Ophthalmic delivery of cyclosporine A by punctal plugs

Abstract

Dry eyes are treated by instillation of eye drops of cyclosporine A emulsion or by punctal plug insertion in canaliculus to block tear drainage. This paper focuses on a novel approach of developing a punctal plug that can also release cyclosporine A to provide a dual mechanism for treating dry eyes. The punctal plug consists of a cylindrical hydroxy ethyl methacrylate core containing drug microparticles surrounded by an impermeable silicone shell that covers about 50% of the core, with the uncovered part directed towards the eyes. The geometry of this design is significantly different from those in patent literature, which are mostly designed to be rods. Plugs release cyclosporine A for a period of about 3 months at zero-order at a rate of about 3 μg/day. The in vivo release rates are expected to be about half of this value. A mathematical model is presented that provides an accurate estimate of the release without any fitting parameter. Pharmacokinetic models are also developed for drug delivered through Restasis® and punctal plugs, and based on these models the release rate of about 1.5 μg/day may be therapeutically effective. The predictions of the ocular pharmacokinetic model are in reasonable agreement with reported measurements in humans.