Sustained subconjunctival delivery of cyclosporine A using thermogelling polymers for glaucoma filtration surgery

Abstract

Filtration surgery is currently being acknowledged as the most effective therapeutic modality for glaucoma; however, excessive scarring of a filtering bleb often leads to surgical failure. Subconjunctival administration of drug delivery systems provides a localized and sustained delivery of antifibrotic drugs to inhibit post-operative scarring. In this study, a long-acting delivery system of Cyclosporine A (CsA) was developed using thermogelling poly-(DL-lactic acid-co-glycolic acid)–poly(ethylene glycol)–poly-(DL-lactic acid-co-glycolic acid) (PLGA–PEG–PLGA) triblock copolymers as the carrier. The drug could be easily entrapped into the polymer aqueous solution by simply mixing them at room temperature, and the prepared formulation was spontaneously transformed into an in situ thermogel loaded with drugs at body temperature. The formulation exhibited a sustained in vitro release of CsA from the thermogel over 2 months. The in vivo efficacy of subconjunctival administration of the CsA-loaded hydrogel system in inhibiting filtering bleb scarring was evaluated on a rabbit model of filtration surgery. No ocular tissue abnormalities and damage were observed. Compared with a local administration of the popular Mitomycin C solution at the surgery site, the CsA-loaded thermogel system remarkably inhibited scar formation, maintained stable low intraocular pressure and promoted filtering bleb survival for more than 10 weeks. This feature was attributed to both the anti-adhesion nature of the thermogel matrix and the antifibrotic effect of the sustainedly released CsA. These results suggest that the injectable PLGA–PEG–PLGA thermogel is a biocompatible carrier for sustained subconjunctival drug delivery, and the CsA-loaded hydrogel formulation has great potential for ocular antifibrotic therapy after glaucoma filtration surgery and others.