(559e) Highly Targeted Ocular Drug Delivery By Iontophoresis and Swollen Hydrogel Pushing in the Suprachoroidal Space

Suprachoroidal space (SCS) injection using a microneedle has been demonstrated as a means to better target drug delivery specifically to the posterior eye (e.g., macula and optic nerve). Injecting into the SCS, a potential space between the choroid and sclera, allows drug to flow circumferentially at the choroid-sclera interface typically from an anterior injection site to near the limbus with high bioavailability. The safety and tolerability of SCS injection using a microneedle have been shown in clinical trials. lthough SCS injection targets drug delivery to choroid and retina, it does not specifically target the posterior pole. Moreover, since typical SCS injection volumes (e.g., ≤ 100 μL in the rabbit eye) are insufficient to flow injected drugs around the macula or optic disk, greater targeting efficiency within the SCS could provide still better safety and efficacy, which is a current limitation of SCS injection. To advance drug targeting to posterior SCS, a previous study introduced iontophoresis-mediated drug delivery method where charged drug model particles were delivered to the back of the eye via the SCS. Although over 50% of the drug particle was delivered to the posterior segment of the SCS (i.e., > 6 mm from the limbus), there was still around 25% of the drug particles around injection sites (i.e., < 3 mm from the limbus). Thus, herein, we additionally injected physically synthesized hyaluronic acid (HA) hydrogel into the SCS right after the iontophoresis to further deliver the drugs around the injection site to the posterior. The HA hydrogel injection not only pushes the particles round the injection site, but also transfer the particles further toward the posterior by hydrogel swelling. In this drug delivery system, a customized Ag/AgCl electrode was located to around a microneedle for iontophoresis. We applied this system to rabbit eye ex vivo and in vivo to provide an assessment of delivery and safety of this iontophoretic SCS injection system.

A hollow microneedle with 30-gauge and 750 µm length was used to inject negatively charged fluorescent particles into the SCS of the rabbit eye ex vivo. Customized ring type of a Ag/AgCl electrode was attached around a microneedle and the electrode was connected to a DC power supply. To demonstrate the similar injection condition to the in vivo, a PDMS microdevice was fabricated to apply iontophoresis to the rabbit eye ex vivo. Two holes, 0.75 inch diameter, were made and connected by a single channel, 0.75 x 0.2 x 2.2 inch. A rabbit eye ex vivo and a disk typed Ag/AgCl electrode (0.5 inch diameter) was placed in both holes. The channel was filled with Hank’s balanced salt solution (HBSS) buffer. When 50 µL of the particle solution was infused into the SCS through the microneedle, electric current (0.5 mA) was applied for 3 min from the injection site to another Ag/AgCl electrode. To deliver the particles around the injection site (the anterior SCS) to the back of the eye, 50 µL of 4% (w/v) hyaluronic acid hydrogel was infused into the SCS right after the iontophoresis. To confirm the effect of the HA hydrogel swelling, the injected rabbit eyes were incubated in HBSS buffer at 37 ℃ for 6 h. After the injection and the incubation, particle distribution in the SCS was analyzed. Based on the ex vivo results, SCS injection into the New Zealand White rabbit eyes in vivo. Intraocular pressure (IOP) was measured after the injection for 2 weeks. To confirm the safety of this drug delivery system, injected rabbit eyes in vivo were analyzed 2 days and 2 weeks after the injection by histology.

Particles (50 µL) injected into the SCS of the rabbit eyes ex vivo in the 1) absence of an electric field were distributed more toward the anterior region, ~50% of particles was found in the anterior quadrant of the SCS (i.e., < 3 mm from the limbus) and only ~10% of particles was found in the posterior quadrant of the SCS (i.e., > 6 mm from the limbus). The particle injection 2) without iontophoresis and with hydrogel injection (50 µL) was delivered ~28% of particles in the anterior SCS and ~32% of particles in the posterior SCS. When 3) the iontophoresis was applied only (no hydrogel pushing), ~24% of particles were delivered to the anterior SCS and ~49% of particles located in the posterior SCS. The particles, where 4) the iontophoresis was applied first and then hydrogel pushing was followed, were distributed ~18% of particles in the anterior SCS and ~55% of particles in the posterior SCS. After 5) 6 h incubation of the eye which was applied iontophoresis first and injected HA hydrogel second, ~13% of particles were distributed in the anterior SCS and ~63% of particles in the posterior SCS.

The iontophoresis and the hydrogel pushing were applied into the rabbit eyes in vivo. Two weeks after the injection, the particle distribution was analyzed, ~15% of particles in the anterior SCS and ~65% of particles in the posterior SCS. IOP was measured for 2 weeks after the injection. Although the IOP was lowered about 4 mmHg right after the injection, it recovered around 9 days after the injection. In terms of the safety issues, any inflammatory response and retinal damages were not found in the rabbit eyes in 2 days and 2 weeks after the injection confirmed by histology analysis.

The charged particles injected into the SCS were delivered more preferentially to the posterior of the SCS by the iontophoresis. Followed HA hydrogel injection into the SCS pushed the particles localized around the injection site toward the posterior, and the swollen hydrogel delivered the particles further to the posterior. Thus, we conclude that iontophoresis and hydrogel pushing in the suprachoroidal space can target delivery of particles to the back of the eye, which may be of use for drug delivery of posterior ocular diseases.