocular delivery: Pharmacokinetic study in Rabbit’s eye

The present study aimed to prepare nanofibrous inserts for sustained ocular drug delivery of Azithromycin (AZM) toward conquering the obstacles of conventional topical drug delivery. Nanofibers were fabricated by electrospinning using polycaprolactone (PCL) and cellulose acetate (CA) which are biocompatible and biodegradable polymers. Prepared nanofibers were evaluated in terms of physicochemical, morphological properties, pharmacokinetic study and ocular irritation. SEM images revealed average diameters of about 160 nm and 190 nm for CA and PCL nanofibers, respectively. These ocular drug delivery systems were strong, flexible, and stable under humid and dry conditions. Quantification was performed using microbiological assay by M. luteus as a microorganism. While PCL-based nanofibrous inserts released AZM in a two-step manner initiated by a burst release via Peppas kinetical model, CA-based inserts showed a gradual release profile without any burst release which followed the first-order model. Results showed that these inserts were non-cytotoxic and non-irritating. The nanofibers showed antibacterial efficacy against Escherichia coli and Staphylococcus aureus. In addition, according to a pharmacokinetic study in Rabbit’s Eye, a higher Cmax and lower Tmax were achieved by PCL nanofibers compared to CA-based ones. The pharmacokinetic study of nanofibers in rabbit eyes showed that all formulations were able to maintain the effective concentration of AZM for about 6 days. In conclusion, the prepared nanofibers can be effectively utilized for prolonged ocular delivery of AZM in the treatment of conjunctival infections.

Flurbiprofen-encapsulated microsphere laden into heat-triggered situ gel for ocular delivery

Flurbiprofen-encapsulated microsphere laden into heat-triggered situ gel for ocular delivery

Impact of nursing interventions on the prevention of ocular surface disorders in critical care patients: A systematic review.

Intensive care unit (ICU) patients are at an increased risk of ocular surface injuries because of various factors such as reduced tear production and impaired protective mechanisms. Despite the significance of ocular care in ICU settings, there is a lack of consensus on effective interventions, leading to inadequate prevention of ocular surface disease (OSD). This systematic review aimed to assess the effectiveness of nursing eye care in preventing OSD in ICU patients. Secondary objectives included identifying primary risk factors for ocular injuries and examining the most effective preventive methods. A systematic review following PRISMA guidelines was conducted, encompassing a literature search, article selection, quality assessment and data synthesis. Studies meeting inclusion criteria were observational studies and clinical trials, focusing on adults admitted to ICUs under sedation and receiving mechanical ventilation. Of 3545 initially identified articles, 12 studies met inclusion criteria. These studies involved a total of 1853 participants. Various interventions were assessed, including saline rinsing, lubricating drops, gel lubricants, occlusion with polyethylene dressing, passive blinking and eyelid closure with tape. Moist chamber occlusion every 6 h combined with gel lubrication emerged as the most effective method in preventing OSD. Gel lubrication along with moist chamber occlusion proved to be the most effective strategy in preventing ocular injuries in ICU patients. Conversely, the routine use of physiological saline was associated with increased severity of corneal lesions. Properly defined protocols and well-trained nursing teams are crucial for reducing ocular injuries in ICU settings. The findings underscore the importance of implementing evidence-based eye care protocols in ICUs, emphasizing the use of gel lubrication and ocular surface protection to mitigate the risk of OSD. This highlights the need for comprehensive training programmes for ICU nursing staff to ensure optimal ocular care delivery.

Development of Contact Lenses Loaded Thiolated Nanoparticles for Ocular Delivery of Tobramycin

Development of Contact Lenses Loaded Thiolated Nanoparticles for Ocular Delivery of Tobramycin

Polymeric Mixed Micelle-Loaded Hydrogel for the Ocular Delivery of Fexofenadine for Treating Allergic Conjunctivitis.

This study was designed to formulate a polymeric mixed micelle (PMM) formulation to sustainably release fexofenadine (FEX) to treat allergic conjunctivitis effectively. A 32 factorial design was employed where the studied factors were PL90G amount (X1) and Pluronic (F127 and P123) mixture ratio (X2), and the dependent variables were entrapment efficacy (EE, Y1, %), particle size (PS, Y2, nm), zeta potential (ZP, Y3, mV), and the percent of drug released after 6 h (Q6h, Y4, %). The optimized formula was blended with a hydrogel base to develop an FEX-PMM hydrogel, where the safety and efficiency of this hydrogel were evaluated using in vivo studies. The EE% of FEX-PMM ranged from 62.15 ± 2.75 to 90.25 ± 1.48%, the PS from 291.35 ± 6.43 to 467.95 ± 3.60 nm, the ZP from -5.41 ± 0.12 to -9.23 ± 0.23 mV, and the Q6h from 50.27 ± 1.11 to 95.38 ± 0.92%. The Draize test results confirmed the safety of the FEX-PMM hydrogel. Furthermore, the FEX-PMM hydrogel showed rapid recovery in animals with induced allergic conjunctivitis compared to the free drug hydrogel. These results assure PMM's capability to deliver FEX to the conjunctival surface in a sustained pattern, consequently achieving better therapeutic outcomes.

Efflux transporter inhibitory (EXTRIN) micelles for enhanced ocular drug delivery

Efflux transporters such as P-glycoprotein (P-gp) and Multidrug resistance proteins-2 (MRP-2) are often highly expressed on cornea and conjunctiva, significantly restricting the absorption of topically administered drugs into the eye. We hypothesized that nanocarrier with P-gp and MRP-2 inhibitory activity may enhance drug permeation across the cornea. Due to ease in development and scale-up, a lipidic nanocarrier was proposed and therefore lipids and surfactants were screened for P-gp and MRP-2 modulation using erythromycin (Ery), a known substrate for both P-gp and MRP-2 as model drug and freshly excised goat cornea as membrane. Out of the studied lipids/surfactants, Peceol and Pluronic F127 showed maximum inhibitory effects against P-gp and MRP-2 and were used to develop efflux transporter inhibitory micelles (EXTRIN-micelles). Dynamic laser scattering showed that EXTRIN-micelles were 348 ± 14.5 nm with PDI <0.09. Preclinical studies in rabbits demonstrated significantly higher (p < 0.05) corneal retention of EXTRIN-micelles compared to solution. Further, EXTRIN-micelles delivered significantly higher (p < 0.001) Ery concentrations to aqueous humor compared to solution. In conclusion, EXTRIN-micelles are potential carriers for enhanced ocular delivery of drugs.

Development of ocular delivery systems for macitentan and ex vivo study of intraocular permeation

Macitentan is a drug that acts as a non-selective antagonist of endothelin receptors. It has been officially approved for the treatment of cases of pulmonary arterial hypertension. There are studies in animal models that indicate a therapeutic potential for this drug in the treatment of glaucoma, a degenerative eye disease marked by a progressive reduction in the visual field that can progress to irreversible blindness. In the present work, ophthalmic formulations of macitentan were developed with the aim of evaluating their potential to deliver the active ingredient to therapeutically relevant sites. An HPLC-DAD method was adapted from the literature and validated to quantify macitentan in each step. Physicochemical characterization studies of the formulations were performed, and a Franz vertical diffusion cell was used in an analysis of the in vitro/ex vivo permeation using cornea and sclera of porcine eyes to represent biological membranes. The developed formulations presented different permeation profiles according to the presence or absence of water in the base formulation and the type of viscosity promoting agent used. The formulations that showed the highest percentage of permeation were evaluated for mucus adhesiveness and the most promising were further analyzed for stability that included measuring drug content, pH, and viscosity. One formulation was developed for the ocular release of macitentan with a high percentage of drug permeation, adequate viscosity and stability that could represent an advancement in the treatment of glaucoma with a high potential for patient adherence.

A novel liposomal formulation for ocular delivery of caspofungin: an experimental study by quality by design-based approach.

Aim: This study focuses on the development of a Caspofungin liposome for efficient ocular delivery by enhancing corneal penetration.Method: Quality by design (QbD) approach was adopted to identify critical factors that influence final liposomal formulation. The liposome developed using thin film hydration after optimization was subjected to characterization for physicochemical properties, irritation potential and corneal uptake.Results: The numerical optimization suggests an optimal formulation with a desirability value of 0.706, using CQAs as optimization goals with 95% prediction intervals. The optimized formulation showed no signs of irritation potential along with observation of significant corneal permeation.Conclusion: The liposomal formulation increased the permeability of Caspofungin, which could enhance the efficacy for the treatment of conditions, like fungal keratitis.