Scleral PERK and ATF6 as targets of myopic axial elongation of mouse eyes.

Axial length is the primary determinant of eye size, and it is elongated in myopia. However, the underlying mechanism of the onset and progression of axial elongation remain unclear. Here, we show that endoplasmic reticulum (ER) stress in sclera is an essential regulator of axial elongation in myopia development through activation of both PERK and ATF6 axis followed by scleral collagen remodeling. Mice with lens-induced myopia (LIM) showed ER stress in sclera. Pharmacological interventions for ER stress could induce or inhibit myopia progression. LIM activated all IRE1, PERK and ATF6 axis, and pharmacological inhibition of both PERK and ATF6 suppressed myopia progression, which was confirmed by knocking down above two genes via CRISPR/Cas9 system. LIM dramatically changed the expression of scleral collagen genes responsible for ER stress. Furthermore, collagen fiber thinning and expression of dysregulated collagens in LIM were ameliorated by 4-PBA administration. We demonstrate that scleral ER stress and PERK/ATF6 pathway controls axial elongation during the myopia development in vivo model and 4-PBA eye drop is promising drug for myopia suppression/treatment.

Effects of PPAR-γ and RXR-α on mouse meibomian gland epithelial cells during inflammation induced by latanoprost.

The purpose of this study is to investigate the effects of latanoprost on the secretion of cytokines and chemokines from meibomian gland epithelial cells, and to evaluate the modulation of peroxisome proliferator-activated receptor γ (PPAR-γ) and retinoid X receptor α (RXR-α) during latanoprost-induced inflammation. Mouse meibomian gland epithelial cells were cultured in proliferation and differentiation medium, respectively. Cells were exposed to latanoprost, rosiglitazone (PPAR-γ agonist), or LG100268 (RXR-α agonist), respectively. The expression of IL-6, IL-1ß, TNF-α, MMP-9, MCP-1, and CCL-5 were detected by real-time PCR and ELISA. The effect of latanoprost, rosiglitazone, LG100268, and inflammatory cytokines on the differentiation of meibocyte were evaluated by related gene expression and lipid staining. The expression of Keratin-1, 6, 17 protein was detected by western immunoblotting. The results showed that the above cytokines could be induced by latanoprost in meibomian gland epithelial cells. LG100268 and rosiglitazone could inhibit the production of IL-6 and TNF-α induced by latanoprost, respectively. Latanoprost suppressed the expression of differentiation-related mRNA through a positive feedback loop by enhancement of COX-2 expression via FP receptor-activated ERK signaling. The expression of Keratin-17 was upregulated by rosiglitazone and suppressed by LG100268. The application of IL-6 and TNF-α showed negative effects on lipid accumulation in meibomian gland epithelial cells. These results demonstrated that latanoprost could induce inflammation and suppress differentiation of mouse meibomian gland epithelial cells. The activation of PPAR-γ and RXR-α showed an anti-inflammatory effect, showing a potential role to antagonize the effect of latanoprost eyedrops on meibomian gland epithelial cells.

Epac1 and PKA regulate of P2X7 and NLRP3 inflammasome proteins in the retinal vasculature.

Others have shown that the purinergic 2X7 receptor (P2X7R) and the NOD-like receptor family protein 3 (NLRP3) inflammasome are involved in multiple inflammatory diseases. In this study, we tested whether Epac1 and PKA lie upstream of P2X7R actions on the NLRP3 inflammasome. We also evaluated whether eye drops of a P2X7R inhibitor protected the retina against ischemia/reperfusion (I/R) injury by measuring retinal thickness and degenerate capillary formation after exposure to I/R and treatment with A438079 eye drops. Mice were exposed to the I/R model followed by eye drops of A438079 for 2 or 10 days. Additionally, primary human retinal endothelial cells (REC) grown in normal and high glucose were treated with ATP (to stimulate P2X7R), an Epac1 agonist, or forskolin (to stimulate PKA), followed by measurements of P2X7R and NLRP3 inflammasome proteins. Eye drops containing A438079 protected the retina against neuronal and vascular damage after exposure to I/R. When REC were treated with ATP to stimulate P2X7R, NLRP3 inflammasome proteins were all increased compared to high glucose only. Epac1 and PKA agonists reduced P2X7R levels in REC grown in high glucose. In conclusion, these data suggest that P2X7 regulates retinal responses to the I/R stress, and that P2X7 increases NLRP3 inflammasome proteins in human REC. Epac1 and PKA can inhibit of P2X7, which will reduce NLRP3 inflammasome proteins in REC grown in high glucose.

Progress in the use of plasma rich in growth factors in ophthalmology: from ocular surface to ocular fundus.

INTRODUCTION: The use of blood derivatives and especially Plasma rich in growth factors (PRGF), for regenerative purposes has been a common trend along the last decades in the field of oral surgery, dermatology, orthopedics, and more recently in ophthalmology. AREAS COVERED: PRGF is a type of platelet-rich plasma that is being explored for the treatment of ocular injuries. The present review article highlights 50 ophthalmology-related publications about the application of PRGF in the treatment of acute and chronic pathologies in ophthalmology as well as most relevant challenges and future prospects. EXPERT OPINION: PRGF technology provides a wide range of formulations that can be used therapeutically in many different acute and chronic ocular pathologies. In addition to eye drops enriched with autologous growth factors, PRGF enables the preparation of both immunologically safe and fibrin-based formulations. Recent advances in the field have promoted PRGF storage for 12 months under freezing conditions, its daily use for 7 days at room temperature and the freeze-dried formulation. The thermally treated immunosafe formulation has shown promising clinical results for the treatment of several diseases such as Sjögren syndrome, graft versus host disease or cicatrizing conjunctivitis. In addition, several fibrin formulations have been preclinically evaluated and clinically incorporated as an adjuvant to ocular surface or glaucoma surgeries, dermal fat graft procedures, limbal stem cell expansion and retinal surgeries. The present review explores the latest scientific and clinical data, current challenges, and main prospects of this technology for the treatment of several ocular injuries.

An Overview of Advanced In Vitro Corneal Models: Implications for Pharmacological Testing.

The cornea is an important barrier to consider when developing ophthalmic formulations, but proper modeling of this multilayered tissue remains a challenge. This is due to the varying properties associated with each layer in addition to the dynamics of the tear film. Hence, the most representative models to date rely on animals. Animal models, however, differ from humans in several aspects and are subject to ethical limitations. Consequently, in vitro approaches are being developed to address these issues. This review focuses on the barrier properties of the cornea and evaluates the most advanced three-dimensional cultures of human corneal equivalents in literature. Their application potential is subsequently assessed and discussed in the context of preclinical testing along with our perspective toward the future. Impact statement Most ocular drugs are applied topically, with the transcorneal pathway as the main administration route. Animal corneas are currently the only advanced models available, contributing to the drug attrition rate. Anatomical and physiological interspecies differences might account for a poor translatability of preclinical results to clinical trials, urging researchers to devise better corneal equivalents. This review elaborates on the emerging generation of three-dimensional in vitro models, which comprises spheroids, organoids, and organs-on-chips, which can serve as a stepping stone for advancements in this field.

A hypotonic gel-forming eye drop provides enhanced intraocular delivery of a kinase inhibitor with melanin-binding properties for sustained protection of retinal ganglion cells.

While eye drops are the most common ocular dosage form, eye drops for treating diseases of the posterior segment (retina, choroid, optic nerve) have yet to be developed. In glaucoma, eye drops are used extensively for delivering intraocular pressure (IOP)-lowering medications to the anterior segment. However, degeneration of retinal ganglion cells (RGCs) in the retina may progress despite significant IOP lowering, suggesting that a complementary neuroprotective therapy would improve glaucoma management. Here, we describe a hypotonic, thermosensitive gel-forming eye drop for effective delivery of sunitinib, a protein kinase inhibitor with activity against the neuroprotective targets dual leucine zipper kinase (DLK) and leucine zipper kinase (LZK), to enhance survival of RGCs after optic nerve injury. Further, binding of sunitinib to melanin in the pigmented cells in the choroid and retinal pigment epithelium (RPE) led to prolonged intraocular residence time, including therapeutically relevant concentrations in the non-pigmented retinal tissue where the RGCs reside. The combination of enhanced intraocular absorption provided by the gel-forming eye drop vehicle and the intrinsic melanin binding properties of sunitinib led to significant protection of RGCs with only once weekly eye drop dosing. For a chronic disease such as glaucoma, an effective once weekly eye drop for neuroprotection could result in greater patient adherence, and thus, greater disease management and improved patient quality of life.

Ocular Distribution of Papaverine Using Non-aqueous Vehicles.

Papaverine, a poorly soluble opium alkaloid, has recently been shown to reduce retinal inflammation due to which it may have therapeutic application in the management of Leber's hereditary optic neuropathy. In this study, papaverine eyedrops based on medium chain triglycerides were prepared and the effect of diethyl glycol monoethyl ether (DGME) on their ocular distribution was evaluated using an ex vivo porcine eye model. The route of drug penetration was also studied by orienting the eye to expose either only the cornea or the sclera to the formulation. Furthermore, in vivo studies were performed to confirm ocular tolerability and evaluate ocular drug distribution. Our results showed increased papaverine concentrations in the cornea and sclera in the presence of DGME but with a slight reduction in the retina-choroid (RC) drug concentration when administered via the corneal route, suggesting that DGME enhances drug accumulation in the anterior ocular tissues but with little effect on posterior drug delivery. In vivo, the papaverine eyedrop with DGME showed good ocular tolerability with the highest drug concentration being observed in the cornea (1.53 ± 0.28 µg/g of tissue), followed by the conjunctiva (0.74 ± 0.18 µg/g) and sclera (0.25 ± 0.06 µg/g), respectively. However, no drug was detected in the RC, vitreous humor or plasma. Overall, this study highlighted that DGME influences ocular distribution and accumulation of papaverine. Moreover, results suggest that for hydrophobic drugs dissolved in hydrophobic non-aqueous vehicles, transcorneal penetration via the transuveal pathway may be the predominant route for drug penetration to posterior ocular tissues. Graphical abstract.

Autologous serum eye drops improve tear production, both lachrymal flow and stability tests and conjunctival impression cytology with transfer in dry eye disease.

BACKGROUND: Autologous serum eye drops, produced by separation of liquid and cellular components of the patient's blood, contain biological nutrients present in natural tears. The aim of this study was to analyse changes in conjunctival impression cytology with transfer and both lachrymal stability and flow tests in patients with dry eye disease after treatment with autologous serum eye drops. MATERIALS AND METHODS: Conjunctival impression cytology and lachrymal flow and stability tests, namely Schirmer's and tear break-up time, were prospectively studied in patients with dry eye disease before and 1 month after treatment with autologous serum eye drops. RESULTS: Twenty-four patients (23 women, mean age 53.8±12.6 years) were included in the study. Ten patients (41.7%) had moderate and six (25.0%) had severe dry eye disease. Five patients had rheumatoid arthritis. After treatment, the number and density of conjunctival goblet cells, their size, the size of their nuclei and the nucleus/cytoplasm ratio increased significantly (202.3±107.5 vs 210.1±100.9 cells/mm2, p<0.01). Seven of ten patients with grade 3 or 4 metaplasia had an improvement in the degree of metaplasia. Both Schirmer's test and tear break-up time improved significantly in this subgroup of patients. In the multivariate study, the increase in conjunctival goblet cells was associated with the number of goblet cells and the size of the cytoplasm at baseline. No adverse reactions were noted. DISCUSSION: Treatment with autologous serum eye drops for 1 month was well tolerated and improved tear production, lachrymal flow and stability tests and conjunctival impression cytology with transfer, increasing the density of the goblet cells.

Optimizing ophthalmic delivery of a poorly water soluble drug from an aqueous in situ gelling system.

Poorly soluble drugs are often unsuitable to incorporate in ocular in situ gelling systems due to the aqueous based gelling formulations and low volumes administered. For such formulations to be successful, the administered drug must have sufficient solubility to diffuse from the formulation to the eye and should not affect the gelation of the in situ gelling material. Drug salt forms can improve the solubility of poorly soluble drugs, however, as in situ gel forming formulations are often designed to be crosslinked by salts (present the lacrimal fluid) it can make salt forms difficult to formulate. The aim of this study was to develop an in situ gel forming ophthalmic formulation of a poorly soluble drug flurbiprofen (FBP) through cyclodextrin complex formation and to analyse the impact on gelation, release and permeation through the cornea. Hydroxypropyl-beta-cyclodextrin (HßCD) was used as a complexing agent and low acyl gellan gum was added to the FBP- HßCD complex as a water soluble in situ gelling polymer. Measurements were performed using rheo-dissolution, which utilises a rheometer with a modified lower plate that has the unique ability to allow rheological measurement and analysis of drug release simultaneously. An ex-vivo permeation study was also performed using porcine cornea. Rheological measurements in terms of elastic (G') and viscous (G″) modulus showed rapid gelation of the formulation upon contact with simulated lacrimal fluid (SLF). Approximately, 97% FBP was released when 10% HßCD was used and release was decreased to 79% when the amount of HßCD was increased to 20%. The percentage of drug permeation through the cornea was 55% in 300 min whereas the marketed non gelling eye drop formulation containing FBP sodium showed only 37% permeation. The data presented here, revealed that not only could a poorly soluble drug be complexed with cyclodextrin and loaded into an in situ gelling system without interfering with the gelation, but also permeability the of the drug improved.

Latanoprost niosomes as a sustained release ocular delivery system for the management of glaucoma.

Objective: Glaucoma is a leading cause of irreversible blindness worldwide. Whereas latanoprost is one of the most effective drugs in glaucoma treatment, its eye drops need frequent application leading to lack of patient adherence. This study aimed to develop a patient-friendly niosome-in-gel system for the sustained ocular delivery of latanoprost.Methods: Niosomes were prepared by the reverse-phase evaporation technique and optimized for different formulation parameters, such as cholesterol/surfactant and drug/surfactant ratios. Selected niosomal formulations were incorporated into different gels and their viscosity and drug release kinetics were evaluated. Optimal niosomal gel was evaluated in vivo in rabbits' eyes for irritation potential and ability to reduce intraocular pressure.Results: FT-IR studies showed that there were nonspecific interactions between latanoprost and different niosomal components leading to drug encapsulation efficiency ≥88%. Latanoprost encapsulation efficiency increased with the drug/surfactant ratio and encapsulation efficiency ∼98% was obtained at a ratio of 50%. Pluronic® F127 had the best ability to sustain drug release from the niosomes. In rabbits' eyes, this gel was free of toxic and irritant effects and reduced intraocular pressure over a period of three days, which was significantly longer than that of commercial latanoprost eye drops.Conclusion: Latanoprost niosomal Pluronic® F127 gel may find applications in glaucoma management.

Comparison of thermosensitive in situ gels and drug-resin complex for ocular drug delivery: In vitro drug release and in vivo tissue distribution.

Conventional ophthalmic eye drops are limited by their rapid elimination rate and short time of action. Ion exchange resin has been used to achieve sustained ocular drug delivery but the high selectivity of drug molecules restricts its broad application. In situ gel system seems to be a good strategy to address these problems but the influence of in situ gel type on the sustained release behavior and tissue distribution after ocular application is unclear. Therefore, in this study, using betaxolol hydrochloride as a model drug, poloxamer 407 and methylcellulose as the carriers, two thermosensitive in situ gel systems were prepared and characterized. Influence of formulation composition type and concentration on in vitro drug release was studied. Tissue distribution after ocular delivery of two different thermosensitive in situ gels was studied and compared with commercial BH eye drop (Betoptic S®). In vitro studies demonstrated that addition of 4% HPMC 606W in 15% P407 solution and 5% PEG4000 in 2% MC solution obtained gels with appropriate gelation temperature and similar sustained drug release rate. In vivo tissue distribution study indicated that they presented similar drug concentration in cornea, iris-ciliary and aqueous humor irrespective of gel type, with higher drug concentration achieved after 4 h compared to the commercial resin suspension eye drops. The AUC and MRT of the two in situ gel eye drops were 2 times higher than that of the commercial resin suspension eye drops in cornea. In conclusion, the two thermosensitive in situ gels have prolonged drug release after ocular drug delivery compared with ion exchange resin eye drops, implying their potential applications in clinic with broad drug adoptability.

Rheo-dissolution: A new platform for the simultaneous measurement of rheology and drug release.

There is great potential to improve drug delivery through the use of in-situ gelling delivery systems. Here we demonstrate a technique capable of measuring changes in rheology (gelation and/or dissolution) of in-situ gelling delivery systems on contact with physiological fluid, while simultaneously analysing drug release. An ocular in-situ gelling formulation (gellan and timolol maleate) and an in-situ gelling oral liquid (alginate and metronidazole) were used as exemplar formulations. The method allowed profiling of increasing gellan concentration resulting in a reduction of timolol maleate released into simulated lacrimal fluid. When alginate was used as an in-situ gelling oral formulation there was a rapid increase in G' on contact with simulated gastric fluid. When this was changed to simulated intestinal fluid, drug release rate increased rapidly, coinciding with alginate gel dissolution. This work highlights the potential of this technology as a tool in development and optimisation of these increasingly popular delivery systems.

Thermosensitive glycol chitosan-based hydrogel as a topical ocular drug delivery system for enhanced ocular bioavailability.

In the present study, we developed and evaluated an in situ gelling system based on hexanoyl glycol chitosan (H-GCS) for enhanced ocular bioavailability. An aqueous solution of H-GCS exhibited a typical sol-gel transition at 32 °C. The formed H-GCS hydrogel was characterized by rheology and scanning electron microscopy (SEM). H-GCS had minimal in vitro cytotoxicity against L-929 and HCEC cells over a concentration range of 0-0.8 mg/mL. Additionally, the H-GCS hydrogel exhibited good ocular tolerance and biocompatibility after a single instillation. Moreover, H-GCS hydrogel significantly prolonged the precorneal retention of fluorescein sodium compared with its aqueous solution. An in vivo pharmacokinetic study demonstrated that the levofloxacin-loaded H-GCS hydrogel could provide a significantly higher Cmax and AUC0-12h compared with the levofloxacin aqueous solution, thus increasing ocular bioavailability. Overall, the proposed H-GCS hydrogel acts as an in situ gelling system that might represent a promising vehicle for topical ocular drug delivery.

Chitosan/hydroxyethyl cellulose inserts for sustained-release of dorzolamide for glaucoma treatment: In vitro and in vivo evaluation.

Eye drops containing hydrophilic drugs are commonly used to reduce intraocular pressure (IOP) in glaucoma patients, but compliance to the treatement is commonly reduced by frequent dosing and eventual systemic side effects. Sustained-release drug delivery systems, such as ocular inserts, can reduce dosing, limit systemic exposure, reduce side effects, and, then, improve patient adherence to therapy. Here, we developed and evaluated chitosan/hydroxyethyl cellulose-based ocular inserts for sustained release of dorzolamide, a hydrophilic drug. Dorzolamide inserts (DI) were produced by solvent/casting method and characterized by various physicochemical techniques. Pharmacokinetics studies were performed using scintigraphic images and ex vivo biodistribution. The effectiveness of inserts was tested in glaucomatous rats. Characterization studies showed that the drug strongly interacted with the polymeric matrix, but in vitro results showed that DI took only 3 h to release 75% of dorzolamide entraped. However, scintigraphic images and ex vivo biodistribution studies revealed that more than 50% of 99mTc-dorzolamide remained in the eye after 18 h of DI administration, while only about 30% of the drug remained in the eye after drops instilation. DI exerted significant hypotensive effect for two weeks, after single administration, while IOP values remained high in placebo and untreated groups. Eye drops were effective only during the treatment period. Only DI treatment prevented retinal ganglion cells death. Altogether, these findings evidenced the potential application of polymeric-based inserts for sustained release of dorzolamide in glaucoma management.

Tuning of thermoresponsive pNIPAAm hydrogels for the topical retention of controlled release ocular therapeutics.

Low patient compliance and poor bioavailability of ophthalmic medications are the main limitations of topical eye drops. A potential solution to these disadvantages could be provided by thermoresponsive hydrogels, which could be used as the basis for a gelling eye drop for long-term release of therapeutics. We previously reported such a system capable of being retained in the lower fornix of rabbits, continuously releasing an anti-glaucoma drug for one month. Here, we sought to improve the properties of the existing gels as most relevant to patient use without altering the drug release profile. Specifically, we optimized the sol-to-gel transition temperature and de-swelling kinetics of pNIPAAm gels to avoid risk of the gelled drop reverting to liquid during cold or windy weather, and ensure quick gelation upon administration. A reduction of the gel LCST, faster gelation kinetics, and suitable viscosity for the administration as an eye drop were successfully achieved through modification of the poly(ethylene glycol) content in the water phase and its molecular weight. Our data suggest that drug release is not affected by these changes, with representative drug concentration profiles of the previous and new formulations demonstrating comparable anti-glaucoma release kinetics.

Ultra-small micelles based on polyoxyl 15 hydroxystearate for ocular delivery of myricetin: optimization, in vitro, and in vivo evaluation.

The aim was to develop a nanocarrier based on polyoxyl 15 hydroxystearate (Kolliphor® HS15, HS15) micelles for the solubility, stability, and ocular delivery of myricetin (Myr). An optimized ratio of HS15 and Myr was prepared to fabricate HS15-Myr micelle ophthalmic solution. Myr-encapsulating HS15 micelles (HS15-Myr micelles) were subjected to physicochemical characterizations. The chemical stability of Myr in HS15 micelles and storage stability of HS15-Myr micelle ophthalmic solutions were evaluated. In vitro parallel artificial membrane permeability assay and antioxidant activity of Myr in HS15 micelles were also measured. In vivo ocular tolerance, corneal permeation, and anti-inflammatory efficacy studies were conducted following ocular topical administration. HS15-Myr micelles were successfully prepared and presented transparent appearance with high encapsulation (96.12 ± 0.31%), ultra-small micelle size (a mean diameter of 12.17 ± 0.73 nm), uniform size distribution (polydispersity index [PDI] = 0.137 ± 0.013), and negative surface charge (- [4.28 ± 0.42] mV). Myr in HS15 micelle solution demonstrated higher aqueous stability than the free Myr solution among the accepted pH range for eyedrops. HS15-Myr micelle ophthalmic solution demonstrated high storage stability at 4 °C and 25 °C. HS15 micelles could significantly improve in vitro antioxidant activity and faster membrane permeation of Myr. No irritations or corneal damage were revealed in rabbit eyes after ocular administration of HS15-Myr micelle solution. In vivo corneal permeation study demonstrated that HS15-Myr micelles could penetrate the cornea efficiently in mouse eyes. Further, HS15-Myr micelles also demonstrated significant in vivo anti-inflammatory activity. It can be concluded that HS15 micelles are a potential ophthalmic delivery nanocarrier for poorly soluble drugs such as Myr.

A more efficient ocular delivery system of triamcinolone acetonide as eye drop to the posterior segment of the eye.

As a leading cause of vision impairment of the retina, macular edema (ME) has one of the highest clinical demands for treatment. Current treatment of ME relies heavily on invasive techniques resulting in complications and poor patient compliance. To enhance the efficiency of triamcinolone acetonide as eye drop to the posterior segment of the eye, we developed and characterized a novel formulation, namely, triamcinolone acetonide chitosan-coated liposomes (TA-CHL), prepared by the calcium acetate gradient method with some modifications. TA-CHL provided the mean particle size of 135.46 ± 4.49 nm and high entrapment efficiency (90.66 ± 3.21%), exhibited a sustained release profile, excellent physical stability, and no significant toxicity on cornea, conjunctiva, and retina. Optical coherence tomography system (OCT) was used to detect pharmacokinetics of CHL in vivo, indicating that CHL had good potency for drug delivery. Cellular uptake experiments showed CHL had the higher transduction efficiency into HCEC and ARPE-19 than liposomes. TA-CHL was shown to be potentially effective eye drop to contribute to the posterior segment of the eye.

A Novel Phytantriol-Based Lyotropic Liquid Crystalline Gel for Efficient Ophthalmic Delivery of Pilocarpine Nitrate.

The purpose of this paper was to investigate the potential of liquid crystalline (LC) gels for ophthalmic delivery, so as to enhance the bioavailability of pilocarpine nitrate (PN). The gels were prepared by a vortex method using phytantriol and water (in the ratio of 73:27 w/w). Their inner structures were confirmed by crossed polarized light microscopy, small-angle X-ray scattering, attenuated total reflectance-Fourier transform infrared spectrum, and rheology. The in vitro release studies revealed that PN could keep sustained release from the gels over a period of 12 h. The ex vivo apparent permeability coefficient of the gels demonstrated a 3.83-folds (P < 0.05) increase compared with that of eye drops. The corneal hydration levels of the gel maintained in the normal range of 79.46 ± 2.82%, hinting that the gel could be considered non-damaging and safe to the eyes. Furthermore, in vivo residence time evaluation suggested that a better retention performance of LC gel was observed in rabbit's eyes compared to eye drops. In vivo ocular irritation study indicated that LC gel was nonirritant and might be suitable for various eye applications. In conclusion, LC gels might represent a potential ophthalmic delivery strategy to overcome the limitations of eye drops.

QobuR - A new in vitro human corneal epithelial model for preclinical drug screening.

A new in vitro human corneal epithelial model (QobuR) obtained from normal limbal tissue has been developed to study ocular irritancy of different ophthalmic compounded drugs. Phenotypical characterization and trans-epithelial electrical resistance (TEER) of QobuR revealed essential similarities compared with a native human cornea, displaying functional markers and TEER values near 1500 Ωcm2 at day 7th of cellular differentiation. Using this model, ocular irritancy and barrier integrity alterations were evaluated using MTT reaction and variations in TEER. We found that some of the Non-Irritant products evaluated still damage the corneal epithelial integrity and current protocols for ocular irritancy should therefore include a barrier integrity evaluation. Moreover, in order to comprehensively evaluate corneal permeability of the active ingredients, we propose the use of QobuR as an all-in-one alternative method for evaluating ocular irritancy, barrier disruptions and permeability rates of topically applied ocular drugs to improve current in vitro drug testing procedures.

Evaluating the novel application of cyclosporine 0.1% in ocular surface disease.

INTRODUCTION: Ocular surface disease (OSD) is a highly prevalent symptomatic condition caused by dry eye disease (DED), intrinsic, environmental, or iatrogenic causes. It affects patient's visual function and quality of life. Its pathophysiology is centered on tear hyperosmolarity, inflammation, and epithelial damage. Current management is suboptimal and includes artificial tear supplementation and short-term use of topical steroids in severe cases. The recent approval of cyclosporine 0.1% has transformed management strategies of severe DED and moderate-to-severe OSD. Areas covered: This review summarizes existing information on the efficacy, safety, and tolerability of the new cyclosporine 0.1% formulation. Expert opinion: Topical cyclosporine A 0.1% represents a promising, novel medication for the management of DED, Meibomian gland dysfunction, and inflammatory OSD. It is primarily beneficial for those patients requiring topical immunomodulatory therapy. This topical formulation also has the potential to meaningfully improve the management of moderate-to-severe glaucoma therapy-related OSD. Currently there is limited published clinical data concerning the efficacy of topical cyclosporine. There are, however, theoretical advantages when comparing this cyclosporine formulation with other established commercial preparations. Future research is needed to delineate the precise role and value of this medication.