Poster P1 - Optimizing Topical Drug Delivery Formulations for Posterior Eye Segment Diseases

Introduction: In 2019, estimates by the Word Health Organization indicated there were around 196 million people with age-related macular degeneration (AMD), which has become the leading cause of blindness in patients over 65 years of age. Further, diabetic retinopathy cases were at 146 million in 2019 and are projected to grow to 181 million by 2030. As our population ages, the clinical need for treatment of posterior eye segment diseases will continue to grow as a significant healthcare challenge. This is because the gold standard of care for such diseases consists of monthly intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF). These are not only uncomfortable, but they also require the patient to have access to high quality eyecare at very expensive price points. Thus, current treatments create a significant source of inequity in eyecare access and impose a disproportionate burden on marginalized communities. While no current topical treatment exists for these diseases, we view a treatment option in the form of eyedrops as a less invasive and more accessible alternative. However, a key challenge to topical formulations is that the bioavailability of drugs administered to the eye is very low, with only 5-10% of the active therapeutic entering the eye. To address this challenge, we have optimized thermosensitive in situ gel formulations and polymeric nanoparticles to create a topical ocular drug delivery platform that could be used as a more accessible form of treatment for posterior eye segment diseases.

Materials and

Methods: In situ gel (ISG) formulations were fabricated using Pluronic F-127, a triblock co-polymer of Poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide), chitosan (Ch), alginate, and poly(acrylic acid) (PAA). The concentration of polymers in each formulation was varied to modulate the gelling point. The formulations were evaluated for optical transparency using ultraviolet-visible spectroscopy, and their dynamic viscoelastic behavior was studied using rheology. Self-assembled nanoparticles were synthesized using Hyaluronic acid (HA) and perfluorocarbon compounds via carbodiimide coupling and the nanoprecipitation method. Similarly, we fabricated nanoparticles of Poly(lactic-co-glycolic acid) (PLGA) via the nanoprecipitation method with various concentrations of Pluronic F-127 as surfactant (1-10 % w/w). Coupling reactions were verified using nuclear magnetic resonance. The feed ratios of the perfluorocarbon compounds and PEG were varied and their impact on HA and PLGA nanoparticle size and charge was studied using dynamic light scattering (DLS). The physical entrapment of drugs in nanoparticles was studied and modeled using low molecular weight compounds (methylene blue) and large molecular weight antibodies (IgG).

Results, Conclusions, and Discussions: ISG formulations with Ch and PAA were selected as best due to their highly tunable gelling points and excellent optical properties. Varying the feed ratio of perfluorocarbons in HA nanoparticles and the surfactant ratio in PLGA nanoparticles was identified as a strategy for finely modulating their size (Figure 1). Loading studies using methylene blue indicated high physical entrapment efficiency.
Thermosensitive ISG formulations with excellent optical properties and tunable viscoelastic behavior are critical towards the development of topical posterior eye segment treatments. Amphiphilic and anionic nanoparticles of 100-200nm like those of HA and PLGA nanoparticles in this study have large potential as nanocarriers capable of transcorneal and transscleral permeation to reach retinal tissues. A combination of these will yield a thermosensitive eyedrop formulation with integrated nanocarriers that could substitute intravitreal injections and deliver anti-VEGF to the posterior eye segment via the topical route. Thus, creating a less invasive and more accessible treatment for marginalized communities and millions of patients worldwide.

Acknowledgements (Optional): This work was supported by the NIH (R01-EB022025), the Cockrell Family Chair Foundation, the Office of the Dean of the Cockrell School of Engineering at the University of Texas at Austin (UT) for the Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, and the UT-Portugal Collaborative Research Program. JJR-C was supported by the National Science Foundation Graduate Research Fellowship under Grant No. 2137420.