Distribution, clearance, and controlled release of molecules and particles after microneedle injection into the suprachoroidal space

Abstract

Blindness and visual impairment due to eye disease results in significant loss in patient quality of life. Although therapeutics to treat these diseases may exist, specific targeting of diseased ocular tissue, while sparing other tissues, is difficult with traditional ophthalmic routes of administration. The suprachoroidal space (SCS, a potential space bordered by the choroid and sclera) is being explored as a site for drug delivery since high bioavailability and targeting can be achieved at the retina, choroid, and ciliary body. A hollow microneedle sized to pierce the sclera, while preventing penetration through the chorioretina, enables injections into the SCS in a reliable and efficient manner. The safety and efficacy of microneedle injections into the SCS is being investigated for posterior segment indications in ongoing clinical trials. One goal of this thesis was to investigate the distribution and clearance kinetics of formulations injected into the SCS using a microneedle. Specifically, we identified anatomical barriers in the SCS that impeded circumferential spread of particles. We next looked for other factors that could influence particle and molecule spread. We found that increasing injection volume resulted in increased particle and molecule coverage, with molecules occupying a larger area than particles. Increasing formulation viscosity reduced this discrepancy in area coverage. We next studied the SCS thickness, and found that injection volume had a minor effect and formulation injected had a major effect on it. We investigated the kinetics and routes of clearance of fluid and molecules injected into the SCS. We found that molecules exited the SCS via reflux, pressure-mediated trans-scleral transport, and diffusion-mediated clearance by the choroid. We also showed greatly prolonged residence time in the SCS was possible with very large macromolecules. A second goal was to develop a controlled release system for use in the SCS. We demonstrated 1-month efficacy of a controlled-release microparticle system injected into the SCS to treat glaucoma in a rabbit model. Dose sparing was achieved compared with conventional therapy. This work advances our understanding of the SCS as an emerging route of administration in treating ophthalmic disease.