Formulation and Release of sd-rxRNA® from a Cross-linked, Thiolated CMHA-based Film for Topical Delivery to Reduce the Formation of Corneal Scarring

Abstract

Purpose: Injury to the front of the eye can lead to scarring and negatively impact the transparency of the cornea and vision. Connective tissue growth factor (CTGF) is expressed in cornea after injury and is believed to play a key role in development of ocular fibrosis. RXi has developed a new class of stable, self-delivering RNAi compounds (sd‑rxRNA) that incorporate features of both RNAi and antisense and are spontaneously taken up by cells. RXI‑109 is a CTGF-targeting sd‑rxRNA that is currently in Phase 2 clinical trials for the reduction of dermal scarring and in pre-clinical development for reduction of retinal scarring. Intravitreal administration of RXI‑109 to monkey eyes resulted in dose dependent reduction of CTGF protein levels in the retina and in the cornea. In order to treat injuries of the front of the eye to prevent corneal scarring, a topical formulation would be ideal. Here, the formulation and release of a control sd‑rxRNA from thiolated carboxymethyl hyaluronic acid (CMHA)/poly ethylene glycol diacrylate (PEGDA) hydrogel films from Jade was evaluated to investigate the possibility of sustained topical release.

Methods: sd-rxRNA was formulated in 1.0% and 1.2 % CMHA with a 1.5:1 thiol:acrylate ratio, molded and dried to create thin flexible 6 mm diameter films. Fifty to four-hundred micrograms of sd-rxRNA was incorporated during formulation. The release was monitored for 16 days by measuring UV absorption at 260 nm and was calculated from a standard curve.

Results: sd‑rxRNA was successfully formulated in CMHA films. The majority (50-80%) was released within 24 hours; however, the remaining release continued over approximately 6 days. For the films formulated with 400 µg, release was still detectable at day 16. The accumulated release was between 65% and 95% depending on the dose. The release profile was similar between 1.0% and 1.2% CMHA.

Conclusions: sd-rxRNAs were successfully formulated in CMHA films and show a favorable release profile over a period of approximately two weeks. Future studies will be focused on optimizing the release profile and producing in vivo grade films formulated with RXI‑109 for studies focused on anterior segment uptake of RXI‑109. Sustained topical delivery of RXI‑109 could serve as a potential therapeutic to be administered at the time of corneal injury and lead to reduced scarring and improved vision.