dexamethasone-PCL implant designed for long-term drug release (Fialho et al. 2008). The implant provides controlled and prolonged delivery of dexamethasone in vitro, releasing 25% of its total drug load in 21 weeks, and loses mass slowly, as confirmed by scanning electron microscopy. The implants showed good short-term ocular tolerability in rabbits.

A biodegradable, intravitreal 2-mg cyclosporine A drug delivery system formulated with PGLC has been investigated in an experimental model of chronic uveitis in rabbits (Dong et al. 2006a). The efficacy of the implant was compared with that of orally administered cyclosporine A (15 mg/kg daily), no treatment, and treatment with a nonmedicated implant. At all timepoints in the 14-week study, inflammation was significantly lower in rabbits with experimentally induced uveitis that received the cyclosporine-PGLC drug delivery system as compared with those that received vehicle, sham implant, or oral cyclosporine. Rabbits treated with the cyclosporine-PGLC drug delivery system also showed significantly less electroretinographic b-wave depression. Mean intravitreal cyclosporine levels in rabbits implanted with the cyclosporine-PGLC drug delivery system were 102.2–145.5 ng/mL at 1–3 weeks postimplantation, 491.0–575.2 ng/mL at 4–10 weeks, and 257.3 ng/mL at 14 weeks. No toxicity associated with the implant was detected. A biodegradable tacrolimus-PGLC drug delivery system designed for anterior chamber implantation has been investigated for the prolongation of corneal allograft survival in a rabbit model of high-risk keratoplasty (Shi et al. 2005). The implant, which contains a total of 0.5 mg of FK506, produced peak aqueous humor drug concentrations (17.9 ± 2.3 ng/mL) after 28 days, and drug release was sustained for at least 168 days. The implant significantly prolonged graft survival time and produced no adverse reactions.

9.6.5  Poly(Ortho Ester)-Based Implants

Several preliminary studies have reported the use of POE as a delivery vehicle for 5-fluorouracil (Einmahl et al. 1999, 2001; Bernatchez et al. 1994). Einmahl and colleagues investigated an injectable, sustained-release POE-based 5-fluorouracil ointment in an experimental glaucoma filtration model in rabbits. The ointment significantly decreased intraocular pressure and led to persistence of the filtering bleb at days 9–28 after trabeculectomy (Einmahl et al. 2001). Corneal toxicity with the POE ointment was significantly lower as compared with conventional 5-fluo- rouracil tamponade. Histopathologic analysis indicated that POE was well tolerated and did not lead to fibrosis. The same research group also developed a POE-based ointment capable of delivering dexamethasone and 5-fluorouracil concomitantly for the potential treatment of intraocular proliferative disorders (Einmahl et al. 1999). A POE-based 5-chlorouracil drug delivery system has also been developed and its performance was evaluated in a glaucoma filtration surgery model in rabbits (Polak et al. 2008).

9.6.6  Polyanhydride-Based Implants

Jampel and associates developed biodegradable subscleral PAH-based discs (a copolymer of 25:75 1,3-bis[p-carboxyphenoxy] propane and sebacic acid) for the delivery of various antiproliferative agents and evaluated their effects in vitro and in a primate glaucoma filtration surgery model (Jampel et al. 1990, 1991, 1993; Uppal et al. 1994). PAH discs impregnated with 5-fluorouridine inhibited fibroblast proliferation in vitro, provided sustained drug delivery for at least 16 days in vivo, and prolonged the duration of intraocular pressure reduction following filtration surgery (Jampel et al. 1990). PAH discs were also developed to provide sustained delivery of the antiproliferative agents taxol and etoposide (VP-16) (Jampel et al. 1991). In vitro, the discs delivered taxol for 100 days and at concentrations exceeding taxol’s ID50 threefold for fibroblast proliferation (3 ng/mL). PAH discs with etoposide provided sustained release for 31 days (Jampel et al. 1991). PAH discs impregnated with taxol (50 mg) or etoposide (1 mg) have been investigated as an adjunct to filtration surgery in monkeys (Jampel et al. 1993). PAH disks containing taxol, but not etoposide, had a marked beneficial effect on intraocular pressure and bleb appearance postsurgically. Etoposide-PAH discs (1 mg) placed subconjunctivally in healthy rabbit eyes provided a nearly linear rate (30 mg/day) of drug release over 12 days, except for a burst occurring between days 6 and 7. Steady-state drug levels were 89 ng/mg in the conjunctiva and sclera, 195 ng/mL in the vitreous, and 29 ng/mL in serum; these levels were deemed sufficient to reduce fibroblast proliferation after glaucoma surgery (Uppal et al. 1994).

9.6.7  Other Biodegradable Polymer-Based Implants

Felt-Baeyens and colleagues have developed a scleral implant consisting of a com- pression-molded matrix of triamcinolone acetonide and high molecular weight (100,000–150,000) PMM (PMM2.1.2), a novel synthetic polymer, with ethoxylated derivatives of stearic acid (Simulsol) or oligomers of methylidene malonate as plasticizers (Felt-Baeyens et al. 2006). In rabbits implanted with the triamcinolonePMM devices, significant concentrations of triamcinolone acetonide were achieved in the vitreous and sclera over a 5-week period. Assessments of inflammatory cell counts and protein leakage into the aqueous humor indicated that the implants were well tolerated and did not provoke abnormal inflammation.

Hacker and associates have recently developed and evaluated scleral and vitreal implants consisting of a photocrosslinked poly(propylene fumarate) (PPF)/poly (N-vinyl pyrrolidone) (PVP) matrix for the delivery of the ophthalmic drugs acetazolamide, dichlorphenamide, and timolol maleate (Hacker et al. 2009). Drug release rates of up to 4 mg/day were achieved, and the in vitro release of acetazolamide, dichlorphenamide, and timolol maleate was sustained for approximately 210, 270, and 250 days, respectively. The implants exhibited a small initial burst release

(<10%) with a subsequent dual mode of drug release controlled by diffusion and bulk erosion. Drug-free PPF/PVP matrices, when implanted in rabbits for 2 weeks, showed good ocular biocompatibility. Overall, these preliminary results suggest that PPF/PVP matrices may be useful for long-term delivery of a variety of ophthalmic drugs.

The efficacy and safety of a biodegradable, scleral cyclosporine-PVA matrix reservoir implant has been investigated for the treatment of recurrent uveitis in horses (Gilger et al. 2006). Horses with equine recurrent uveitis received episcleral or deep-scleral lamellar cyclosporine-PVA implants and were monitored for up to 3 years. Scleral penetration of cyclosporine in vitro was poor, and when placed episclerally, the cyclosporine-PVA implant failed to control inflammatory uveitic episodes. In contrast, cyclosporine-PVA implants placed in the deep sclera adjacent to the suprachoroidal space significantly decreased uveitic flare-ups and resulted in therapeutic levels of cyclosporine in most ocular tissues.

9.6.8  Drug Delivery Using Polymeric Particles, Gels,

and Contact Lenses

Additional strategies for ocular drug delivery that have been investigated in preclinical studies include biodegradable injectable polymeric particulates (micro/ nano particles, spheres), drug-polymer gels, and drug-eluting polymer-based contact lenses.

Microsomes are spherical liposomal structures, roughly 0.01–10 mm in diameter, which consist of vesicular lipid bilayers separated by water or an aqueous buffer compartment (Conway 2008; Ghate and Edelhauser 2006, 2008). Microsomes can circumvent cell membrane barriers and protect drugs from metabolic or immune attack, thereby maximizing drug efficacy while minimizing toxicity. Microspheres composed of PLGA, PLA, and other biodegradable polymers have been developed for the sustained ocular delivery of therapeutic drugs (Moritera et al. 1991; Giordano et al. 1995; Wada et al. 1992) such as progesterone (Beck et al. 1979), adriamycin (Moritera et al. 1992), and Pegaptanib (Carrasquillo et al. 2003). Microspheres composed of chitosan, a natural biodegradable biopolymer, have been used for the transcorneal delivery of acyclovir in rabbits (Genta et al. 1997) and to enhance the ocular delivery of ofloxacin from erodible inserts made from polyethylene oxide (Di Colo et al. 2002).

Smaller sized particulate drug delivery systems include nanoparticles, nanospheres, and nanocapsules. Nanoparticles are polymeric colloidal particles, ranging in size from 10 to 1,000 nm, consisting of macromolecular materials for drug dissolution, entrapment, encapsulation, adsorption, or attachment. Nanospheres are solid spheres containing drug bound in a matrix or adsorbed on the surface of a colloidal carrier. Nanocapsules are small capsules with a central cavity surrounded by a polymeric membrane (Conway 2008; Ghate and Edelhauser 2006, 2008).