E4 - Dexamethasone-loaded Biodegradable Microneedles Ocular Drug Delivery System for the Posterior Segment

Introduction: : The eye is a unique place where several routes can be used to achieve ocular drug delivery to treat vision-threatening conditions, including vascular and inflammatory diseases. Dexamethasone (DEX) is a corticosteroid used to treat ocular inflammation, such as posterior uveitis. DEX can be delivered as a topical formulation (eyedrops) or as an oral formulation. Although these administration routes are noninvasive, there is limited drug bioavailability reaching the posterior segment of the eye. An intravitreal injection is a direct route to the posterior segment but is associated with possible complications and discomfort. Suprachoroidal (SC) injection, targeting the suprachoroidal space (SCS), can achieve the drug delivery to the posterior segment. Currently, the SC injection is done using a single-use microneedle system where repeated injections may be needed to treat chronic inflammation. The goal of this study was to develop biodegradable drug-loaded microneedles (MNs) with extended and controlled release of DEX.

Materials and

Methods: : The 6x6 MN array structures with height of 1000μm, individual diameters of 500μm, and interneedle space of 300μm were prepared with stereolithography (SLA), which were then used to cure polydimethylsiloxane (PDMS) negative molds. The design specification of the MN array was based on the human eye anatomy. The Dexamethasone-Polycaprolactone (DEX-PCL) composite was prepared by mixing PCL (molecular weight = 37000) with 500μg of DEX. The composite was cast onto the PDMS molds in a vacuum oven. The DEX-PCL MNs were obtained by demolding. Structural characterization of MNs was done using stereomicroscopic images. DEX release was evaluated by placing DEX-PCL MNs in 5mL of phosphate buffer solution (PBS) incubated at 37℃, and at a pre-determined interval, samples were collected. DEX release concentrations were measured using a microplate reader at 240 nm. For compressive strength testing, individual samples (with and without DEX loaded) were loaded on Instron universal tester at speed of 0.1 mm/s to determine the mechanical strength that can withstand the tissue penetration.

Results, Conclusions, and Discussions:: The structure of MN array was validated by imaging with stereomicroscope where the 6x6 array had conical needle shape, height 1000 ± 50μm, diameter of 500± 50μm, interspacing of 300± 50μm. The DEX release profile showed a steady release rate of 23.3 ± 10.1 μg/day with a complete release achieved at day 21. Although the release was fast, there were no large structural changes based on the microscopic imaging at day 21. The DEX-PCL MNs and PCL MNs achieved 400μm displacement at a mechanical strength of 1.3 ± 0.2 N/microneedle and 1.9 ± 0.2 N/microneedle, respectively.

This study demonstrated the successful fabrication of a PCL MN array with minimal difference in structure. Loading of DEX onto the MN array was successful, and a full release was achieved by day 21. The MN array has high mechanical strength relative to the force required to penetrate ocular tissue, which is approximately 0.5N per microneedle. These MNs may be a viable alternative for posterior ocular drug delivery. Future developments will seek to evaluate ex vivo insertion of the MNs in scleral tissue, as well as biocompatibility and bioactivity using in vitro methods.

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