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Fungal keratitis (FK) is a serious pathogenic condition usually associated with significant ocular morbidity. Natamycin (NAT) is the first-line and only medication approved by the Food and Drug Administration for the treatment of FK. However, NAT suffers from poor corneal penetration, which limits its efficacy for treating deep keratitis. The objective of this work was to prepare NAT solid lipid nanoparticles (NAT-SLNs) to achieve sustained drug release and increased corneal penetration. NAT-SLNs were prepared using the emulsification-ultrasonication technique. Box- Behnken experimental design was applied to optimize the effects of independent processing variables (lipid concentration [X ], surfactant concentration [X ], and sonication frequency [X ]) on particle size (R ), zeta potential (ZP; R ), and drug entrapment efficiency (EE%) (R ) as responses. Drug release profile, ex vivo corneal permeation, antifungal susceptibility, and cytotoxicity of the optimized formula were evaluated. The optimized formula had a mean particle size of 42 r.nm (radius in nanometers), ZP of 26 mV, and EE% reached ~85%. NAT-SLNs showed an extended drug release profile of 10 hours, with enhanced corneal permeation in which the apparent permeability coefficient (P ) and steady-state flux (J ) reached 11.59×10 cm h and 3.94 mol h , respectively, in comparison with 7.28×10 cm h and 2.48 mol h for the unformulated drug, respectively. Antifungal activity was significantly improved, as indicated by increases in the inhibition zone of 8 and 6 mm against ATCC 1022 and a clinical isolate, respectively, and minimum inhibitory concentration values that were decreased 2.5-times against both of these pathogenic strains. NAT-SLNs were found to be non-irritating to corneal tissue. NAT-SLNs had a prolonged drug release rate that improved corneal penetration, and increased antifungal activity without cytotoxic effects on corneal tissues. Thus, NAT-SLNs represent a promising ocular delivery system for treatment of deep corneal keratitis.

This paper describes hitherto developed drug forms for topical ocular administration, that is, eye drops, ointments, in situ gels, inserts, multicompartment drug delivery systems, and ophthalmic drug forms with bioadhesive properties. Heretofore, many studies have demonstrated that new and more complex ophthalmic drug forms exhibit advantage over traditional ones and are able to increase the bioavailability of the active substance by, among others, reducing the susceptibility of drug forms to defense mechanisms of the human eye, extending contact time of drug with the cornea, increasing the penetration through the complex anatomical structure of the eye, and providing controlled release of drugs into the eye tissues, which allows reducing the drug application frequency. The rest of the paper describes recommended in vitro and in vivo studies to be performed for various ophthalmic drugs forms in order to assess whether the form is acceptable from the perspective of desired properties and patient’s compliance.

Dry-eye syndrome (DES) is a general eye disease. Eye drops are the common ophthalmological medication. However, the ocular barrier makes it difficult to attain high drug bioavailability. Nanomedicine is a promising alternative treatment for ocular diseases and may increase drug content in the affected eye. To explore this potential, we constructed nanoparticles (NPs) containing an anti-inflammatory agent for DES treatment. The NPs were made of gelatin-epigallocatechin gallate (EGCG) with surface decoration by hyaluronic acid (HA) and designated \"GEH\". The particle size, surface charge, and morphology were evaluated. The in vitro biocompatibility and anti-inflammation effect of nanoparticles were assayed via culturing with human corneal epithelium cells (HCECs) and in vivo therapeutic effect was examined in a DES rabbit's model. The synthesized GEH NPs had a diameter of approximately 250 nm and were positively charged. A coculture experiment revealed that 20 µg/mL GEH was not cytotoxic to HCECs and that an EGCG concentration of 0.2 µg/mL downregulated the gene expression of and in inflamed HCECs. Large amounts of GEH NPs accumulated in the cytoplasm of HCECs and the ocular surfaces of rats and rabbits, indicating the advantage of GEH NPs for ocular delivery of medication. Twice-daily topical treatment with GEH NPs was performed in a rabbit model of DES. The ocular surface of GEH-treated rabbits displayed normal corneal architecture with no notable changes in inflammatory cytokine levels in the cornea lysate. The treatment improved associated clinical signs, such as tear secretion, and fluorescein staining recovered. We successfully produced GEH NPs with high affinity for HCECs and animal eyes. The treatment can be delivered as eye drops, which retain the drug on the ocular surface for a longer time. Ocular inflammation was effectively inhibited in DES rabbits. Therefore, GEH NPs are potentially valuable as a new therapeutic agent delivered in eye drops for treating DES.

To review the current therapeutic options for the management of diabetic retinopathy (DR) and diabetic macular edema (DME) and examine the evidence for integration of laser and pharmacotherapy. A review of the PubMed database was performed using the search terms diabetic retinopathy, diabetic macular edema, neovascularization, laser photocoagulation, intravitreal injection, vascular endothelial growth factor (VEGF), vitrectomy, pars plana vitreous surgery, antiangiogenic therapy. With additional cross-referencing, this yielded 835 publications of which 301 were selected based on content and relevance. Many recent studies have evaluated the pharmacological, laser and surgical therapeutic strategies for the treatment and prevention of DR and DME. Several newer diagnostic systems such as optical coherence tomography (OCT), microperimetry, and multifocal electroretinography (mfERG) are also assisting in further refinements in the staging and classification of DR and DME. Pharmacological therapies for both DR and DME include both systemic and ocular agents. Systemic agents that promote intensive glycemic control, control of dyslipidemia and antagonists of the renin-angiotensin system demonstrate beneficial effects for both DR and DME. Ocular therapies include anti-VEGF agents, corticosteroids and nonsteroidal anti-inflammatory drugs. Laser therapy, both as panretinal and focal or grid applications continue to be employed in management of DR and DME. Refinements in laser devices have yielded more tissue-sparing (subthreshold) modes in which many of the benefits of conventional continuous wave (CW) lasers can be obtained without the adverse side effects. Recent attempts to lessen the burden of anti-VEGF injections by integrating laser therapy have met with mixed results. Increasingly, vitreoretinal surgical techniques are employed for less advanced stages of DR and DME. The development and use of smaller gauge instrumentation and advanced anesthesia agents have been associated with a trend toward earlier surgical intervention for diabetic retinopathy. Several novel drug delivery strategies are currently being examined with the goal of decreasing the therapeutic burden of monthly intravitreal injections. These fall into one of the five categories: non-biodegradable polymeric drug delivery systems, biodegradable polymeric drug delivery systems, nanoparticle-based drug delivery systems, ocular injection devices and with sustained release refillable devices. At present, there remains no one single strategy for the management of the particular stages of DR and DME as there are many options that have not been rigorously tested through large, randomized, controlled clinical trials. Pharmacotherapy, both ocular and systemic, will be the primary mode of intervention in the management of DR and DME in many cases when cost and treatment burden are less constrained. Conventional laser therapy has become a secondary intervention in these instances, but remains a first-line option when cost and treatment burden are more constrained. Results with subthreshold laser appear promising but will require more rigorous study to establish its role as adjunctive therapy. Evidence to support an optimal integration of the various treatment options is lacking. Central to the widespread adoption of any therapeutic regimen for DR and DME is substantiation of safety, efficacy, and cost-effectiveness by a body of sound clinical trials.

Atorvastatin calcium (AT) is an ocular anti-inflammatory with limited bioavailability when taken orally due to its low solubility in low pH and extensive first-pass effect. To overcome these problems, AT was entrapped in polymeric nanoparticles (NPs) to improve surface properties and sustained release, in addition to achieving site-specific action. AT was entrapped in chitosan (CS)-coated polylactic-co-glycolic acid (PLGA) NPs to form AT-PLGA-CS-NPs (F1). F1 and free AT were embedded in thermosensitive Pluronic 127-hydroxypropyl methylcellulose (HPMC) to form thermosensitive gels (F2) and (F3) while F4 is AT suspension in water. F1 was assessed for size, surface charge, polydispersity index (PDI), and morphology. F2 and F3 were examined for gelation temperature, gel strength, pH, and viscosity. In vitro release of the four formulations was also investigated. The ocular irritancy and anti-inflammatory efficacy of formulations against prostaglandin E -(PGE ) induced ocular inflammation in rabbits were investigated by counting the polymorphonuclear leukocytes (PMNs) and protein migrated in tears. Oval F1 of 80.0-190.0±21.6 nm exhibited a PDI of 0.331 and zeta potential of ‏17.4±5.62 mV with a positive surface charge. F2 and F3 gelation temperatures were 35.17±0.22°C and 36.93±0.31°C, viscosity 12,243±0.64 and 9759±0.22 cP, gel strength 15.56±0.6 and 12.45±0.1 s, and pHs of 7.4±0.02 and 7.4±0.1, respectively. In vitro release of F1, F2, F3, and F4 were 48.21±0.31, 26.48±0.5, 84.76±0.11, and 100% after 24 hrs, respectively. All formulations were non-irritant. F2 significantly inhibited lid closure up to 3 h, PMN counts and proteins in tear fluids up to 5 h compared to other formulations. AT-PLGA-CS-NP thermosensitive gels proved to be successful ocular anti-inflammatory drug delivery systems.

Topical ocular preparations are widely recommended by health care professionals, or chosen by patients, to help manage dry eye disease (DED). The chronic and progressive nature of DED may result in the administration of topical products several times a day, over a period of many years. Given DED is a condition that by definition affects the ocular surface, it is important to understand how the repeated use of eye drops may impact the ocular surface, influence clinical signs, affect symptoms, and impact the overall disease process of dry eye. The component in topical preparations with the greatest potential to adversely affect the ocular surface is the preservative. This paper reviews the literature in relation to the use of preservatives in formulations for dry eye. The ocular effects of benzalkonium chloride (BAK) are summarised and compared to the performance of alternative preservatives and preservative-free formulations. Use of preserved and preservative-free drops in relation to the management of varying stages of DED is discussed.

Intraocular pressure has always been a great challenge for topical ophthalmic drugs. The study aimed to develop ocular surfactant based nanovesicles (NVs) carried in mucoadhesive nanogel providing efficient topical delivery of acetazolamide (ACZ). For the sake of optimizing formulation parameters, the effect of the type of edge activator and its ratio to sorbitan monostearate (Span 60) on the mean particle size, entrapment efficiency (%EE), and zeta potential (ZP) of produced NVs was investigated. The selected formulation composed of Span 60:sodium deoxycholate with ratio 80:20 showed an average diameter of 202.90 nm, %EE of 90.2%, and ZP of -38.1 mV with a spherical and smooth surface. The ACZ loaded nanovesicles (ACZ-NVs) were embedded in different concentrations of Chitosan-sodium tripolyphosphate (CS-TPP) nanogels. The nanogel prepared using 1.5% CS showed the most promising viscosity, adhesion time, and rheological behavior (118,246 cP, 290 min, and thixotropic behavior, respectively). The in vitro release of ACZ showed a controlled release profile after incorporation in nanogels. The in vivo irritation test showed minimal irritation for the nanogel formulation compared to ACZ topical suspension. The effect of intraocular pressure lowering was significantly prolonged using ACZ-NV nanogels compared to ACZ oral tablets. Histopathological examination emphasized the healing power of CS on retinal atrophy. The research work indicated a promising potential for successful topical delivery of ACZ.

Voriconazole (VRC) is a triazole broad spectrum antifungal drug, used in the management of versatile fungal infections, particularly fungal keratitis. The obligatory use of niosomal delivery of VRC may reduce the frequency of dosing intervals resulting from its short biological half time and consequently improve patient compliance. VRC loaded proniosomes (VRC-PNs) were set by the coacervation technique and completely characterized. The developed formula was comprehensively assessed concerning in- vitro release behavior, kinetic investigation, and its conflict against refrigerated and room temperature conditions. A selected noisomal formula was incorporated into ocusert (VRC-PNs Ocu) formulated by 1% w/w hydroxypropyl methyl cellulose HPMC and 0.1% w/w carbopol . Eventually, in vitro antifungal activity against and was assessed by the cup diffusion method. The optimized VRC-PNs (Pluronic F127: cholesterol weight ratio 1:1 w/w) exhibited the highest entrapment efficiency (87.4±2.55%) with a spherical shape, proper size in nano range and a suitable Zeta potential of 209.7±8.13 nm and -33.5±1.85 mV, respectively. Assurance of drug encapsulation in nanovesicles was accomplished by several means such as attenuated total reflection Fourier-transform infrared spectroscopy, differential scanning calorimetry in addition to powder X-ray diffraction investigations. It displayed a biphasic in vitro release pattern and after 6 months of storage at a refrigerated temperature, the optimized formula preserved its stability. VRC-PNs Ocu proved a very highly significant antifungal activity matched with the free drug or nanosuspension which was extra assured by comparing its mean inhibition zone with that of 5% natamycin market eye drops. In conclusion, VRC-PNs Ocu could be considered as a promising stable sustained release topical ocular nanoparticulate system for the management of fungal infections.

Allergic eye disease is common, yet often overlooked in North America. In the U.S., up to 40% of the population is deemed to be affected and this number is growing. Symptoms and signs of ocular allergy can lead to decreased productivity and negatively impact quality of life (QoL). Various treatment options exist to achieve symptom control. For allergic conjunctivitis, ophthalmic agents include antihistamines, mast cell stabilizers, dual-activity agents, nonsteroidal anti-inflammatory drugs (NSAIDs), steroids and some off-label treatments. Immunotherapy is recommended as a therapeutic option. This review provides a summary of the forms of ocular allergies, with a focus on symptoms and signs, impact on QoL, physical examination, diagnosis and therapeutic options of allergic conjunctivitis. Through multidisciplinary collaborations, a simplified algorithm for the treatment of allergic conjunctivitis is proposed for Canadian clinical practice.

The golden years are much less so if you lose your central vision to neovascular agerelated macular degeneration (AMD). Approximately 15 out of 1000 individuals over age 75 will have advanced AMD; 66% will have the neovascular form that is associated with central vision loss. The introduction of anti-VEGF treatment for neovascular AMD 15 years ago (1) has revolutionized care for these patients, much as pan-retinal photocoagulation (PRP) did for patients with proliferative diabetic retinopathy (PDR) and ischemic retinal vein occlusions (RVO) decades earlier. Because neurovascular cell functions are already compromised by underlying disease (e.g., AMD, diabetes, RVOs), potent, long-lasting VEGF antagonism may be detrimental to the health of cells dependent on its trophic activity. Patients with ischemic (e.g., diabetes, ARMD) retinopathies are likely to have ischemia elsewhere (e.g., heart, brain, kidneys), and the sustained presence of potent VEGF antagonists may prevent adequate collateralization and function in these tissues as well.