Posterior Ocular Diseases Research Articles

Preclinical Evaluation of UDCA-Containing Oral Formulation in Mice for the Treatment of Wet Age-Related Macular Degeneration.

As a posterior ocular disease, wet age-related macular degeneration (WAMD) has been known to be related to vision loss, accompanying ocular complications. The intravitreous injection of VEGF antibodies has been reported to be an effective treatment to relieve symptoms of WAMD. However, the limitations of this treatment are high costs and invasiveness. For this reason, oral delivery route can be considered as a cost-effective way and the safest method to deliver drug molecules to the eyes. Accordingly, ursodeoxycholic acid (UDCA) was included in the oral formulation as the potential substance for the cure of WAMD in the animal model. Various pharmacological activities, such as antioxidant or anti-inflammatory effects, have been reported for UDCA and recent reports support the effects of UDCA in ocular treatment. However, due to poor water solubility and low pKa (around 5.0), it has been challenging to formulate aqueous solution of UDCA in the neutral pH range. In the present study, we confirmed the aqueous solubility of the oral UDCA formulation and performed a preclinical study, including pharmacokinetic profiling and WAMD model efficacy study in mice after oral administration of the drug solution. The results demonstrated that the formulation improved bioavailability of UDCA and efficiently delivered UDCA to the eye tissues after oral absorption. UDCA formulation was found to have inhibitory effects of choroidal neovascularization with a functional recovery in mice retinas. Taken together, our results suggest that the oral UDCA formulation could be used as a potent supplement for the cure of WAMD and related retinal diseases.

Hyaluronic Acid-Antibody Fragment Bioconjugates for Extended Ocular Pharmacokinetics.

Treatment of ocular diseases associated with neovascularization currently requires frequent intravitreal injections of antivascular endothelial growth factor (anti-VEGF) therapies. Reducing the required frequency of anti-VEGF injections and associated clinical visits may improve patient adherence to the prescribed treatment regimen and improve outcomes. Herein, we explore conjugation of rabbit and fragment antibodies (Fab) to the biopolymer hyaluronic acid (HA) as a half-life modifying strategy, and assess the impact on Fab biophysical properties and vitreal pharmacokinetics. HA-Fab conjugates of three distinct molecular weights and hydrodynamic radii (RH) were assessed for in vivo pharmacokinetic performance relative to unconjugated Fab after intravitreal injection in rabbits. Covalent conjugation to HA did not significantly alter the thermal stability or secondary or tertiary structure, or diminish the potency of the Fab, thereby preserving its pharmacological properties. Conjugation to HA did significantly slow the in vivo clearance of Fab from the rabbit vitreous in an RH-dependent manner. Compared to free Fab (observed vitreal half-life of 2.8 days), HA-Fab conjugates cleared with observed half-lives of 7.6, 10.2, and 18.3 days for 40 kDa, 200 kDa, and 600 kDa HA conjugates, respectively. This work elucidates a possible strategy for long-acting delivery of proteins intended for the treatment of chronic posterior ocular diseases.

Octopus-like Flexible Vector for Noninvasive Intraocular Delivery of Short Interfering Nucleic Acids.

Gene therapy is promising for chronic posterior ocular diseases, which are causal factors for severe vision impairment and even blindness worldwide. However, the inherent absorption barriers of the eye restrict intraocular delivery of therapeutic nucleic acids via topical instillation. Safe and efficient nonviral vectors for ocular gene therapy are still unmet clinical desires. Herein, an octopus-like flexible multivalent penetratin (MVP) was designed to facilitate condensation and delivery of therapeutic nucleic acids using multiarm polyethylene glycol (PEG) as a core and conjugating penetratin at each end of the PEG arms as outspread tentacles. Among the MVPs, 8-valent penetratin (8VP) stably compacted nucleic acids into positively charged polyplexes smaller than 100 nm, promoting cellular uptake efficiency (approaching 100%) and transfection rate (over 75%). After being instilled into the conjunctival sac, 8VP enabled rapid (<10 min) and prolonged (>6 h) distribution of nucleic acids in the retina via a noncorneal pathway. In a retinoblastoma-bearing mice model, topical instillation of 8VP/siRNA efficiently inhibited the protein expression of intraocular tumor without toxicity. MVP is advantageous over the commercial transfection reagent in safety and efficiency, and therefore provides a promising vector for noninvasive intraocular gene delivery.

In Situ Gel of Triamcinolone Acetonide-Loaded Solid Lipid Nanoparticles for Improved Topical Ocular Delivery: Tear Kinetics and Ocular Disposition Studies.

Triamcinolone acetonide (TA), an intermediate acting corticosteroid, is used in the treatment of posterior ocular diseases, such as inflammation, posterior uveitis, and diabetic macular edema. The objective of this investigation was to prepare TA-loaded solid lipid nanoparticles (TA-SLNs) and in situ gel (TA-SLN-IG) formulations for delivery into the deeper ocular tissues through the topical route. TA-SLNs were prepared by hot homogenization and ultrasonication method using glyceryl monostearate and Compritol® 888ATO as solid lipids and Tween®80 and Pluronic® F-68 as surfactants. TA-SLNs were optimized and converted to TA-SLN-IG by the inclusion of gellan gum and evaluated for their rheological properties. In vitro transcorneal permeability and in vivo ocular distribution of the TA-SLNs and TA-SLN-IG were studied using isolated rabbit corneas and New Zealand albino rabbits, respectively, and compared with TA suspension, used as control (TA-C). Particle size, PDI, zeta potential, assay, and entrapment efficiency of TA-SLNs were in the range of 200–350 nm, 0.3–0.45, −52.31 to −64.35 mV, 70–98%, and 97–99%, respectively. TA-SLN-IG with 0.3% gellan gum exhibited better rheological properties. The transcorneal permeability of TA-SLN and TA-SLN-IG was 10.2 and 9.3-folds higher compared to TA-C. TA-SLN-IG showed maximum tear concentration at 2 h, indicating an improved pre-corneal residence time, as well as higher concentrations in aqueous humor, vitreous humor and cornea at 6 h, suggesting sustained delivery of the drug into the anterior and posterior segment ocular tissues, when compared to TA-SLN and TA-C. The results, therefore, demonstrate that the lipid based nanoparticulate system combined with the in situ gelling agents can be a promising drug delivery platform for the deeper ocular tissues.

Inner layer-embedded contact lenses for ion-triggered controlled drug delivery

Drug leakage during manufacturing and storage process is the main obstacle hindering the application of contact lenses as the carrier for extended ocular drug delivery. In this study, we have designed a novel inner layer-embedded contact lens capable of ion-triggered drug release for extended ocular drug delivery. Using betaxolol hydrochloride as a drug model, drug-ion exchange resin complex dispersed polymer film was used as an inner layer, and silicone hydrogel was used as an outer layer to fabricate inner layer-embedded contact lens. Influence of composition of the inner film and crosslinking degree of the outer hydrogel on drug release profile was studied and optimized for weekly use. The ion-triggered drug eluting property enables the inner layer-embedded contact lens being stable when stored in distilled water at 5 °C for at least 30 days with ignorable drug loss and negligible changes in drug release kinetics. In vivo pharmacokinetic study in rabbits showed sustained drug release for over 168 h in tear fluid, indicating significant improvement in drug corneal residence time. A level A IVIVC was established between in vitro drug release and in vivo drug concentration in tear fluid. In conclusion, this inner layer embedded contact lens design could be used as a platform for extended ocular drug delivery with translational potential for both anterior and posterior ocular disease therapy.

Inner layer-embedded contact lenses for pH-triggered controlled ocular drug delivery

Contact lenses (CLs) are ideally suited for controlled ocular drug delivery, but are limited by short release duration, poor storage stability and low drug loading. In this study, we present a novel inner layer-embedded contact lens capable of pH-triggered extended ocular drug delivery with good storage stability. Blend film of ethyl cellulose and Eudragit S100 was used as the inner layer, while pHEMA hydrogel was used as outer layer to fabricate inner layer-embedded contact lens. Using diclofenac sodium(DS) as a drug model, influence of polymer ratio in the blend film, EC viscosity, drug/polymer ratio, inner layer thickness and outlayer thickness of pHEMA hydrogel on drug release behavior was studied and optimized for daily use. The pH-triggered drug eluting pattern enables the inner layer-embedded contact lens being stored in phosphate buffer solution pH 6.8 with ignorable drug loss and negligible changes in drug release pattern. In vivo pharmacokinetic study in rabbits showed sustained drug release for over 24 h in tear fluid, indicating significant improvement in drug corneal residence time. A level A IVIVC was established between in vitro drug release and in vivo drug concentration in tear fluid. In conclusion, this inner layer embedded contact lens design could be used as a platform for extended ocular drug delivery with translational potential for both anterior and posterior ocular diseases therapy.

Development of Sustained Drug Release Devices for Posterior Ocular Diseases

Development of Sustained Drug Release Devices for Posterior Ocular Diseases

Preparation and Evaluation of Biodegradable Scleral Plug Containing Curcumin in Rabbit Eye

ABSTRACTBackground: To test whether biodegradable curcumin-loaded scleral plug is a promising choice for treating posterior ocular diseases, the study investigated the in vitro release profile of the scleral plug and its safety in vivo.Methods: Scleral plugs containing 0.5 mg, 1.0 mg and 1.5 mg curcumin were synthesized by a compression-sintering method. These scleral plugs were placed in tubes containing balanced salt solution (BSS) buffer, which was replaced by fresh buffer daily. The curcumin concentration in the removed aliquot was tested daily for 14 days using high-performance liquid chromatography (HPLC). In the study, 44 rabbits were randomly divided into four groups: control, 0.5 mg, 1.0 mg and 1.5 mg curcumin groups. The scleral plug was trans-scleral fixed in the right eye of the rabbits in the three curcumin-treated groups. The control rabbits only received sclerotomy. The treated rabbit eyes were examined by a slit-lamp biomicroscope, an indirect ophthalmoscope and electroretinogram (ERG), and subjected to histological analysis.Results: The concentration of the 1.5 mg curcumin-loaded scleral plug was higher than 15 μg/ml for consecutive 14 days in vitro. The in vivo experiments revealed intraocular pressure, a-wave and b-wave amplitudes of ERG, and conjunctival reaction degree were not significantly different between the four groups. Retinal structure was normal in the curcumin-treated groups. The sclerotomy wound healed after the plug was completely degraded. Anterior chamber reaction or complications were not observed.Conclusion: The study suggests that curcumin-loaded scleral plug could sustain high concentration of curcumin in vitro and is safe in vivo. It might be a promising alternative choice for the treatment of posterior ocular diseases.

Clinical Applications of Dexamethasone for Aged Eyes.

The risk of severe eye problems has been found to increase significantly with age, particularly between the fifth and sixth decades of life. Cataracts, dry eye, neovascular age-related macular degeneration, diabetic retinopathy and retinal vein occlusion (RVO) are very common and very different age-related ocular diseases that reduce the patient's quality of life. The rationale for using corticosteroids to treat anterior and posterior ocular segment diseases is driven by inflammation. Dexamethasone, one of the most powerful corticosteroids available, is widely used for topical or intravitreal administration. Topical dexamethasone has proven efficacy for the management of postoperative inflammation in the anterior segment after cataract surgery and symptom relief in dry-eye disease. A new sustained-release 700µg dexamethasone intravitreal implant (DEX) was recently approved for the treatment of macular edema following RVO, diabetic macular edema, or non-infectious uveitis, and its use is increasing, especially when other therapeutic agents have failed. The most common side effects are increased intraocular pressure and cataract formation. The potency of DEX, alone or in combination with other agents, makes DEX a promising option for treating several retinal diseases.

Poly(ortho ester) nanoparticles targeted for chronic intraocular diseases: ocular safety and localization after intravitreal injection

Treatment of posterior eye diseases is more challenging than the anterior segment ailments due to a series of anatomical barriers and physiological constraints confronted by drug delivery to the back of the eye. In recent years, concerted efforts in drug delivery have been made to prolong the residence time of drugs injected in the vitreous humor of the eye. Our previous studies demonstrated that poly(ortho ester) (POE) nanoparticles were biodegradable/biocompatible and were capable of long-term sustained release. The objective of the present study was to investigate the safety and localization of POE nanoparticles in New Zealand white rabbits and C57BL/6 mice after intravitreal administration for the treatment of chronic posterior ocular diseases. Two concentration levels of POE nanoparticles solution were chosen for intravitreal injection: 1.5 mg/ml and 10 mg/ml. Our results demonstrate that POE nanoparticles were distributed throughout the vitreous cavity by optical coherence tomography (OCT) examination 14 days post-intravitreal injection. Intraocular pressure was not changed from baseline. Inflammatory or adverse effects were undetectable by slit lamp biomicroscopy. Furthermore, we demonstrate that POE nanoparticles have negligible toxicity assessed at the cellular level evidenced by a lack of glia activation or apoptosis estimation after intravitreal injection. Collectively, POE nanoparticles are a novel and nontoxic as an ocular drug delivery system for the treatment of posterior ocular diseases.

Topical delivery of aqueous micellar resolvin E1 analog (RX-10045)

PurposeThe primary objective of this study were to optimize aqueous micellar solution of isopropyl ester prodrug of resolvin (RX-10045), study in vivo ocular compatibility and tissue distribution following topical administration. MethodsAn optimized ratio of hydrogenated castor-oil and octoxynol-40 (1.0:0.05wt%) was prepared to entrap RX-10045 in the hydrophobic core of micelles. RX-10045 aqueous micelles were subjected to characterization. In vitro stability studies were performed at 4°C, 25°C and 40°C. In vivo studies were conducted in New Zealand albino rabbits following topical drop administration. ResultsAqueous RX-10045 micellar solutions were successfully prepared. Micelles had a mean diameter of ∼12nm with low negative surface charge. RX-10045 demonstrated high stability in citrate buffer (0.01M) at 40°C. Hackett–McDonald ocular irritation scores were extremely low comparable to negative control. No significant difference in intraocular pressure was noted. Electroretinography studies did not reveal any retinal damage after multiple dosing of RX-10045 micellar solution. Ocular tissue distribution studies demonstrated appreciable drug concentrations in anterior ocular tissues. Moreover, RX-10008 (active metabolite of RX-10045) was detected in retina/choroid upon topical drop instillation. ConclusionsA clear, stable, aqueous 0.1% RX-10045 micellar formulation was successfully prepared. Micellar solution was well-tolerated and did not have any measurable tissue damage in rabbit ocular tissues. Micelles appear to follow conjunctival/scleral pathway to reach back-of-the-eye tissue (retina). Topical aqueous formulations may be employed to treat posterior ocular diseases. Such micellar topical formulations may be more patient acceptable over invasive routes of administrations such as intravitreal injection/implants.

Progress of anti-vascular endothelial growth factor therapy for ocular neovascular disease: benefits and challenges

Objective This review aims to summarize the progress of current clinical studies in ocular angiogenesis treated with anti-vascular endothelial growth factor (VEGF) therapy and to discuss the benefits and challenges of the treatment. Data sources Pubmed, Embase and the Cochrane Library were searched with no limitations of language and year of publication. Study selection Clinical trials and case studies presented at medical conferences and published in peer-reviewed literature in the past decade were reviewed. Results Anti-VEGF agents have manifested great potential and promising outcomes in treating ocular neovascularization, though some of them are still used as off-label drugs. Intravitreal injection of anti-VEGF agents could be accompanied by devastating ocular or systemic complications, and intimate monitoring in both adult and pediatric population are warranted. Future directions should be focused on carrying out more well-designed large-scale controlled trials, promoting sustained duration of action, developing safer and more efficient generation of anti-VEGF agents. Conclusions Anti-VEGF treatment has proved to be beneficial in treating both anterior and posterior neovascular ocular diseases. However, more safer and affordable antiangiogenic agencies and regimens are warranted to be explored.

Polymer-based Therapies for Posterior Segment Ocular Disease

Polymer-based Therapies for Posterior Segment Ocular Disease

Hyaluronan-modified core–shell liponanoparticles targeting CD44-positive retinal pigment epithelium cells via intravitreal injection

Retinal inflammation, a common process of posterior ocular diseases, may lead to severe vision loss or even blindness. Retinal pigment epithelium (RPE) cells are generally considered as the therapeutic target of inflammation pathogenesis. However, the lack of retina-specific distribution for general intravitreous drug delivery systems makes the anti-inflammation treatment inefficient. In the present study, a hyaluronan (HA)-modified core–shell liponanoparticles (HA-LCS-NPs) was designed to improve the treatment efficiency by increasing RPE-targeted distribution. Our in vitro RPE cell uptake study showed that a higher HA grafting density (5.8%) and a higher molecular weight (200–400 kDa) modification of HA improved the intracellular uptake of HA-LCS-NPs. In addition, in vivo distribution evaluation in experimental autoimmune uveitis (EAU) rats revealed that HA-LCS-NPs could specifically target RPE cells through the interaction between the CD44 receptor and the HA ligand, while chitosan nanoparticles (CS-NPs) were limited to the vitreous cavity and the core–shell liponanoparticles (LCS-NPs) only reached the inner layers of the retina. At 7 d post-injection, approximately 75% of the fluorescence of HA-LCS-NPs still remained in the RPE/choroid. In conclusion, HA-LCS-NPs might present a promising intraocular drug delivery system to achieve RPE-targeted distribution and prolonged intraocular residence.

Zur operativen Therapie des Oberlidentropiums - ausgewählte Aspekte

The upper lid entropion is a rare eyelid malposition in which the external lid margin turns inward against the ocular surface. It may be classified as congenital (tarsal malformation, hypoplasia of tarsus, eyelid hyperlaxity) but is more commonly an acquired condition (traumatic, immunopathological, inflammation, involutional forms). Surgery is the treatment of choice for correction of upper lid entropion. Appropriate surgical techniques are available for the respective conditions. This article gives an overview of the most commonly used treatment strategies including non-surgical and surgical procedures. Transcutaneous and intermarginal access routes have proven to be safe methods for minimal or moderate upper lid entropion. Combined surgical procedures (e.g., rotation of tarsoconjunctiva, posterior lamellar graft, everting sutures and autologous cultivated oral mucosal epithelial transplantation and so on) should be applied as treatment strategies for severe upper lid entropion with cicatricial changes in the tarsoconjunctival layer, shortage of posterior lamella and severe ocular surface disease.

Age-Related Macular Degeneration

See related article, pages 613–617. Age-related macular degeneration (AMD) is a chronic degenerative disease of the macula (central part of the retina) that in its late or advanced stage results in progressive loss of central vision.1 There are 2 stages of this disease: early AMD, characterized by the appearance of a lipid-like deposit called drusen, and late AMD, in which patients have loss of vision as a consequence of 1 of 2 processes: geographic atrophy or neovascularization. In geographic atrophy (“dry” AMD), there is confluent atrophy of the choriocapillaries and associated retinal pigment epithelium. In neovascular (“wet”) AMD, there is an ingrowth of new vessels in the choroid that invades the retina, resulting in leakage of serous fluid, lipids, and blood with subsequent fibrous scarring. Although most stroke physicians are aware that AMD is an important cause of vision loss in elderly persons,2 many may not be aware that AMD and stroke are actually very similar diseases. Both conditions share common vascular risk factors (eg, smoking, hypertension), pathogenic mechanisms (eg, carotid artery …

Drug delivery to posterior intraocular tissues: third Annual ARVO/Pfizer Ophthalmics Research Institute Conference.

The third Annual ARVO/Pfizer Ophthalmic Research Institute Conference was held Friday and Saturday, May 4 and 5, 2007 at the Fort Lauderdale Grande Hotel and Yacht Club, Fort Lauderdale, Florida. The conference, funded by the ARVO Foundation for Eye Research through a grant from Pfizer Ophthalmics, provided an opportunity to gather experts from within and outside ophthalmology to develop strategies to address drug delivery to posterior intraocular tissues—a topic of great interest, as the major route of drug delivery is via intravitreous injection. A working group of 33 participants, focused interdisciplinary contributors, 19 observers from ARVO/Pfizer, and clinical and basic ophthalmic researchers convened to identify (1) unmet patient needs regarding current drug delivery, novel treatment of retinal diseases, the potential for novel drug design opportunities, drug delivery methods for targeted localized and sustained release, and delivery of macromolecules (siRNA, DNA); and (2) to evaluate the usefulness of nanoparticles, microbeads, and implants for drug delivery, as well as physical means of drug delivery (ionophoresis, electroporation, and microneedles). Session I: Unmet Needs and New Drug Opportunities in Treating Disorders of the Posterior Segment Session II: Animal Models of Posterior Ocular Diseases Session III: New Drug Design and Delivery Systems: What Do Experts See Beyond the Horizon? Session IV: Ocular Drug Delivery Using Nanoparticles, Microbeads, and Microneedles Session V: Transscleral, Intravitreous, and Suprachoroidal Drug Delivery Session VI: Ocular Tissue Dissection, Modeling, and Ocular Tissue Assays Session VII: Iontophoresis, Electroporation, Electrophoresis, and Photo-acoustic Delivery Each session began with a 10-minute introduction followed by a 30-minute lecture by a distinguished expert. Allan S. Hoffman, ScD, Professor of Bioengineering at the University of Washington, Seattle, presented “Design of Polymer Carriers for Intracellular Delivery of Biomolecular Drugs” and Mansoor Amiji, RPh, PhD, Professor and Associate Chairman of Pharmaceutical Science at Northeastern University (Boston, MA), presented “Nanotechnology for Advanced Drug Delivery.” During the remainder of each session, participants, and attendees discussed pertinent questions, voiced opinions, and identified unanswered questions. These discussions confirmed current and future needs for ocular drug delivery to the posterior segment.

Effects of repeated doses of ivermectin on ocular onchocerciasis: community-based trial in Sierra Leone

Ivermectin seems to be a safe and effective treatment for onchocerciasis when given in a single dose, but less is known about the effects of repeated doses. Also, there seem to be differences in its effectiveness in anterior and posterior segment ocular disease. The ocular effects of ivermectin were studied in 586 villagers who were taking part in a double-blind, placebo-controlled, randomised trial in Sierra Leone. Only those who had received four doses, with 6-month intervals, of ivermectin or placebo were eligible. The 296 ivermectin-treated subjects and the 272 who received placebo were comparable with respect to age, sex, Onchocerca infection, blindness, and visual impairment before treatment. After treatment, the ivermectin group had less anterior segment disease than the placebo group, with significantly lower prevalences of microfilariae in the anterior chamber and cornea, and punctate keratitis (all p<0·001), and iritis (p<0·05). There was no significant difference in the prevalence of sclerosing keratitis, optic atrophy, or chorioretinitis between the groups. Visual acuities tended to be better in the ivermectin group, but the difference was not significant. There was a small but significant (p<0·01) excess of vascular sheathing in the ivermectin group. These differences persisted when subjects who were blind or visually impaired at baseline were excluded from analysis. The long-term effects of ivermectin, particularly on posterior segment disease, need further evaluation. In the mean time, the mass distribution of ivermectin should be promoted for all communities with hyperendemic onchocerciasis at risk of anterior segment disease.