Sustained-release intrascleral and intravitreal drug implants and inserts have been developed for the treatment of ocular diseases. These polymer-based drug delivery systems are designed to achieve prolonged therapeutic drug concentrations in ocular target tissues that are not readily accessible by conventional means, while limiting the side effects from systemic drug exposure, frequent intraocular injections, and high peak drug concentrations associated with pulsed dosing, as well as improving patient compliance. Such drug delivery systems also offer potential cost savings over other shorter acting therapies, such as intravitreal injections, which require more frequent retreatment and a greater number of physician’s office visits. Various types of polymeric delivery systems have been explored for sustained drug delivery to the eye. Such systems can be distinguished on the basis of whether they are constructed using biodegradable or nonbiodegradable polymers (Yasukawa et al. 2006; Kiernan and Mieler 2009; Gaudana et al. 2009).

9.2  Nonbiodegradable Ocular Drug Delivery Systems

The two most common types of nonbiodegradable implants are reservoir-type devices (in which a drug core is slowly released across a nonbiodegradable semipermeable polymer or is released from a nonbiodegradable polymer with an opening of fixed area) and implant-type devices (in which a nonbiodegradable free-floating pellet is injected intravitreally or a nonbiodegradable plug is anchored to the sclera).

Most of the clinically available ocular implants to date have been of the nonbiodegradable reservoir type, typically consisting of a combination of polyvinyl alcohol (PVA) and ethylene vinyl acetate (EVA) (Davis et al. 2004). PVA, a permeable nonbiodegradable polymer, is used as the main structural element, and EVA, a nonbiodegradable polymer that is hydrophobic and relatively impermeable to hydrophilic drugs, is used for the device’s drug-restricting membrane (Conway 2008; Kearns and Williams 2009; Yasukawa et al. 2006; Davis et al. 2004). Drug release from reservoir-type devices occurs following diffusion of water through the outer EVA coating, which partially dissolves the enclosed drug and forms a saturated drug solution that diffuses into the surrounding tissue (Conway 2008; Kearns and Williams 2009). Reservoir-type systems display near zero-order drug-release kinetics after establishing a steady-state concentration gradient across the nonbiodegradable semipermeable membrane and have relatively constant release rates as long as solid drug remains within the core. The duration of drug release is limited mainly by the rate of drug dissolution within the reservoir. The rate of drug release can be delayed by increasing the surface area or thickness of the drug-restricting polymer, and hastened by increasing the surface area available for drug diffusion or by using a more permeable membrane. Nonbiodegradable reservoir-type devices are typically designed to release drug over a span of months or years for the treatment of chronic conditions that require long-term drug therapy.

Although nonbiodegradable implants can be useful in some clinical situations, they have several distinct drawbacks (Table 9.1). For example, large incisions and sutures or some other form of anchoring may be necessary. Furthermore, additional implants may be required in order to maintain efficacy once the drug supply in the initial implant is exhausted. Lastly, removal procedures may be needed to prevent fibrous encapsulation of drug-depleted implants. The implantation and removal of nonbiodegradable implants can be associated with serious side effects such as retinal detachment, vitreous hemorrhage, and cataract formation (Conway 2008; Kearns and Williams 2009; Yasukawa et al. 2006; Kiernan and Mieler 2009; Chu 2008; Kimura and Ogura 2001; Mohammad et al. 2007).

Examples of nonbiodegradable polymeric drug delivery systems that have been used clinically for the treatment of ocular disorders include Retisert® (fluocinolone acetonide), Ocusert® (pilocarpine hydrochloride), Vitrasert® (ganciclovir), I-vation™ (triamcinolone acetonide), Iluvien™ (fluocinolone acetonide), and Lumitect® (cyclosporine) (Table 9.2).

9.2.1  Retisert

Retisert® (Bausch and Lomb, Inc., Rochester, NY/pSivida Ltd.) is a disc-shaped, nonbiodegradable intravitreal implant (3 × 2 × 5 mm) consisting of a matrix of fluocinolone coated with silicone and PVA attached to a 5.5-mm silicone suture tab (Kiernan and Mieler 2009; Conway 2008). It is surgically inserted in the vitreous at the pars plana near the ciliary processes through a 3- to 4-mm incision and is affixed using sutures. The device has an initial drug delivery rate of 0.6 mg/day and reaches a steady-state delivery rate of 0.3–0.4 mg/day over roughly 30 months. In April 2005, Retisert® received fast-track approval status and orphan drug designation from the U.S. Food and Drug Administration for the treatment of chronic noninfectious uveitis of the posterior segment (Mohammad et al. 2007). In a phase 3 clinical trial in patients with diabetic macular edema, the implant showed efficacy but was associated with a high incidence of cataract (95%) and intraocular pressure elevation (35%) after 3 years, indicating that it may not be suitable for long-term treatment (Kane et al. 2008).

9.2.2  Ocusert

Ocusert® is a nonbiodegradable conjunctival insert that provides sustained delivery (zero-order kinetics) of pilocarpine hydrochloride for the treatment of glaucoma (Macoul and Pavan-Langston 1975; Quigley et al. 1975). Launched in the mid­ -1970s by Alza Corp., Ocusert® was the first commercially marketed controlled-release