Topical Ophthalmic Application Research Articles

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.

The Management and Treatment of Keratoconjunctivitis in A 6-Month-Old Lamb: A Case Report

Introduction: Infectious keratoconjunctivitis, commonly known as pinkeye or contagious ophthalmia, is a bacterial disease that affects the healthy eyes. This infection causes inflammation in the tissue lining the eyelid, the conjunctiva, and the cornea of one or both eyes. Case report: A 6-month-old male Afshari breed sheep with symptoms of blepharospasm, keratoconjunctivitis, and ocular discharge was referred to a veterinary clinic in Mashhad, Iran. Upon ophthalmic examination of both eyes, the signs included conjunctivitis, generalized corneal opacity, blepharospasm, epiphora, positive menace response, and elevated intraocular pressure were observed. The clinical signs suggested Infectious keratoconjunctivitis by Mycoplasma. To detect Mycoplasma, immunofluorescence tests, and growth inhibition tests were conducted using anti-sera. Mycoplasma was isolated from the samples. The sheep was treated with a single intramuscular injection of long-acting tetracycline at a dosage of 20mg/kg. The topical tetracycline ointments were used and applied 4 times daily for 6 days. The topical ophthalmic application of 1% atropine ointment 3 times daily was used due to pain as a consequence of uveitis for 3 days. Due to the mydriasis caused by atropine, animals undergoing treatment were provided with shade. For pain relief, meloxicam (1 ml/50 kg) is utilized to alleviate the clinical signs of the disease. After 10 days of treatment, the clinical signs returned to normal. Conclusion: The clinical signs and subclinical tests confirmed keratoconjunctivitis caused by Mycoplasma. The successful treatment of this disease by following the above-mentioned treatment method can help clinicians and researchers in similar cases.

Optimization of Lipid Nanoparticles by Response Surface Methodology to Improve the Ocular Delivery of Diosmin: Characterization and In-Vitro Anti-Inflammatory Assessment.

Diosmin is a flavonoid with a great variety of biological activities including antioxidant and anti-inflammatory ones. Its cytoprotective effect in retinal pigment epithelium cells under high glucose conditions makes it a potential support in the treatment of diabetic retinopathy. Despite its benefits, poor solubility in water reduces its potential for therapeutic use, making it the biggest biopharmaceutical challenge. The design of diosmin-loaded nanocarriers for topical ophthalmic application represents a novelty that has not been yet explored. For this purpose, the response surface methodology (RSM) was used to optimize nanostructured lipid carriers (NLCs), compatible for ocular administration, to encapsulate diosmin and improve its physicochemical issues. NLCs were prepared by a simple and scalable technique: a melt emulsification method followed by ultrasonication. The experimental design was composed of four independent variables (solid lipid concentration, liquid lipid concentration, surfactant concentration and type of solid lipid). The effect of the factors was assessed on NLC size and PDI (responses) by analysis of variance (ANOVA). The optimized formulation was selected according to the desirability function (0.993). Diosmin at two different concentrations (80 and 160 µM) was encapsulated into NLCs. Drug-loaded nanocarriers (D-NLCs) were subjected to a physicochemical and technological investigation revealing a mean particle size of 83.58 ± 0.77 nm and 82.21 ± 1.12 nm, respectively for the D-NLC formulation prepared with diosmin at the concentration of 80 µM or 160 µM, and a net negative surface charge (−18.5 ± 0.60 and −18.0 ± 1.18, respectively for the two batches). The formulations were analyzed in terms of pH (6.5), viscosity, and adjusted for osmolarity, making them more compatible with the ocular environment. Subsequently, stability studies were carried out to assess D-NLC behavior under different storage conditions up to 60 days, indicating a good stability of NLC samples at room temperature. In-vitro studies on ARPE-19 cells confirmed the cytocompatibility of NLCs with retinal epithelium. The effect of D-NLCs was also evaluated in-vitro on a model of retinal inflammation, demonstrating the cytoprotective effect of D-NLCs at various concentrations. RSM was found to be a reliable model to optimize NLCs for diosmin encapsulation.

Preparation and characterization of amphotericin B-loaded silk fibroin nanoparticles-in situ hydrogel composites for topical ophthalmic application

Preparation and characterization of amphotericin B-loaded silk fibroin nanoparticles-in situ hydrogel composites for topical ophthalmic application

Prednisolone and dexamethasone are systemically absorbed after topical application of ophthalmic suspensions in healthy dogs.

To quantify plasma concentrations of prednisolone and dexamethasone (peripheral and jugular) and cortisol following topical ophthalmic application of 1% prednisolone acetate and 0.1% dexamethasone to healthy adult dogs. 12 purpose-bred Beagles. Dogs received 1 drop of 1% prednisolone acetate (n = 6) or neomycin polymyxin B dexamethasone (ie, 0.1% dexamethasone; 6) ophthalmic suspension in both eyes every 6 hours for 14 days. Blood samples (peripheral and jugular) were collected on days 0, 1, 7, and 14 and analyzed for plasma prednisolone and dexamethasone concentrations. Plasma cortisol concentrations were measured at the beginning of the study and following topical drug administration. Both drugs demonstrated systemic absorption. Prednisolone was detected on days 1, 7, and 14 (median plasma concentration, 24.80 ng/mL; range, 6.20 to 74.00 ng/mL), and dexamethasone was detected on days 1, 7, and 14 (2.30 ng/mL; 0 to 17.70 ng/mL). Neither prednisolone nor dexamethasone were detected in plasma samples on day 0 (baseline). Sampling from the jugular vein resulted in higher plasma drug concentrations than from a peripheral vein when samples from each day were combined. Plasma cortisol concentrations were significantly lower than baseline following 14 days of treatment with topical prednisolone acetate and dexamethasone. Prednisolone and dexamethasone are detected in the plasma of healthy dogs following topical ophthalmic administration 4 times/d with prednisolone concentrations being close to a physiologic dose of orally administered prednisolone. Additional research is needed to evaluate the systemic absorption of these medications in dogs with ocular inflammation.

Safety and efficacy of Ayurveda interventions in diabetic retinopathy

Introduction: Diabetic retinopathy (DR), a complication of diabetes mellitus, is a leading cause of blindness on a global level. Nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR), both with and without diabetic macular edema (DME), are the stages of DR. The conventional treatment strategies for DR include intravitreal injections, laser photocoagulation, and surgical approach. There are quite a few individual studies available in various databases showing the efficacy of Ayurveda intervention in DR. However, a systematic review of these studies is not available to date. The aim of this study is to perform a systematic review of various clinical studies of Ayurveda treatments in DR, along with meta-analysis, if possible. This shall help in providing more precise estimates of the effectiveness of management of DR using Ayurveda interventions. Methods and Analysis: A systematic review of randomized controlled trials (RCTs), quasi-randomized controlled trials (QRCTs), controlled clinical trials (CCTs), multiple arms clinical trials, and single-group studies on DR published/unpublished from January 1990 to November 2020 will be conducted. The database search will be performed using the words with Boolean operators: Ayurveda OR Ayurvedic AND Diabetic Retinopathy as title, abstract, or keyword. Clinical trials of patients fulfilling the diagnostic criteria based on signs and symptoms of DR in any of its stages, irrespective of age and either gender, will be selected. Studies that are based on the Ayurvedic treatments such as Shodhana (purification therapies), Shamana (pacification therapies), Netra Kriyakalpa (topical ophthalmic application of medications), Moordha Taila Prayoga (topical application of medicine on head), Mukha Kriya Kramas (usage of medicine on/in mouth and on face such as Mukhalepa, Kabala, Gandoosha) irrespective of dosage, type, schedule, drug, form, and advised Pathayapathya (lifestyle changes) as intervention or control will be selected. Response to treatment, both subjective and objective, is the primary outcome and onset of serious adverse events is the secondary outcome. Ethics and Dissemination: Ethical approval was obtained from the Institutional Ethics Committee. The results obtained will be published in a peer-reviewed journal. Trial Registration Number: International Prospective Register for Systematic Reviews (PROSPERO) number CRD42019136750.

Ophthalmic complaints in face-mask wearing: prevalence, treatment, and prevention with a potential protective effect against SARS-CoV-2

ABSTRACT: The global pandemic of severe acute respiratory syndrome, COVID-19 affects the world’s economics, social and health systems and has a great impact on every person’s life. In an attempt to control the spread of the disease, regular usage of face masks became an ordinary routine. A large proportion of the population is reporting ocular symptoms through the period of mask-wearing that are still underestimated. Thus the eyes are not only widely exposed to a potential viral invasion but are also under the influence of an additional irritant factor, the face mask usage. The results of our pilot study indicate that the presence and severity of the ocular complaints are dependent on the type of mask and the duration of usage. Now, in the COVID-19 outbreak, the protection of the anterior ocular surface is necessary more than ever to contribute to personal eye health. Based on the concept for the protective role of the tear film and specifically, its lipid layer against the SARS-CoV-2 invasion, all substances sustaining tear film balance and lipid layer thickness could be beneficial in ensuring the local defense mechanisms. Some medications approved for the treatment of dry eye symptoms may have a defensive effect against the viral invasion, which should be additionally evaluated. The topical ophthalmic application of Cyclosporine A, Chloroquine, Azithromycin, Povidone Iodine, Hypertonic saline drops might contribute to local protection and ensure high local dose in minimum systemic effects.

Cysteamine eye drops in the treatment of cystinosis – an Australian perspective

AbstractCystinosis is a rare but very serious genetic disorder. Advancements in medical science, in the past few decades, have transformed this previously terminal condition into a manageable disease. Ophthalmic sequelae of cystinosis are caused by accumulation of cystine crystals in ocular tissues and are very troublesome for most cystinosis patients. Accumulation of crystals in the cornea causes debilitating photophobia and pain that does not respond to systemic cysteamine therapy. If left untreated, this can lead to structural damage (corneal ulcers, scarring and band keratopathy) and eventually result in corneal blindness requiring corneal transplant. Topical ophthalmic application of cysteamine can alleviate the symptoms and, if instituted early, may prevent the damage. There is no commercially manufactured ophthalmic cysteamine product available in Australia and patients who receive treatment are usually supplied with extemporaneously prepared cysteamine eye drops or ointment. Stability issues, various factors influencing product effectiveness and patient adherence are only few of the problems that make formulation and compounding of cysteamine ophthalmic products a complex task.

Structural characteristics of oil-poor dilutable fish oil omega-3 microemulsions for ophthalmic applications

Docosahexaenoic acid (DHA) promotes synthesis of anti-inflammatory prostaglandins and relief of dry eye symptoms. However, topical ophthalmic application of DHA is difficult because of its lipophilic property. Therefore, it is important to develop aqueous-based formulation with enhanced capabilities.Novel, unique water-dilutable microemulsions (MEs) were constructed to allow loading of naturally occurring rigid long-chain triglyceride of DHA (TG-DHA). The TG-DHA serves as solubilizate and as the oil phase, therefore preparation is poor in oil. The structural transformations of MEs upon water dilution were studied by SAXS, viscosity, electrical conductivity, self-diffusion NMR, DSC, cryo-TEM, and DLS techniques.At low water content a new type of water-in-oil (W/O) structure is formed. The glycerol/water phase hydrates the headgroups of surfactants, and the oil solvates their tails, forming “ill-defined bicontinuous domains”. Upon further water dilution more structured bicontinuous domains of high viscosity are formed. After additional dilution, the mesophases invert to oil-in-water (O/W) droplets of ∼8nm.In the structures composed of up to 25wt% water, the TG-DHA spaces and de-entangles the surfactant tails. Once the bicontinuous structures are formed, the surfactants and TG-DHA content decrease and their interfacial layer shrinks, leading to entanglement and buildup of viscous non-Newtonian mesophase. Above 70wt% water TG-DHA is embedded in the core of the O/W droplets, and its effect on the droplets’ structure is minimal.This new dilutable ill-defined microemulsion can be a potential delivery vehicle for ophthalmic TG-DHA transport.

Comparison of two- and three-times-daily topical ophthalmic application of 0.005% latanoprost solution in clinically normal dogs.

To determine whether 2- or 3-times-daily application of topical ophthalmic 0.005% latanoprost solution is more effective at lowering intraocular pressure (IOP) in clinically normal dogs. 9 clinically normal dogs. For each dog, I drop of latanoprost 0.005% solution was applied to 1 eye every 8 or 12 hours each day for 5 days; the contralateral eye received topical ophthalmic treatment with 1 drop of saline (0.9% NaCl) solution at the times of latanoprost application. Ocular examinations of both eyes were performed every 6 hours starting 48 hours prior to and ending 42 hours after the treatment period. Following a 5-week washout interval, the procedures were repeated but the previously latanoprost-treated eye of each dog received latanoprost application at the alternate frequency. Mean ± SD IOP reduction in the latanoprost-treated eyes was 31 ± 6.9% with 2-times-daily application and 33 ± 8.2% with 3-times-daily application. A 2-way repeated-measures ANOVA revealed significant differences in IOP with contributions by treatment (2 or 3 times daily), time of day (diurnal variation), and individual dog. The maximum mean daily IOP reduction in latanoprost-treated eyes was detected on day 3 of latanoprost treatment in each group. Eyes treated 3 times daily had significantly smaller pupil diameter and greater conjunctival hyperemia than eyes treated 2 times daily. The clinical importance of the ocular hypotensive effects of 3-times-daily topical ophthalmic application of 0.005% latanoprost solution in dogs with glaucoma warrants investigation.

Systemic absorption and adverse ocular and systemic effects after topical ophthalmic administration of 0.1% diclofenac to healthy cats.

To quantify plasma concentrations and determine adverse ocular, renal, or hepatic effects associated with repeated topical ophthalmic application of 0.1% diclofenac to healthy cats. 8 healthy sexually intact male cats. A randomized, placebo-controlled crossover study was conducted. A topical formulation of 0.1% diclofenac was administered 4 times/d for 7 days to 4 cats, and artificial tear (control) solution was administered to the other 4 cats. After a 12-day washout period, cats received the other treatment. Ophthalmic examinations were performed daily. Plasma samples were obtained on days 1 and 7 for pharmacokinetic analysis. A CBC, serum biochemical analysis, urinalysis, determination of urine protein-to-creatinine ratio, and determination of glomerular filtration rate were performed before the start of the study and after each 7-day treatment period. Mild conjunctival hyperemia was the only adverse ocular effect detected. Maximal drug concentration and area under the curve were significantly higher on day 7 than on day 1. Diclofenac-treated cats had a significantly lower glomerular filtration rate than did control-treated cats after the second but not after the first treatment period, presumably associated with iatrogenic hypovolemia. Topical ophthalmic administration of 0.1% diclofenac was well tolerated in healthy cats, with only mild signs of ocular irritation. Detectable systemic concentrations of diclofenac were achieved with accumulation over 7 days. Systemic absorption of diclofenac may be associated with reduced glomerular filtration rate, particularly in volume-contracted animals. Topical ophthalmic 0.1% diclofenac should be used with caution in volume-contracted or systemically ill cats.

Effect of topical ophthalmic application of cidofovir on experimentally induced primary ocular feline herpesvirus-1 infection in cats

To evaluate the efficacy of twice-daily ophthalmic application of 0.5% cidofovir solution in cats with experimentally induced primary ocular feline herpesvirus-1 (FHV-1) infection. Twelve 6-month-old sexually intact male cats. Cats were randomly assigned to either a treatment or control group. Ocular infection with FHV-1 was induced (day 0) in all cats via inoculation of both eyes with 10(4) plaque-forming units of a plaque-purified FHV-1 field strain. Twice daily for 10 days beginning on day 4 after virus inoculation, the treatment group received 1 drop of 0.5% cidofovir in 1% carboxymethylcellulose in both eyes, and the control group received 1 drop of 1% carboxymethylcellulose in both eyes. A standardized scoring method was used to evaluate clinical signs of FHV-1 infection in each cat once daily for 24 days. The amount of ocular viral shedding was assessed by use of a quantitative real-time PCR procedure every 3 days during the study period. Clinical scores and viral quantification were averaged over the pretreatment (days 0 to 3), treatment (days 4 to 14), and posttreatment (days 15 to 24) periods for each cat. During the treatment period, clinical scores and amount of viral ocular shedding were significantly lower in the treatment group, compared with findings in the control group. Twice-daily application of 0.5% cidofovir solution in both eyes significantly decreased the amount of viral shedding and the severity of clinical disease in cats with experimentally induced ocular FHV-1 infection.

Clinical pharmacokinetics of dorzolamide.

Dorzolamide is a carbonic anhydrase inhibitor for topical ophthalmic application. It is used in the treatment of glaucoma to lower the intraocular pressure. After absorption via the cornea and stroma, it inhibits carbonic anhydrase in the ciliary process, which leads to a reduction of aqueous humour production and therefore to the desired therapeutic effect. In the systemic circulation, dorzolamide is bound mainly to carbonic anhydrase in red blood cells. It is slowly metabolised to N-de-ethyldorzolamide, which in turn is also stored in red blood cells. The very slow elimination (half-life >4 months) of both substances takes place via the renal route. However, the inhibition of carbonic anhydrase in red blood cells is moderate in the course of a topical treatment, avoiding systemic adverse effects. This review summarises the pharmacokinetic and pharmacodynamic properties of dorzolamide and its metabolite in eye tissues and in the systemic circulation.

Methylmethacrylate sulfopropylmethacrylate copolymer nanoparticles for drug delivery: Part III: Evaluation as drug delivery system for ophthalmic applications

Copolymer nanoparticles were investigated as carrier systems for the topical ophthalmic application of the muscarinic agonists arecaidine propargyl ester (APE) and (S)-(+)-aceclidine in rabbits and compared to conventional eye drop preparations. The copolymer nanoparticles were prepared by free radical polymerization of methylmethacrylate (MMA) and sulfopropylmethacrylate (SPM). The in-vivo activity of the drug-containing carrier systems was tested by the measurement of the miotic effect observed after local administration in rabbits. It has been found that the copolymer nanoparticles were able to produce a significant increase of the ocular APE bioavailability as determined by the area under the miosis-time-curve (AUC). The nanoparticle preparations were tolerated without any irritating effect in the rabbit eye. Besides the copolymer nanoparticles, different formulations containing bioadhesive or viscosity-enhancing polymers with and without additional nanoparticles were tested. The administration of APE-loaded copolymer nanoparticles was found to be equivalent in efficacy to solutions containing the soluble polymers without nanoparticles. The combination of the nanoparticles with bioadhesive polymers further increased the ocular drug bioavailability. Hyaluronic acid alone or in combination with copolymer nanoparticles was observed to be the most effective soluble polymer for ophthalmic application by enhancing the AUC of miosis-time-curve 2-fold. Similar effects induced by the carrier systems were obtained with (S)-(+)-aceclidine. However, the magnitude of the enhancement of the miotic effect that is achievable by the binding of the drug to nanoparticles over free drug is much more pronounced with the short acting drug APE than with (S)-(+)-aceclidine.

Ocular ß-Blockers and Systemic Effects

As pointed out by Swenson, 1 there can be drug-induced systemic effects from topical ophthalmic application of a β-adrenergic antagonist. Over the past eight years, the National Registry of Drug-Induced Ocular Side Effects in the Department of Ophthalmology at the Oregon Health Sciences University, Portland, has been monitoring this medication. It is evident that some patients who receive topical ocular timolol maleate obtain therapeutic plasma timolol levels. 2,3 Of the 1,900 cases of possible adverse reactions secondary to ophthalmic timolol reported to the Registry, 63% are systemic side effects. One reason why systemic blood levels of this drug may occur is the order pass effect. Essentially, this means that when timolol is administered orally, the drug first passes through the liver where most of it is metabolized before being exposed to the target organs. However, timolol eyedrops drain through the nasolacrimal system rapidly, and an estimated 80% of the drug may