most of the reported problems are associated with implants made of PGA or PGA copolymers. The majority of clinical studies in which complications were reported involved mild reactions suggestive of a nonspecific foreign-body reaction to crystallites as the cause. Most of these complications resolve with time or after minimal intervention (Athanasiou et al. 1998). The host response to polymeric implants is multifactorial and affected by the physical and chemical properties of the polymer and by the physical properties of the implant (volume, shape, and surface characteristics). The response is tissue dependent, organ dependent, and species dependent (Shive and Anderson 1997). Implantation of PLGA in bone or soft tissue of animals causes no inflammatory response, or only a mild response that diminishes with time, and is not associated with toxicity or allergy.

9.5  Clinically Evaluated Biodegradable Ocular

Drug Delivery Systems

Several biodegradable polymer-based ocular drug delivery systems have been approved for the treatment of human ocular disorders, and several others are now being evaluated in clinical trials. These include Ozurdex, Surodex, Verisome, Lacrisert, a brimonidine-PLGA/PLA drug delivery system, and punctal plugs for the delivery of bimatoprost and latanoprost (Table 9.5).

9.5.1  Ozurdex™

Dexamethasone is one of the most potent of the corticosteroids but has a short halflife following intravitreal injection (Kwak and D’Amico 1992). Ozurdex™, a sus- tained-release implantable dexamethasone posterior-segment drug delivery system (formerly Posurdex, Allergan Inc, Irvine, CA) has been developed to deliver therapeutic concentrations of dexamethasone in the eye for up to 6 months from a single implant. Ozurdex is a biodegradable implant consisting of 0.7 mg dexamethasone within a solid, rod-shaped PLGA copolymer (Novadur™, Allergan, Inc.) matrix (Figs. 9.7 and 9.8). The implant is designed to release dexamethasone biphasically, with peak doses for 2 months initially, followed by lower therapeutic doses for up to 6 months. A novel single-use applicator is used to insert the drug pellet (6.5 × 0.45 mm) into the vitreous through a 22-gauge pars plana injection (Fig. 9.7). The procedure is performed in-office rather than in a surgical setting and does not require sutures for wound closure.

A 6-month, randomized, phase 2 trial evaluated the efficacy and safety of Ozurdex (0.7 or 0.35 mg) inserted via pars plana incision in patients with persistent macular

210

Table 9.5  (continued)

CME cystoid macular edema; DME diabetic macular edema; FDA Food and Drug Administration; HPC hydroxypropyl cellulose; HPMC hydroxypropyl methylcellulose; PLGA poly(lactic-co-glycolic acid); RVO retinal vein occlusion

aSee individual product labels for complete information

.al et Lee .S.S

Most ocular adverse events in patients treated with Ozurdex were mild, reported within 1 week after surgery, and similar in frequency between the treatment and observation groups beyond day 8. A mild increase in the incidence of hyperemia, pruritus, vitreous hemorrhage, and anterior chamber cells was observed in the treatment groups relative to the control groups on day 8, which was expected as a result of the surgical procedure. After day 8, only two adverse events occurred significantly more frequently in the treatment group: anterior chamber flare (5% for Ozurdex vs. 0% for observation only) and increased intraocular pressure (6 and 0%, respectively). Only 2 patients (2%) in each of the Ozurdex treatment groups and 1 patient (1%) in the observation group had an intraocular pressure increase of 10 mmHg or more from baseline at day 90. No cases of sterile endophthalmitis were reported, which may have been related to the favorable drug-release characteristics of Ozurdex (i.e., the injectable pellet does not result in the particle dispersion and visual obscuration effects commonly associated with intravitreal triamcinolone acetonide injections).

A multicenter phase 2 pilot study recently examined the safety and performance of Ozurdex 0.7 mg administered using a nonincisional applicator system as compared­

with pars plana incisional placement of the same drug delivery system in patients with clinically observable macular edema resulting from diabetic retinopathy, retinal vein occlusion (branch and central vein), uveitis, or Irvine–Gass syndrome (Haller et al. 2009). With both procedures, a substantial percentage of patients showed significant improvements in visual acuity (up to a 3-line increase) as ­compared with a control group, with therapeutic effects persisting up to 180 days in some eyes. The procedures were well tolerated, and neither resulted in endophthalmitis or retinal detachment. Furthermore, none of the patients in the applicator group required sutures to close the insertion wound. Notably, the incidence of ocular adverse events, vitreous hemorrhage, and intraocular pressure elevation was lower with the applicator system than with pars plana incisional placement.

Ozurdex was recently evaluated in a prospective, multicenter, randomized, single-masked controlled study using data from a subset of patients (n = 41) with persistent macular edema resulting from uveitis or Irvine–Gass syndrome. A significantly greater percentage of patients who received Ozurdex 0.35 or 0.7 mg had at least a 10-letter improvement in best-corrected visual acuity [41.7% (5/12) and 53.8% (7/13), respectively] as compared with an observation-only control group [14.3% (2/14)] and the improvement in visual acuity persisted to day 180. There were also significantly greater reductions in fluorescein leakage in treated patients than in observed patients. Ozurdex was well tolerated throughout the study. Intraocular pressure increases of >10 mmHg were seen in 5 of 13 patients in the 0.7-mg group, 1 of 12 patients in the 0.35-mg group, and no patients in the observation group. No cases of endophthalmitis were reported (Williams et al. 2009).

The efficacy of Ozurdex in the treatment of vision loss due to macular edema associated with retinal vein occlusion was recently examined in two identical, multicenter, masked, randomized, 6-month, sham-controlled clinical trials consisting of 1,267 patients in total. Ozurdex led to significant and more rapid improvements