Eye Drop Formulation Research Articles

A green chemistry approach towards synthesizing hydrogel for sustained ocular delivery of brinzolamide: In vitro and ex vivo evaluation

Brinzolamide is a carbonic anhydrase inhibitor used in the eye drop form for the treatment of glaucoma. It requires frequent dosing to attain therapeutic concentration. Therefore, this study aimed to prepare sustained ocular drug delivery of brinzolamide. The objective of the study was to prepare a hydrogel loaded with a nanostructured lipid carrier (NLC) of brinzolamide. The hydrogel was prepared by a green synthesis approach using genipin as a natural crosslinking agent and polymers such as carboxymethyl chitosan and poloxamer 407. The melt emulsification-ultra sonication method was used to prepare a nanostructured lipid carrier of brinzolamide, which was loaded into a hydrogel using a swelling and loading method. The NLC formulation has shown small particle sizes of 111.20 ​± ​2.15 ​nm, polydispersity index of 0.280 ​± ​0.005 and % entrapment efficiency of 82.16% ​± ​0.14%. The NLC-loaded hydrogels of brinzolamide formulations were studied for swelling properties and showed temperature and pH-responsive swelling behavior. The optimized hydrogel formulation has been studied for in vitro drug release and showed drug release for a longer duration (24 ​h) than marketed eye drops (8 ​h). In an ex vivo study, hydrogel formulations showed transcorneal permeability 4.54 times greater than marketed eye drops. The hydrogel formulation of brinzolamide produced by the green synthesis method has shown sustained-release properties with no sign of ocular irritation. Hence, the hydrogel of brinzolamide-loaded NLC would be the potential drug delivery approach in the near future for sustained ocular drug delivery in glaucoma management.

A Novel Eye Drop Formulation for Potential Treatment of Neovascular Age-Related Macular Degeneration.

PurposeDrug delivery to posterior ocular tissues via topical eye drop administration is arduous due to the unique anatomy and physiology of the eye. Therefore, treatments for posterior eye disease have to be administered via intravitreal injection or systemic route, both of which have their drawbacks. Herein, the objective of this work was to demonstrate that a specially designed eye drop formulation could effectively deliver small-molecule vascular endothelial growth factor (VEGF) inhibitor to posterior ocular tissues for antiangiogenic therapy.MethodsThe unique eye drop formulation, termed ITRI AXN eye drops, was obtained from self-assembly of (2-hydroxypropyl)-β-cyclodextrin with a VEGF tyrosine kinase inhibitor, a hydrophilic polymer, hypromellose, and a complex stabilizer, caffeine. In vivo ocular pharmacokinetics studies were performed with New Zealand White (NZW) rabbits and Non Human Primates (NHP). The antiangiogenesis effect was evaluated on the Long-Evans rat with laser-induced choroidal neovascularization and pigmented Dutch-Belted rabbits with VEGF-induced retinal neovascularization.ResultsThe successful drug transport from ocular surface to posterior ocular cavity was indicated by a drug biodistribution pattern in pharmacokinetic studies. Excellent drug exposure in the choroid and retina with the concentrations of 900- and 750-fold greater than drug IC50 0.5 hours post the eye drop administration (drug level: 0.8%) was observed on the NHP study. The obtained formulation also demonstrated a comparable antiangiogenic outcome with the intravitreal injection of anti-VEGF antibody on rat and rabbit disease models.ConclusionsOur eye drop formulation has demonstrated great promise in antiangiogenic therapy against retinal and choroidal neovascularization in animal models. The results suggest that the aim of this work can be successfully achieved by the novel eye drop formulation.Translational RelevanceThe preclinical results provide evidence that ITRI AXN eye drops could effectively deliver therapeutics to the choroid and retina for antiangiogenic therapy.

Therapeutic Effects of Fenofibrate Nano-Emulsion Eye Drops on Retinal Vascular Leakage and Neovascularization.

Simple SummaryAge-related macular degeneration (AMD) and diabetic retinopathy (DR) are the leading causes of blindness and lack non-invasive drug treatments. Macular edema and neovascularization are the key pathogenic features responsible for vision loss in AMD and DR. Clinical studies showed that fenofibrate, a PPARα agonist, has robust therapeutic effects on macular edema and retinal neovascularization after oral administration. However, the efficacy of oral fenofibrate remains to be improved, due to limited amounts of the drug delivered to the retina after systemic administration. To increase the drug availability in the retina, this study developed a novel nano-emulsion fenofibrate eye drop. Topical administration of the fenofibrate eye drop delivered significantly higher drug concentrations to the retina/vitreous, relative to the systemic administration. The fenofibrate eye drop alleviated retinal inflammation and vascular leakage in both DR and AMD models. Further, the fenofibrate eye drop also alleviated laser-induced choroidal neovascularization. These findings suggest that topical administration of the nano-emulsion-based eye drop of a PPARα agonist has potential to become a non-invasive therapeutic strategy for long-term treatment of DR and AMD.Macular edema caused by retinal vascular leakage and ocular neovascularization are the leading causes of severe vision loss in diabetic retinopathy (DR) and age-related macular degeneration (AMD) patients. Oral administration of fenofibrate, a PPARα agonist, has shown therapeutic effects on macular edema and retinal neovascularization in diabetic patients. To improve the drug delivery to the retina and its efficacy, we have developed a nano-emulsion-based fenofibrate eye drop formulation that delivered significantly higher amounts of the drug to the retina compared to the systemic administration, as measured by liquid chromatography–mass spectrometer (LC-MS). The fenofibrate eye drop decreased leukocytes adherent to retinal vasculature and attenuated overexpression of multiple inflammatory factors in the retina of very low-density lipoprotein receptor knockout (Vldlr−/−) mice, a model manifesting AMD phenotypes, and streptozotocin-induced diabetic rats. The fenofibrate eye drop also reduced retinal vascular leakage in these models. The laser-induced choroidal neovascularization was also alleviated by the fenofibrate eye drop. There were no detectable ocular toxicities associated with the fenofibrate eye drop treatment. These findings suggest that fenofibrate can be delivered efficiently to the retina through topical administration of the nano-emulsion eye drop, which has therapeutic potential for macular edema and neovascularization.

NEED OF AWARENESS ABOUT OVER THE COUNTER STEROID INTAKE – A CASE SERIES.

Steroids are anti-inammatory drugs widely prescribed by all physicians and are very commonly used to treat ocular as well as systemic conditions. Unmonitored use of steroids is common in situations when it is easily available over-the-counter especially in eye drop formulations, resulting in several side effects.(1) Chronic administrations of steroids in all forms can raise intraocular pressure (IOP) resulting in optic neuropathy causing steroid-induced glaucoma. (2) We have reported four cases of steroid induced glaucoma that presented to the Ophthalmology OPD. The purpose is to familiarize and create awareness in all clinicians especially ophthalmologists and practitioners of alternate medicine prescribing steriods about the potential dangers of administering steroids without monitoring the eye and the dangers of irreversible blindness in some instances of habitual self-prescription by patients.

A Rapid Corneal Healing Microneedle for Efficient Ocular Drug Delivery.

Fungal keratitis (FK) remains a serious clinical problem worldwide, so the ultimate goal of the treatment is to develop a minimally invasive, safe, and effective method for ocular drug delivery. Here, a minimally invasive delivery system is reported for treating FK by using a dissolving microneedle (MN)-array patch based on Poly(D,L-lactide) (PLA) and hyaluronic acid (HA). By altering the concentration of PLA, MN patches with excellent properties are modified and optimized. The 30% PLA-HA MN patches penetrate the corneal epithelial layer reversibly with no apparent ocular irritation as well as a short recovery time of less than 12 h, and increase the residence time by 2.5 h in the conjunctival sac, thereby offering higher drug bioavailability. Remarkably, the rabbit model of FK shows that the topical MN(+) patch medication exerts superior therapeutic effects compared with the conventional eye drop formulation, and also presents comparable therapeutic efficacy with that of the clinical mainstay strategy (i.e., intrastromal injection). Therefore, the MN patch, acting as an ocular drug delivery system with high efficacy and ability of rapid corneal healing, promises a cost-effective household solution for the treatment of FK, which may also lead to a new approach for treating FK in clinics.

Development of Lutein-Containing Eye Drops for the Treatment of Dry Eye Syndrome.

Dry eye syndrome (DES) is a common ophthalmological disease that decreases tear secretion and causes dryness, photophobia, pain, severe corneal rupture, and even blindness. Ocular and lacrimal gland inflammation is one of the pathological mechanisms underlying DES. Therefore, effective suppression of inflammation is a crucial strategy for the treatment of DES. Lutein, commonly found in healthy foods, has anti-inflammatory effects in corneal or retina-related cells and may be a potential therapy for DES. The addition of lutein to artificial tears (AT) as an eye-drop formulation for DES treatment in a mouse model was studied in the present work. Polyvinyl alcohol (PVA) was used as a thickener to increase the viscosity of eye drops to prolong drug retention on the ocular surface. A WST-8 assay in human corneal epithelial cells (HCE-2) showed that a concentration of <5 μM lutein (L5) and <1% PVA (P1) maintained the cell viability at 80%. A real-time PCR showed that the inflamed human corneal epithelial cells (HCECs) cocultured with L5P1 had downregulated expression of inflammatory genes such as IL-1β, IL-6, and TNF-α. In a benzalkonium chloride- (BAC) induced DES mouse model, AT/L5P1 could repair damaged corneas, elevate tear secretion, increase the number of goblet cells, and inhibit the production of inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, in the cornea. In conclusion, we demonstrate that lutein/PVA as eye drops could prolong the drug ocular retention time and effectively to decrease inflammation in DES mice. Therefore, lutein, obtained from eye drops, has a potential therapeutic role for DES.

Dextran Sulfate Polymer Wafer Promotes Corneal Wound Healing.

Eye injuries due to corneal abrasions, chemical spills, penetrating wounds, and microbial infections cause corneal scarring and opacification that result in impaired vision or blindness. However, presently available eye drop formulations of anti-inflammatory and antibiotic drugs are not effective due to their rapid clearance from the ocular surface or due to drug-related side effects such as cataract formation or increased intraocular pressure. In this article, we presented the development of a dextran sulfate-based polymer wafer (DS-wafer) for the effective modulation of inflammation and fibrosis and demonstrated its efficacy in two corneal injury models: corneal abrasion mouse model and alkali induced ocular burn mouse model. The DS-wafers were fabricated by the electrospinning method. We assessed the efficacy of the DS-wafer by light microscopy, qPCR, confocal fluorescence imaging, and histopathological analysis. These studies demonstrated that the DS-wafer treatment is significantly effective in modulating corneal inflammation and fibrosis and inhibited corneal scarring and opacification compared to the unsulfated dextran-wafer treated and untreated corneas. Furthermore, these studies have demonstrated the efficacy of dextran sulfate as an anti-inflammatory and antifibrotic polymer therapeutic.

A Comparative Study Between Preoperative Subconjunctival Bevacizumab Injection And Postoperative Topical Application In Prevention Of Recurrence After Excision Of Primary Pterygium In Egyptian Patients

Abstract Purpose to compare between recurrence incidence after primary pterygium excision when using preoperative subconjunctival injection of Bevacizumab (Avastin) and using it as a postoperative eye drops. Methods thirty two eyes of thirty patients (two patients had bilateral pterygium) with primary pterygia were clinically examined, classified into 3 groups and operated by simple excision with bare sclera technique. Group 1 included 10 patients received Bevacizumab (Avastin) in the form of eye drops (10 mg/ml) 3 times daily for 6 days postoperative. Group 2 included 10 patients received preoperative Bevacizumab in the form of subconjunctival injection (1.25 mg/0.05ml) single dose 1 week preoperative. Group 3 included 10 patients (12 eyes) 2 patients with bilateral Pterygium didn’t receive any form of Bevacizumab. Postoperative follow up was done clinically and by serial photography at 1 week, 1 month, 3 months and 6 months searching for signs of recurrence and/or complications. Results The results showed different grades of recurrence in 18 eyes of 32.True recurrence was seen in 7 patients of 18 (1 patient in group 1, 2 in group 2 and 4 in group3).Recurrence grades in group 1and 2 who used the Bevacizumab (20%grade II, 50% grade III, and 30% grade IV). Recurrence could be predicted by 100% depending on fibrovascular tissue appearing in the surgical bed at 3 months postoperative (P value 0.038).Preoperative fleshy pterygium has high statistical significance in realation to recurrence(P value = 0.006).Patient’s sex, residence and occupation had no statistically significant value in the process of recurrence (P value &amp;gt; 0.05). Patients with recurrent Pterygia (in group 1&amp;2) had statistically significant changes in the corneal K- readings at 3 months and 6 months.No significant difference in the limbal or central corneal thickness in the operated eye and the other eye (Pvalue &amp;gt; 0.05). Conclusion Bevacizumab (Avastin) is a well tolerated drug with multiple drug delivery methods.The eye drops give better results than the subconjunctival injection.Appearance of fibrovascular tissue in the surgical bed at 3 months predict the recurrence by 100%. Preoperative fleshy pterygia will mostly recur again whatever Bevacizumab form was used .The corneal thickness by anterior segment OCT has no role in prediction or detection of early pterygium recurrence.

Prerequisites to Use Preservative-Free Drugs in Medication Therapy of Glaucoma

Purpose — to analyze the literature data on the benefits of preservative-free medication therapy for glaucoma.Materials and methods. 482 articles in the Pubmed database published from 1975 to 2020 were analyzed using the terms: “glaucoma”, “preservatives”, “preservative-free therapy”, “benzalkonium chloride”. The review includes 78 articles. Inclusion criteria: studies that examined the effect of local antihypertensive therapy on the condition of the ocular surface in comparison with preservative-free drugs.Discussion. BAC is the most common preservative used in ophthalmology, accounting for 70 % of eye drop formulations. But it has a pronounced toxic effect on the ocular surface, so other classes of preservatives have been developed. These include polyquaternium-1 detergent; oxidizing preservatives — stabilized oxychlorocomplex and sodium perborate; ionic buffer preservative. However, most of the publications are devoted to BAC, as it is considered the most toxic and, at the same time, the most commonly used preservative. There is a large number of switching studies from preservative therapy to preservative-free, in which almost all groups of drugs used for the treatment of glaucoma were studied, but the use of antihypertensive drugs is associated not only with the action of preservatives, but also with the active substance, excipients and buffers. However, most switching studies demonstrate the benefits of preservative-free drugs. Other studies compared preservative and preservative-free drugs with the same active ingredients, in which a comparable hypotensive effect and safety profile was revealed, which indicates that BAC is not required for adequate penetration of the active substance to the point of application. At the same time, statistically significant advantages in the tolerability of preservativefree therapy were also revealed.Conclusion. Glaucoma preservative therapy has a toxic effect on the ocular surface, which leads to a decrease in the quality of life and compliance. Switching to preservative-free drugs can help reduce iatrogenic complications during long-term treatment of patients with glaucoma

Novel Formulation of Eye Drops Containing Choline Salicylate and Hyaluronic Acid: Stability, Permeability, and Cytotoxicity Studies Using Alternative Ex Vivo and In Vitro Models.

This work investigated the potential of a novel formulation of eye drops containing a non-steroidal anti-inflammatory drug—choline salicylate (CS)—and hyaluronic acid (HA). Thus, these drops may exert both anti-inflammatory and regenerative activity. The experiment was conducted through the careful characterization of physicochemical properties, stability, and quality of eye drops. Moreover, microbiological analysis, as well as penetration and cytotoxic studies, were performed. The UV, HPLC-UV, and HPLC-MS/MS methods were used to determine the purity and stability of CS. The penetration rate of CS was assessed using a hydrophilic membrane and ex vivo porcine cornea model. Additionally, the cytotoxic effects were evaluated using the SIRC cell line. The interaction between HA and CS was tested using size-exclusion chromatography and IR spectrophotometry. As a result, HA increased the viscosity of the drops, which prolonged their contact with the ocular surface, thus ensuring more effective penetration of CS into the corneal structure. After long-term storage, an interaction in the pharmaceutical phase between CS and HA was observed. However, this interaction did not affect the viability of rabbit corneal cells. Our findings showed that eye drops with CS and HA, stored at 2–8 °C in light-protected conditions, met the criteria of stability and safety.

Controlling progression of bacterial biofilm by herbal eye care formulation

Pseudomonas aeruginosa and Staphylococcus aureus causing common eye-infection ‘keratitis’ develop resistance to antibiotics by forming biofilm. Present study evaluates anti-biofilm properties of three commercially available eye care herbal formulations against P. aeruginosa and S. aureus. Eye drop formulations were tested for total phenolic content and antimicrobial activity. Biofilm growth over glass in the presence of herbal formulation was examined under fluorescence microscope. The herbal formulations rich in phenolics, tested at 10% (v/v) concentration showed growth inhibitory effect on planktonic cells. During biofilm mode of growth, 10% of herbal formulation caused considerable decline in growth of biofilm, although did not inhibit it completely. The response to different herbal formulations varied markedly among the different bacterial strains tested. Herbal components can significantly affect the surface topology of biofilms, thereby restricting the attachment of the cell to the substratum.

Retinoprotective Effects of PACAP Eye Drops in Microbead-Induced Glaucoma Model in Rats.

Glaucoma is associated with increased intraocular pressure (IOP), causing the apoptosis of retinal ganglion cells (RGCs) and the loss of their axons leading to blindness. Pituitary adenylate cyclase activating polypeptide (PACAP) is neuroprotective in several neural injuries, including retinopathies. The aim of this study was to investigate the effects of PACAP1-38 eye drops in a model of glaucoma. IOP was elevated bilaterally by injections of microbeads to block the aqueous humor outflow. The control groups received the same volume of saline. Animals were treated with PACAP1-38 (1 µg/drop, 3 × 1 drop/day) or vehicle for 4 weeks starting one day after the injections. Retinal morphology by histology and optical coherence tomography, function by electroretinography, and IOP changes were analyzed. Animals were sacrificed 8 weeks after the injections. Microbeads injections induced a significant increase in the IOP, while PACAP1-38 treatment lowered it to normal levels (~10 mmHg). Significant retinal degeneration and functional impairment were observed in the microbead-injected group without PACAP1-38 treatment. In the microbeads + PACAP1-38 group, the retinal morphology and functionality were close to the normal values. In summary, our results show that PACAP1-38, given in form of eye drops, is neuroprotective in glaucoma, providing the basis for potential future therapeutic administration.

A non-invasive nanoparticle-based sustained dual-drug delivery system as an eyedrop for endophthalmitis

Endophthalmitis is an infectious disease that affects the entire eye spreading to the internal retinal layers and the vitreous and causes severe sight-threatening conditions. Current treatment strategies rely on intraocular injections of antibiotics that are invasive, may lead to procedural complications and, ultimately, blindness. In this study, we developed a non-invasive strategy as an eyedrop containing nanoparticle-based dual-drug delivery system in which the hydrophobic poly-L-lactide core was loaded with azithromycin or triamcinolone acetonide, and the hydrophilic shell was made of chitosan. The developed nanoparticles were ~200–250 nm in size, spherical in shape, moderately hydrophilic, lysozyme tolerant, cytocompatible, and hemocompatible. Application of these chitosan-coated nanoparticles as eye drops to C57BL/6 mice showed higher bioavailability in choroid and retina when compared to the uncoated nanoparticles. The delivery system showed sustained release of drug for 300 h and exhibited antimicrobial effects against Gram-positive and Gram-negative bacteria and anti-inflammatory effects on activated microglial cells. Interestingly, the combination of the nanoparticles loaded with azithromycin and the nanoparticles loaded with triamcinolone acetonide acted synergistically as compared to either of the nanoparticles/drugs alone. Overall, the developed dual-drug delivery system is non-invasive, has antimicrobial and anti-inflammatory effects, and shows potential as an eye drop formulation against endophthalmitis.

Improving Adherence to Topical Medication in Patients with Glaucoma.

The glaucomas form a heterogenous group of conditions, which collectively account for one of the most common irreversible causes of blindness worldwide. The only treatment, for which there is evidence, to stop or slow glaucomatous disease progression is to lower intraocular pressure (IOP); this is most often initially achieved with topical medication. Adherence to anti-glaucoma therapy is known to be low even when compared with adherence to therapy for other chronic conditions. We performed a PubMed search to review evidence as to how adherence to and persistence with anti-glaucoma medications might be improved. Approaches to improving adherence include technological (such as using smart drop bottles or automated reminders) use of instillation aids, improving communication with patient education and improving tolerability of eye drop formulations. There is limited short-term evidence that automated reminders can be effective and, unfortunately, instillation aids have not proved to be efficacious with respect to improving adherence. A range of factors have been identified which affect adherence and persistence, although only a multi-faceted approach has proven evidence of efficacy, compared to improved patient education alone. There is now a wider range of available preservative-free eye drops, which have been shown to be non-inferior in achieving IOP control, with fewer side effects and improved short-term adherence. Further studies relating to adherence are warranted, particularly given the projected increase in glaucoma prevalence worldwide.

Pharmacological evaluation of innovative eye drop formulations containing TS-polysaccaride, hyaluronic acid and glycyrrhizin for irritative ocular diseases using in vitro reconstituted human corneal epithelium model

In vitro reconstructed human corneal tissue models are closer to in vivo human corneal tissue in term of morphology, biochemical and physiological properties, and represent a valid alternative to animal use for evaluating the pharmacological effects ophthalmic topically applied medical devices. In this experimental work the in vitro reconstructed human corneal tissues have been used for assessing the potential beneficial effects of an innovative ophthalmic formulation containing hyaluronic acid, glycyrrhizin and TS-polysaccharide for the treatment of symptomatic states on the eye surface including dry eye, itching, foreign body sensation and redness due allergic reaction. Corneal tissues have been treated with benzalkonium chloride for 24 h to induce cell damage and then treated with the tested items for 16 h. After the incubation period, tissue viability, TNF-α, IL-6 and MMP-9 have been assessed. Diclofenac has been used as reference anti-inflammatory drug. The novel formulation protected the tissues against benzalkonium chloride damage, while exerted a mild but not significant reduction of the anti-inflammatory mediator TNF-α.

Development of the technology of a liposomal form of eye drops based on a peptide complex

Development of the technology of a liposomal form of eye drops based on a peptide complex

Polymeric Micelles for the Enhanced Deposition of Hydrophobic Drugs into Ocular Tissues, without Plasma Exposure.

Commercial topical ocular formulations for hydrophobic actives rely on the use of suspensions or oil in water emulsions and neither of these formulation modalities adequately promote drug penetration into ocular tissues. Using the ocular relevant hydrophobic drug, cyclosporine A (CsA), a non-irritant ocular penetration enhancer is showcased, which may be used for the formulation of hydrophobic actives. The activity of this penetration enhancer is demonstrated in a healthy rabbit model. The Molecular Envelope Technology (MET) polymer (N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan), a self-assembling, micelle-forming polymer, was used to formulate CsA into sterile filtered nanoparticulate eye drop formulations and the stability of the formulation tested. Healthy rabbits were dosed with a single dose of a MET–CsA (NM133) 0.05% formulation and ocular tissues analyzed. Optically clear NM133 formulations were prepared containing between 0.01–0.1% w/v CsA and 0.375–0.75% w/v MET polymer. NM133 0.01%, NM133 0.02% and NM133 0.05% were stable for 28 days when stored at refrigeration temperature (5–6 °C) and room temperature (16–23 °C), but there was evidence of evaporation of the formulation at 40 °C. There was no change in drug content when NM133 0.05% was stored for 387 days at 4 °C. On topical dosing to rabbits, corneal, conjunctival and scleral AUC0–24 levels were 25,780 ng.h g−1, 12,046 ng.h g−1 and 5879 ng.h g−1, respectively, with NM133 0.05%. Meanwhile, a similar dose of Restasis 0.05% yielded lower values of 4726 ng.h/g, 4813 ng.h/g and 1729 ng.h/g for the drug corneal, conjunctival and scleral levels, respectively. NM133 thus delivered up to five times more CsA to the ocular surface tissues when compared to Restasis. The MET polymer was non-irritant up to a concentration of 4% w/v. The MET polymer is a non-irritant ocular penetration enhancer that may be used to deliver hydrophobic drugs in optically clear topical ocular formulations.

Assessment of a New Nanostructured Microemulsion System for Ocular Delivery of Sorafenib to Posterior Segment of the Eye.

Eye drop formulations allowing topical treatment of retinal pathologies have long been sought as alternatives to intravitreal administration. This study aimed to assess whether a novel nanostructured microemulsions system (NaMESys) could be usefully employed to deliver sorafenib to the retina following topical instillation. NaMESys carrying 0.3% sorafenib (NaMESys-SOR) proved to be cytocompatible in vitro on rabbit corneal cells, and well-tolerated following b.i.d. ocular administration to rabbits during a 3-month study. In rats subject to retinal ischemia-reperfusion, NaMESys-SOR significantly inhibited retinal expression of tumor necrosis factor-alpha (TNFα, 20.7%) and inducible nitric oxide synthase (iNos, 87.3%) mRNAs in comparison to controls. Similarly, in streptozotocin-induced diabetic rats, NaMESys-SOR inhibited retinal expression of nuclear factor kappa B (NFκB), TNFα, insulin like growth factor 1 (IGF1), IGF1 receptor (IGF1R), vascular endothelial growth factor receptor 1 (VEGFR1) and 2 (VEGFR2) mRNAs by three-fold on average compared to controls. Furthermore, a reduction in TNFα, VEGFR1 and VEGFR2 protein expression was observed by western blot. Moreover, in mice subject to laser-induced choroidal neovascularization, NaMESys-SOR significantly inhibited neovascular lesions by 54%. In conclusion, NaMESys-SOR was shown to be a well-tolerated ophthalmic formulation able to deliver effective amounts of sorafenib to the retina, reducing proinflammatory and pro-angiogenic mediators in reliable models of proliferative retinopathies. These findings warrant further investigations on the full therapeutic potential of NaMESys-SOR eye drops, aiming to address unmet needs in the pharmacotherapy of retinal neovascular diseases.

Ингибиторы ангиотензин-превращающего фермента в составе кальций-фосфатных наночастиц как перспективные препараты для снижения внутриглазного давления

Purpose. To find out the possibility of using angiotensin-converting enzyme (ACE) inhibitors included in calcium-phosphate nanoparticles (CFPs) to reduce intraocular pressure (IOP). Material and methods. Preparation of calcium-phosphate nanoparticles, introduction of ACEI in them, comparative evaluation of the action of enalaprilat, lisinopril and the beta-blocker timolol in the composition of CPF by determining their effect on intraocular pressure in rabbits. Results. Enalaprilat, lisinopril and the beta-blocker timolol in the composition of CPF statistically more significantly reduce intraocular pressure compared to simple solutions of these drugs. Conclusion. The introduction of drugs that reduce IOP into the CPF increases their bioavailability with the instillation method of administration, while their biological activity is preserved, and the effectiveness of the therapeutic effect increases. The results indicates the prospects of using CFPs to include ocular antihypertensive drugs used in the form of eye drops. Key words: calcium-phosphate nanoparticles, angiotensin-converting enzyme inhibitor, intraocular pressure.

Aqueous eye drops containing drug/cyclodextrin nanoparticles deliver therapeutic drug concentrations to both anterior and posterior segment.

Using topical application to deliver therapeutic concentrations of drugs to the posterior segment of the eye remains very challenging. As a result, posterior segment diseases are usually treated by intravitreal injection or implant. While topical treatments are commonly used for anterior segment conditions, they sometimes require frequent applications. Eye drop formulations based on γ-cyclodextrin (γCD)-based nanoparticle aggregates were developed, which in animal models and clinical studies deliver therapeutic concentrations of drugs (dorzolamide and dexamethasone) to both anterior and posterior segments of the eye. An early study in humans showed dorzolamide/γCD eye drops could achieve comparable intraocular pressure decreases to commercial dorzolamide eye drops, but with less frequent application. Pilot studies with dexamethasone/γCD eye drops suggested that they could be effective in a range of conditions, including diabetic macular oedema, cystoid macular oedema and vitritis secondary to uveitis, postcataract surgery inflammation and postoperative treatment in trabeculectomy. Phase II studies with similar dexamethasone/γCD nanoparticle eye drops in diabetic macular oedema and postcataract surgery inflammation have recently been completed. This technology has the potential to be used with other classes of drug molecules and to replace or complement invasive treatments, providing safer, non-invasive therapies, particularly for posterior segment conditions, that can be self-administered as eye drops by patients.