Controlled Release of Dexamethasone From an Intravitreal Delivery System Using Porous Silicon Dioxide.

Retinal vasculature diseases have become more prevalent as a result of the aging population.1 The population over age 40 has increased by 20% from years 2000 to 2010 in the United States (data available in the public domain at http://www.visionproblemsus.org/introduction.html). Vision loss from macular edema or scarring associated with retinal neovascularization has become the leading cause of blindness in people aged 50 years or older. For example, incidences of diabetic macular edema2,3 and macular edema from retinal vein occlusions4,5 have been on the rise and the expenditure associated with their medical care is challenging for the medical community and the patients it serves.6 Even in a booming era of biological therapeutics, steroids still are a major player in the medical care of these refractory eye diseases due to their well-established efficacy at a fraction of the expense of anti-VEGF biological therapeutics.7–9 Triamcinolone acetonide (TA) is a naturally slow-release formulation of steroid and has been injected intravitreally for various retinal diseases.10 However, intravitreal TA is associated with a high incidence of elevation of IOP, which has limited its application. Dexamethasone (Dex) is a cortical steroid that has a very short vitreous half-life11 compared to the depository steroid TA.12,13 However, Dex is more potent than TA, and the recently Food and Drug Administration (FDA) approved long-acting Dex delivery system Ozurdex appears to cause less ocular hypertension and cataract formation than intravitreal TA or intravitreal implants of fluocinolone acetonide (Retisert).14 Dex has been used for treatment of posterior segment eye diseases including uveitis, proliferative vitreoretinopathy, diabetic macular edema, and wet form of age-related macular degeneration.15,16 There is considerable interest in delivering Dex to the back of the eye by sustained release systems.17–20 Poly(lactic-co-glycolic acid) (PLGA) microparticles and nanoparticles have been investigated for sustained delivery of Dex through intravitreal injection.17,21 The advantages of particulate formulations over implants, such as Ozurdex or Iluvien, are that the particles can be delivered through a traditional fine needle (27 gauge or smaller) to avoid invasive surgery or the use of a larger needle, such as 22 gauge for Ozurdex or 25 gauge for Iluvien. In addition, microparticulate formulations have less risk of migrating into the anterior chamber, mitigating the risk of corneal or IOP issues that are reported commonly with injectable implants, such as Ozurdex and Iluvien.22–24 Anterior migrated implant requires surgical repositioning or removal due to corneal complications.22–24 The Ozurdex or Iluvienis meant to treat macular diseases at the posterior segment but the implant localizes at the anterior segment, which not only decreases its therapeutic efficacy, but also potentially increases the risk of complications, such as cataract formation and IOP elevation in addition to the risk of migration into anterior chamber. In the current study, we investigated pharmacokinetics and pharmacodynamics of the engineered oxidized porous silicon (pSiO2) particles loaded with Dex in vitro and in vivo. The porous silicon (pSi) we propose to use in this study differs from the most commonly used biomaterial, such as PLGA. The pore size distribution of pSi is very narrow and the pore diameter can be tuned between 10 and 100 nm. These features allow us to adjust the loading of different drug molecules and to study the ocular kinetics of drug release with high precision. In addition, pSi is more resistant to heat, pH, mechanical stress, and hydrolysis-induced degradations. The goal of the study was to characterize this novel intravitreal delivery system of Dex in a rabbit eye model.