Tolerability, pharmacokinetics, and pharmacodynamics of a brinzolamide episcleral sustained release implant in normotensive New Zealand white rabbits

Abstract

Although episcleral drug delivery is a practical and minimally invasive method for sustained release ocular therapeutics, many polymer drug delivery systems induce ocular inflammation and have variable duration of drug release limiting their clinical use. The purpose of this study was to evaluate the in vitro release, tolerability, ocular drug distribution, and pharmacodynamics of brinzolamide released from episcleral silicone matrix devices. In vitro release of low-dose (12 mm × 2 mm; 7.5 mg total drug) and high-dose (20 mm × 2 mm; 12 mg total drug) silicone matrix implants (30% brinzolamide by weight) for 63 days was measured by high-performance liquid chromatography. New Zealand White (NZW) rabbits had either a blank silicone implant (n = 2 eyes), or a low or high-dose brinzolamide implant placed episclerally (n = 8 eyes each). Ocular inflammatory scoring and intraocular pressure (IOP) was measured at 0, 1–7, 10, 14, 21, and 28 days after implantation. Tissues were collected at either day 7 or 28 post implantation for histopathology and aqueous and vitreous humor drug analysis. In vitro release of brinzolamide revealed an initial burst of drug followed by a steady sustained release, with an estimated >12-month release profile. Both high and low-dose implants were well tolerated in NZW rabbits with minimal conjunctival hyperemia that resolved day 21. Eyes with brinzolamide implants had approximately 15–20% sustained reduction of IOP through day 28 after implantation compared to placebo implant eyes. Histopathology revealed mild focal mononuclear cellular infiltrates and fibrosis around the implant site at day 7 and day 28, but no evidence of intraocular toxicity. Brinzolamide was detected in the vitreous humor in a dose and time dependent manner. Episcleral brinzolamide-loaded silicone-matrix implants were extremely well tolerated and delivered sustained drug levels and therapeutic effect for up to 28 days in a rabbit model with an estimated duration of delivery of greater than 12 months.