Ocular lamellar crystalline gels for sustained release and enhanced permeation of resveratrol against corneal neovascularization

Abstract

Corneal neovascularization (CNV) is the major cause of blindness after eye injury; however, only several drugs can be applied and the invasive administration ways (i.e., intravitreal injection and subconjunctival injection) are used. Resveratrol is a highly effective anti-VEGF agent against CNV. However, its applications are limited due to its strong hydrophobicity and instability. Here, we developed a resveratrol-loaded ocular lamellar crystalline gel (ROLG) for high inhibition of CNV. ROLGs were composed of resveratrol, glyceryl monooleate (GMO), ethanol, and water, and their lamellar crystalline structures were identified by polarizing light microscopy and small-angle X-ray scattering. High drug loading (4.4 mg/g) of ROLGs was achieved due to the hydrogen bonding between GMO and resveratrol. Resveratrol showed sustained release with 67% accumulative release in 7 h, which was attributed to the slow erosion of gels. Resveratrol in ROLGs had a high corneal permeation 3 times higher than resveratrol in hyaluronic acid suspensions (RHSs). ROLGs were administered to rats only once a day because of their strong retention on the cornea surface. ROLGs were safe due to the very little contact of ethanol in ROLGs to the cornea. CNV post-rat corneal alkaline injury was highly inhibited by ROLGs, resulting from the attenuation of corneal VEGF expression and then corneal healing was improved. The ROLG was a promising ocular medicine for the prevention of CNV.

Perspective use of bio-adhesive liquid crystals as ophthalmic drug delivery systems

“…In presence of tested formulation, the epithelial and stroma structures were also maintained as unaltered, unlike what happens when porcine cornea was treated with a patch soaked in NaOH 0.1 N for 10 min (Fig. 7 c) confirming the great safety profile of GMO-based formulation for ophthalmic administration 36 , 37 . The desired and chemically induced damage led to an evident destruction of the corneal epithelium (black arrow) and a disorganization of stroma (white arrow).…”

Resveratrol increases tear production and spontaneous ocular pain after corneal abrasion in male, but not female, rats using a preclinical model of photorefractive keratectomy (PRK)

“…Resveratrol treatment had no effect on corneal epithelial thickness. A previous study found that once daily topical application of a resveratrol-loaded gel for 14 days following a corneal alkaline burn promoted recovery of the corneal epithelium in rats (Li M. et al, 2021). The current study only used 3 applications of resveratrol prior to and just after corneal abrasion and looked at one time point after abrasion.…”

“…There have also been studies on the potential therapeutic effects of resveratrol in ocular diseases, although they have not focused on its analgesic properties (Abengozar-Vela et al, 2019;Li M. et al, 2021;Marino et al, 2013;Shetty et al, 2020;Tsai et al, 2015) (see reviews (Delmas et al, 2021;Fremont, 2000)).…”