in best-corrected visual acuity at days 30–90 as compared with sham treatment (Haller et al. 2010).

Ozurdex received US FDA approval in June 2009 for the treatment of macular edema associated with retinal vein occlusion; as of October 2009, more than 2,500 patients have been enrolled in Ozurdex clinical trials. Phase 3 trials are currently in progress to evaluate Ozurdex for the treatment of patients with diabetic macular edema (clinicaltrials.gov study IDs NCT00168389 and NCT00168337) and uveitis (NCT00333814).

9.5.2  Surodex

Surodex™ (Allergan, Inc., Irvine, CA) is a rod-shaped biodegradable matrix implant (1.0 × 0.5 mm) consisting of dexamethasone and PLGA with hydroxypropyl methylcellulose (HPMC). It is designed to provide sustained drug release at a constant rate of 60 mg over 7–10 days (Lee et al. 2008), does not require suture fixation, and is well tolerated (Lee and Chee 2005; Lee et al. 2008). The implant is inserted in the anterior chamber to control postoperative inflammation following cataract surgery; it has been shown to significantly reduce anterior chamber cells and flare and to have anti-inflammatory efficacy at least as good as that of topical steroids (Chang et al. 1999; Tan et al. 1999, 2001; Seah et al. 2005).

9.5.3  Verisome

Verisome™ (Ramscor, Inc., Menlo Park, CA) is a nonpolymer-based and proprietary intraocular drug delivery technology. It was developed to provide zero-order sustained release of drugs in the form of long-acting biodegradable solids, gels, or liquids that can be administered intravitreally via a standard 30-gauge injection. The technology has a customizable duration of action and can be adapted for a variety of pharmacotherapies using methods involving small molecules, peptides, proteins,andmonoclonalantibodies(http://www.iconbioscience.com/TechnologyOverview.html). IBI 20089, an investigational triamcinolone acetonide formulation employing the Verisome system, was shown in rabbits to provide sustained delivery of triamcinolone at a mean daily dose of 1.1 mg/mL for up to 1 year per injection (Hu et al. 2008). The safety and efficacy of IBI 20089 was recently investigated in a phase 1 trial in 10 patients with cystoid macular edema associated with retinal vein occlusion (Lim et al. 2009). An IBI 20089 formulation delivering 13.8 mg triamcinolone was found to significantly reduce macular thickness after 120 days of treatment and was more effective than a 6.9-mg formulation. The size of the delivery system was visibly reduced as the drug was released and it was well tolerated, with the exception of one case of intraocular pressure elevation that required surgery.

9.5.4  Lacrisert

Lacrisert® (Aton Pharma, Inc., Lawrenceville, NJ), introduced in 1981, is a sterile, translucent, rod-shaped, water-soluble, biodegradable ophthalmic insert made of hydroxypropyl cellulose (HPC) (5 mg), a physiologically inert substance that ­stabilizes and thickens the precorneal tear film and prolongs tear breakup time. The implant is designed for daily administration into the inferior cul-de-sac of the eye and is approved to relieve the signs and symptoms of moderate to severe dry eye ­syndrome, including keratitis sicca (Lacrisert prescribing information 2007).

Lacrisert can be particularly beneficial for patients who respond poorly to therapy with artificial tears. Once-daily treatment with Lacrisert was shown to provide greater relief of dry eye symptoms than four-times-daily treatments with topical artificial tears. Survey results also indicate that patients prefer Lacrisert over artificial tears (Lacrisert Prescribing Information 2007). The implant can be self-admin- istered up to twice a day, using a specially designed applicator, and is generally well tolerated. Side effects, typically mild and transient, include blurred vision, ocular discomfort/irritation, eyelash matting/stickiness, photophobia, hypersensitivity, eyelid edema, and hyperemia.

9.6  Experimental Biodegradable Ocular Drug Implants Under

Preclinical Development

Numerous polymer-based ocular drug delivery systems designed for the delivery of a wide range of drugs (steroids, hormones, anticancer drugs, antifungals, etc.) and incorporating a variety of different types of polymers (e.g., PLA, PLGA, PLGC, PLTMC, PCL, POE, and PAH) have been evaluated in preclinical in vitro and in vivo studies (Table 9.6).

9.6.1  Poly(Lactic Acid)-Based Implants

A biodegradable intrascleral implant consisting of betamethasone phosphate and PDLLA has been evaluated in a preliminary pharmacokinetic/safety study (Okabe et al. 2003). Drug release from the implants in vitro occurred in a biphasic pattern, with an initial burst followed by a second phase of diffusional release, and persisted for at least 8 weeks. Following implantation of the betamethasone-PDLLA discs into the scleral pocket in rabbits, drug concentrations in the vitreous and retinachoroid remained within the therapeutic range for suppression of inflammation for more than 8 weeks. Drug concentrations were higher in the retina-choroid than in the vitreous and undetectable in the aqueous humor. The implant showed good ocular biocompatibility based on electrophysiological and histological assessments, and

Table 9.6  Examples of biodegradable polymeric ocular drug delivery systems at the preclinical stage of development

for the treatment of tractional retinal detachment due to experimental proliferative vitreoretinopathy in rabbits (Rubsamen et al. 1994). The implant, which contained 1 mg of fluorouracil, produced sustained intravitreal concentrations of fluorouracil between 1 and 13 mg/mL for at least 14 days, and the concentrations remained above 0.3 mg/mL for nearly 21 days. Successful retina attachment occurred in 8 of 9 rabbits that received the fluorouracil-PLGA implant, but in only 1 of 9 rabbits that received drug-free PLGA implants, and the drug implant was also uniquely effective in preventing epiretinal membrane proliferation. Electroretinographic and ­histopathologic assessments revealed no evidence of toxicity associated with either the drug implant or PLGA alone.

In 1997, Miyamoto and associates examined the feasibility of using a biodegradable PLGA-based scleral implant to deliver fluconazole (a bis-triazole antifungal agent) for the treatment of fungal endophthalmitis (Miyamoto et al. 1997). Fluconazole-PLGA implants were shown to gradually release fluconazole over a period of 4 weeks in vitro, with faster release rates (1 week) observed for implants containing high fluconazole concentrations (50 vs. 10–30%). In rabbits that received the implant, vitreal fluconazole concentrations remained within the 99% inhibitory concentration for Candida albicans for 3 weeks after implantation.

An intravitreal all-trans retinoic acid-PLGA implant was investigated for its ability to inhibit proliferative vitreoretinopathy induced in rabbits by core vitrectomy and fibroblast injection (Dong et al. 2006b). The safety and efficacy of the implants, formulated with PLGA (MW = 109,000 kDa) and either 420, 650, or 1,070 mg alltrans retinoic acid, were compared with those of nonmedicated implants and a nointervention control group. The severity of proliferative vitreoretinopathy was significantly reduced in rabbits that received the 650and 1,070-mg implants but not in rabbits that received the 420-mg implant or the control treatments. In rabbits implanted with the all-trans retinoic acid drug delivery system, drug release was found to peak at 6–7 weeks and no retinal toxicity was observed.

A biodegradable drug delivery system consisting of triamcinolone and PLGA has been investigated for the treatment of postsurgical complications in rabbits following cataract removal and intraocular lens implantation (Eperon et al. 2008). The drug delivery system was formulated using PLGA with a molecular weight of 48,000 and had a loading capacity of roughly 1,050 mg triamcinolone. High-molecular weight PLGA (i.e., 80,000) was found to have slower drug release kinetics as compared with lower molecular weight PLGA (i.e., 34,000 or 48,000). Following cataract surgery, intraocular lenses were inserted along with a nonmedicated drug delivery system or 1–2 triamcinolone-PLGA implants. At days 63–84, postoperative ocular inflammation, measured by inflammatory cell infiltration and protein leakage in the aqueous humor, was significantly reduced in rabbits that received a single triamcinolone-PLGA implant and was reduced to an even greater degree in rabbits that received two implants. These results suggested that the triamcinolone-PLGA drug delivery system could replace oral drug treatment and reduce the need for intraocular drug injections in human cataract patients.

The pharmacokinetics and safety profile of a biodegradable dexamethasone acetate-PLGA drug delivery system has been investigated in rabbits (Fialho et al. 2006). The implant, consisting of 1,000 mg dexamethasone in a 50:50 PLGA matrix, ­produced vitreous drug concentrations that were within the anti-inflammatory therapeutic range (0.15–4.00 mg/mL) over an 8-week period. A release burst was noted after 4 weeks and the levels of dexamethasone acetate started to decline after 7 weeks. The implant was not associated with significant electroretinographic or ­histological abnormalities or elevation of intraocular pressure. The study’s authors suggested that the implant could be used as an alternative to repeated intravitreal triamcinolone injections for the treatment of subacute retinal disorders, such as ­diabetic macular edema, retinal vein occlusion, and Irvine–Gass syndrome.

A biodegradable polymeric scleral plug consisting of ganciclovir in an 80:20 PLGA (MW = 70,000 and 5,000, respectively) matrix was investigated by Sakurai and associates in a rabbit model of human cytomegalovirus retinitis (Sakurai et al. 2001). Following induction of experimentally induced cytomegalovirus retinitis, rabbits treated with a single intravitreal injection of ganciclovir solution showed a significant reduction, as compared with untreated animals, in vitreoretinal lesions after 1 week; however, this difference waned by week 2. In contrast, rabbits implanted with the ganciclovir-PLGA scleral plug showed significant reduction in vitreoretinal lesions out to 3 weeks. Implantation of the plug was not associated with surgical complications such as hypotony or endophthalmitis. The results of the study suggested the potential use of the biodegradable ganciclovir scleral plug as an alternative to the nonbiodegradable ganciclovir implant Vitrasert®.

Sakurai and coworkers also evaluated a biodegradable polymeric scleral plug consisting of the immunosuppressive agent tacrolimus (FK506) in a 50:50 PLGA matrix (MW = 63,000) for the treatment of experimental uveitis in a rabbit model (Sakurai et al. 2003). The tacrolimus-PLGA plug implanted in the vitreous cavity was effective in achieving vitreal drug concentrations of 480–350 ng/g for 4 weeks and produced significant inhibition of uveitic inflammation for at least 6 weeks, as assessed by anterior chamber cell counts, flare, vitreous opacity, and protein leakage. Histopathologic and electroretinographic assessments showed that the plug was not associated with significant retinal toxicity. The authors suggested the potential use of the tacrolimus-PLGA plug for the treatment of patients with severe chronic uveitis who are intolerant to currently available therapies.

The Oculex drug delivery system (Oculex Pharmaceuticals, Inc., Sunnyvale, CA) is a biodegradable intraocular implant consisting of cyclosporine in a biodegradable PLGA matrix. Preliminary studies by Theng and colleagues on the pharmacokinetics of the Oculex drug delivery system (containing 0.5 mg cyclosporine) implanted in the anterior segment of rabbit eyes indicate that high drug concentrations can be sustained in the corneal epithelium, stroma, and endothelium for at least 3 months, while low concentrations are achieved in the aqueous, and systemic absorption is negligible (Theng et al. 2003). The Oculex drug delivery system was not associated with any adverse reactions. The authors concluded that further studies were warranted to determine the potential of the device for the prophylaxis and treatment of corneal transplant rejection in humans.

Yasukawa and associates investigated the efficacy of biodegradable PLGAbased scleral implants containing cis-hydroxyproline, an inhibitor of collagen secretion, on experimental proliferative vitreoretinopathy in rabbits (Yasukawa et al. 2002). PLGA formulations with copolymer ratios of 65:35 (MW = 103,000) and 50:50 (MW = 93,000) were compared following induction of proliferative vitreoretinopathy with autologous fibroblasts. Drug release occurred in a triphasic manner and was sustained over 4 and 7 weeks, respectively, with PLGA 65:35 and PLGA 50:50 implants. PLGA 65/35 implants decreased the incidence of retinal detachment from 89% in controls to 57% on day 28 whereas PLGA 50:50 implants had no significant effect. A synergetic therapeutic effect was observed in rabbits that received dual PLGA 65:35 and PLGA 50:50 implants. The implants, which did not demonstrate any significant signs of toxicity, were suggested for further development as a potential treatment for proliferative vitreoretinopathy.

Aukunuru and colleagues developed a sustained-release biodegradable subcutaneous implant consisting of a matrix of N-4-(benzoylaminophenylsulfonyl glycine) (BAPSG), a novel aldose reductase inhibitor, and PLGA (85:15). They evaluated the therapeutic efficacy of the device in a diabetic rat model (Aukunuru et al. 2002). The implant, which released approximately 44% of its loaded drug after 18 days, was found to reduce cataract scores, vascular endothelial growth factor expression, galactitol accumulation, and glutathione depletion in ocular tissues. Thus, the BAPSG-PLGA implant may someday prove to be valuable for the treatment of human diabetic retinopathy and other secondary ocular complications associated with diabetes.

In addition to being investigated as a component of biodegradable implantable drug matrix pellets, PLGA has been evaluated as a constituent in injectable, biodegradable microsome drug delivery systems for the treatment of intraocular pathologies. For example, Jiang and colleagues recently evaluated the ability of intravitreally injected biodegradable microspheres loaded with glial cell linederived neurotrophic factor (GDNF) to protect retinal ganglion cells and their axons in a rat model of glaucoma (Jiang et al. 2007). GDNF microsphere treatment significantly increased retinal ganglion cell survival and axon survival, attenuated the reduction of retinal inner plexiform layer thickness, decreased glial cell activation in the retina and optic nerve, and led to a moderate reduction in optic nerve head cupping. These results suggest that GDNF-PLGA microspheres may be useful as a neuroprotective therapy in human glaucoma.

Surodex® is an implantable rod-shaped biodegradable polymer matrix consisting of 60 mg dexamethasone and PLGA. The efficacy of the Surodex implant has been investigated in a rat model of high-risk corneal transplantation (Kagaya et al. 2002). After 8 weeks, all corneal grafts were rejected in untreated rats and 83% of grafts were rejected in rats treated with 0.1% betamethasone eye drops TID; however, no grafts were rejected in rats that received the Surodex drug delivery system implanted into the anterior chamber. These findings suggest the potential of Surodex implants as an immunosuppressive and anti-inflammatory agent for the suppression of graft rejection following corneal transplantation.

9.6.3  Poly(d,l-Lactic-Co-Glycolic Acid)/Poly(l-Lactide-Co-1,

3-Trimethylene Carbonate)-Based Composite Implants

Preliminary data have recently been reported comparing the ocular biocompatibility of 50:50 PDLGA, 85:15 PDLGA, and Inion GTR™ [a 70:30 blend of 85:15 PLGA and 70:30 poly(L-lactide-co-1,3-trimethylene carbonate) (PLTMC)] copolymers in cell line cultures from various ocular tissues (i.e., human corneal epithelial cells, rabbit stromal fibroblasts, bovine corneal endothelial cells, human conjunctival epithelial cells, and human retinal pigment epithelial cells) (Huhtala et al. 2008). All three polymers showed acceptable in vitro biocompatibility. Following exposure to degradation products extracted from the polymers, cell viabilities ranged from 80 to 95% for PDLGA 50:50, 47–87% for PDLGA 85:15, and 66–92% for Inion GTR. The Inion GTR membrane has been estimated to have the longest half-life of the three polymers tested, with a degradation time of 1–2 years vs. 2–4 months for PDLGA 50:50 and 6–12 months for PDLGA 85:15; the faster degradation time of PDLGA 50:50 relative to PDLGA 85:15 is due to a higher content of hydrophilic glycolic units. The authors suggested that all three biopolymers can be used as scaffolds for tissue engineering or surgical implants in the therapy of ocular diseases. An ocular tolerability study in rabbits examined the effects of implantation of these three polymers in comparison with those of a collagen implant (AquaFlow™) as a benchmark (Rönkkö et al. 2009). The implants caused a similar degree of very mild eye irritation and all implants showed initial fine fibrous tissue encapsulation, which resolved after the implants had completely degraded. Infrared microscopy showed that spectral characteristics of the tissue capsule surrounding the PLTMC and 50:50 PDLGA implants differed significantly from the tissue capsule that formed around 85:15 PDLGA. Despite these differences in tissue response, all of the implants were deemed to be acceptable biomaterials for drainage devices in glaucoma surgery.

9.6.4  Poly(e-Caprolactone)- and Poly(Glycolide-Co-Lactide-

Co-Caprolactone)-Based Implants

Ocular drug delivery systems using PCL, a slowly degrading polymer, and PGLC (a PCL/PLGA copolymer) have been investigated in several animal studies. The results of a preliminary study in rabbits on the long-term safety and pharmacokinetics of a dexamethasone-PCL intravitreous implant have recently been reported by Silva-Cunha et al. (2009). The implant provided controlled and sustained delivery of dexamethasone­ at concentrations within the therapeutic range for at least 55 weeks, at which time approximately 79% of the drug remained in the implant, indicating a very slow rate of degradation. Clinical and histologic observations showed that the implants were well tolerated. The study suggested the feasibility of using PCL implants to provide sustained drug delivery for months to years. Fialho and colleagues­ reported the development of a biodegradable intravitreal