Topical delivery of aqueous micellar resolvin E1 analog (RX-10045)

Abstract

Purpose: The primary objective of this study were to optimize aqueous micellar solution of isopropyl ester prodrug of resolvin (RX-10045), study in vivo ocular compatibility and tissue distribution following topical administration.

Methods: An optimized ratio of hydrogenated castor-oil and octoxynol-40 (1.0:0.05 wt%) was prepared to entrap RX-10045 in the hydrophobic core of micelles. RX-10045 aqueous micelles were subjected to characterization. In vitro stability studies were performed at 4 °C, 25 °C and 40 °C. In vivo studies were conducted in New Zealand albino rabbits following topical drop administration.

Results: Aqueous RX-10045 micellar solutions were successfully prepared. Micelles had a mean diameter of ∼12 nm with low negative surface charge. RX-10045 demonstrated high stability in citrate buffer (0.0 1M) at 40 °C. Hackett-McDonald ocular irritation scores were extremely low comparable to negative control. No significant difference in intraocular pressure was noted. Electroretinography studies did not reveal any retinal damage after multiple dosing of RX-10045 micellar solution. Ocular tissue distribution studies demonstrated appreciable drug concentrations in anterior ocular tissues. Moreover, RX-10008 (active metabolite of RX-10045) was detected in retina/choroid upon topical drop instillation.

Conclusions: A clear, stable, aqueous 0.1% RX-10045 micellar formulation was successfully prepared. Micellar solution was well-tolerated and did not have any measurable tissue damage in rabbit ocular tissues. Micelles appear to follow conjunctival/scleral pathway to reach back-of-the-eye tissue (retina). Topical aqueous formulations may be employed to treat posterior ocular diseases. Such micellar topical formulations may be more patient acceptable over invasive routes of administrations such as intravitreal injection/implants.

Keywords: Aqueous; Back-of-the-eye; Drug delivery; Eye drop; Formulation; Inflammation; Micelles; Posterior; Rabbits; Resolving; Retina/choroid; Sclera; Topical.