A Novel Episcleral Cyclosporine Implant for Keratoconjunctivitis Sicca

Abstract

Abstract: : Purpose:Treatment with topical ophthalmic cyclosporine formulations for keratoconjunctivitis sicca related to Sjogren’s syndrome or graft–versus–host disease is limited by poor tissue penetration and ocular surface toxicity. We developed a cyclosporine episcleral implant to provide therapeutic drug concentrations to the lacrimal gland and ocular surface to treat keratoconjunctivitis sicca. Methods:Episcleral cyclosporine implants were manufactured with a silicone–based matrix design, and in vitro release rates were performed. Preclinical evaluation included toxicology (clinical examination, serial electroretinography and histopathology) in normal rabbits and dogs, pharmacokinetics in normal rabbits, and pharmacodynamics in a canine model of aqueous tear deficiency and keratoconjunctivitis sicca. Results:The cyclosporine implants showed sustained release of drug over time with in vitro assays for 1–year. Histopathology showed normal ocular tissues in both dogs and rabbits 6–months after implantation. The cyclosporine implant produced lacrimal gland, corneal, and conjunctival drug levels 1– to 2–log units higher than those reported with a variety of topical cyclosporine formulations and oral dosing. The cyclosporine implant was effective in a canine model of keratoconjunctivitis sicca with all animals able to discontinue topical cyclosporine and maintain normal Schirmer tear scores over a 6–month follow–up. Conclusions:This preclinical evaluation showed that the episcleral cyclosporine implant was safe, delivered potentially therapeutic cyclosporine levels to the lacrimal gland, cornea, and conjunctiva, and showed efficacy in a clinically relevant model of keratoconjunctivitis sicca. The episcleral cyclosporine implant shows promise in the treatment of keratoconjunctivitis sicca associated with Sjogren’s syndrome and graft–versus–host disease following allogeneic hematopoietic stem cell transplantation.

Keywords: cyclosporine • cornea: tears/tear film/dry eye • sclera