Targeting Ocular Drug Delivery: An Examination of Local Anatomy and Current Approaches.

Ocular drug delivery remains the focus of much modern research. Primary routes of administration include the surface, the intravitreal space, the subretinal space, and the subconjunctival space, each with its own series of unique challenges, limitations, and advantages. Each of these approaches requires careful consideration of the local anatomy, physical barriers, and key cells as well as the interface between the anatomy and the drug or drug system being delivered. While least invasive, the topical route poses a challenge with the many physical barriers that prevent drug penetration into the eye; while injection into the intravitreal, subretinal, and subconjunctival spaces are direct and targeted but limited due to the many internal clearance mechanisms and potential for damage to the eye. Polymeric-based, sustained-release drug delivery systems have been identified as a potential solution to many of these challenges; however, the design and successful implementation of a sustained-release system that is well-tolerated, bioactive, biocompatible, and degradable remains, in many cases, only in the early stages. The drugs and biomaterials in question also require special attention as small chemical changes could result in vastly different outcomes. This paper explores the anatomy and key cells of these four primary drug delivery routes as well as the interface between drug and drug delivery systems and the anatomy, reviewing the recent developments and current state of research in each area. Finally, this paper also examines the frequently used drugs and biomaterials found in ocular drug delivery and summarizes the primary interactions observed.

Compartmental and COMSOL Multiphysics 3D Modeling of Drug Diffusion to the Vitreous Following the Administration of a Sustained-Release Drug Delivery System.

The purpose of this study was to examine antibiotic drug transport from a hydrogel drug delivery system (DDS) using a computational model and a 3D model of the eye. Hydrogel DDSs loaded with vancomycin (VAN) were synthesized and release behavior was characterized in vitro. Four different compartmental and four COMSOL models of the eye were developed to describe transport into the vitreous originating from a DDS placed topically, in the subconjunctiva, subretinally, and intravitreally. The concentration of the simulated DDS was assumed to be the initial concentration of the hydrogel DDS. The simulation was executed over 1500 and 100 h for the compartmental and COMSOL models, respectively. Based on the MATLAB model, topical, subconjunctival, subretinal and vitreous administration took most (~500 h to least (0 h) amount of time to reach peak concentrations in the vitreous, respectively. All routes successfully achieved therapeutic levels of drug (0.007 mg/mL) in the vitreous. These models predict the relative build-up of drug in the vitreous following DDS administration in four different points of origin in the eye. Our model may eventually be used to explore the minimum loading dose of drug required in our DDS leading to reduced drug use and waste.

Controlled Release of Vancomycin From a Thermoresponsive Hydrogel System for the Prophylactic Treatment of Postoperative Acute Endophthalmitis.

PURPOSE: To investigate the efficacy of a poly(ethylene glycol) diacrylate and poly(N-isopropylacrylamide) based thermo-responsive hydrogel drug delivery system (DDS) to deliver prophylactic vancomycin (VAN) following ocular surgery. METHODS: VAN was encapsulated in a hydrogel DDS and characterized in terms of initial burst, release kinetics, bioactivity, and cytotoxicity. Long-Evans rats received an intravitreal injection of Staphylococcus aureus to produce acute endophthalmitis in four experimental groups. One of four treatments were then applied: (1) bolus subconjunctival injection of VAN, (2) blank DDS, (3) saline treatment, and (4) subconjunctival injection of VAN DDS. Animals were scored for infection (0-3) at 12, 24, 48, and 72 hours, and eyes were harvested at 24 and 48 hours for histology. RESULTS: Following a 36% initial burst, VAN release from the DDS continued at a steady rate for 2 weeks plateauing at 84% after 504 hours. Bioactivity was maintained for all release samples and cytotoxicity analysis for the DDS revealed cell viability >90%. Not until after 12 hours did any of the groups show evidence of infection; however, at 24 hours, animals that received the VAN DDS had significantly lower infection scores (0 ± 0) than those that received a bolus VAN injection, blank DDS, or saline (1.5 ±1.5, 2.3 ± 0.87, and 2.9 ± 0.25; respectively). At 48 and 72 hours, the VAN DDS and bolus VAN treatment groups performed comparably and showed significantly better infection scores than the control groups. CONCLUSIONS: This DDS appears to have promise as a vehicle for short term, prophylactic antibiotic delivery. TRANSLATIONAL RELEVANCE: This DDS may prevent the development of postoperative endophthalmitis.

Extended ocular drug delivery systems for the anterior and posterior segments: biomaterial options and applications.

INTRODUCTION: The development of new therapies for treating various eye conditions has led to a demand for extended release delivery systems, which would lessen the need for frequent application while still achieving therapeutic drug levels in the target tissues. Areas covered: Following an overview of the different ocular drug delivery modalities, this article surveys the biomaterials used to develop sustained release drug delivery systems. Microspheres, nanospheres, liposomes, hydrogels, and composite systems are discussed in terms of their primary materials. The advantages and disadvantages of each drug delivery system are discussed for various applications. Recommendations for modifications and strategies for improvements to these basic systems are also discussed. Expert opinion: An ideal sustained release drug delivery system should be able to encapsulate and deliver the necessary drug to the target tissues at a therapeutic level without any detriment to the drug. Drug encapsulation should be as high as possible to minimize loss and unless it is specifically desired, the initial burst of drug release should be kept to a minimum. By modifying various biomaterials, it is possible to achieve sustained drug delivery to both the anterior and posterior segments of the eye.