Intraocular Sustained Drug Delivery for Retinal Diseases

Studies show drug delivery implants help us tailor medication to the disease.

Intraocular Sustained Drug  Delivery for Retinal Diseases
Studies show drug delivery implants help us tailor medication to the disease.

By Glenn J. Jaffe, MD

Why would we want a variety of drug delivery systems for posterior segment disease? Two important reasons come to mind. First, it's very difficult to achieve constant drug levels when you give drugs topically or systemically. And second, it's also difficult to achieve long-lasting delivery at therapeutic levels without producing side effects.

Sustained drug delivery systems are practical alternatives to these avenues.


One of the advantages of a sustained drug delivery system is that you can tailor it to the disease. For uveitis, for example, you might choose a system that lasts years. For a wound-healing disease like proliferative vitreoretinopathy (PVR), you may want something that lasts only weeks to months. Patient compliance and systemic side effects aren't problems.

Biodegradable devices offer flexible configuration and no residual device; they're most suitable for relatively short-term delivery (weeks or months).

One disadvantage of biodegradable sustained drug delivery systems is nonlinear drug release. The device degrades, gradually changing its surface area and, therefore, its delivery rate. This actually can be beneficial in cases such as PVR, where a spike of drug release followed by a slow, logarithmic decline is desirable.

One very interesting delivery system developed by Neurotech employs genetically engineered cells to produce a necessary protein. The whole system is then implanted into the vitreous. The system is made of a nonbiodegradable, semi-permeable polymer membrane across which cells deliver ciliary neurotrophic factor (CNTF) into the vitreous cavity.


My colleagues and I1,2 developed a nonbiodegradable fluocinolone acetonide implant to treat uveitis and other conditions. Nonbiodegradable devices can overcome delivery duration problems inherent with biodegradable devices or intravitreal injections, such as intravitreal triamcinolone acetonide injection. The disadvantage of nonbiodegradable devices is that a device is retained inside the eye after the drug has been depleted. This is not a problem as long as the retained device is not toxic.

Fluocinolone is a synthetic corticosteroid. We had shown in a pilot trial that a dexamethasone implant in a nonbiodegradable device very effectively controlled inflammation, but for only 10 months. We wanted something that would last much longer. Because fluocinolone is insoluble, we configured it in a small delivery device that would release the drug over a long period.

The device is constructed from a fluocinolone drug core that's surrounded by silicone and polyvinyl alcohol laminated coatings. It's designed to release at either 0.5 mcg or 2.0 mcg per day, which corresponds to a 0.5-mg or a 2.0-mg device, respectively. The implant will release for 3 years.


To test the device, a randomized, masked multicenter trial was conducted. The target population was 250 uveitis patients, randomized to receive either the 2.0-mg or 0.5-mg device. The study eye was more severely involved than the fellow eye.

At 1 year, the recurrence rate in the eyes that had undergone fluocinolone implantation was 4.3%. By comparison, the fellow (less involved) eye had a 56% recurrence rate. In terms of visual acuity, there was no change in the fellow eye. In the drug-implanted eye, 25% of patients had three or more lines of vision improvement.

What we don't know is whether patients with more severe uveitis are more prone to pressure problems, whether steroid- or nonsteroid-induced. Many patients did require therapy for pressure problems -- 10% before enrollment and 30% at the 1-year mark. Filtering operations were required in 12% of the implanted eyes and none of the fellow eyes, yet these patients did well anyway.

Of the implanted eyes, 26% of the phakic patients required cataract extraction, whereas only 4% needed it in the fellow eye. Very few of the devices were explanted.


The fluocinolone implant is used for diabetic macular edema (DME) as well. A multicenter, randomized trial enrolled 80 patients who had undergone laser photocoagulation. Treat-ment groups received the 0.5-mg or the 2.0-mg implant. The standard-of-care group received repeat laser photocoagulation or was observed.

The 2-year study results showed 54% global resolution of edema in the implanted eyes, compared to 29% in the standard-of-care group. If we look at visual acuity, the eyes that had standard of care actually dropped about two letters, whereas the device-implanted eyes showed nearly a two-line improvement.

The trabeculectomy rate in the implanted group was about 20%. Some 32% of implanted eyes required drops or other therapy for increased pressure, compared to none of the standard-of-care group. Cataract extraction was needed almost universally in these eyes: 13% in the standard-of-care group and 75% at 2 years in the device-implanted group.


A great deal of research is in progress or planned for sustained drug delivery systems. In one study, researchers are looking at a biodegradable dexamethasone device for macular edema after laser or medical therapy. Rather than search for a specific disease indication, these researchers sought out a disease indication (macular edema), whether it was caused by diabetes, vein occlusion, uveitis or post-cataract surgery.

A recent phase II study compared a 350-mcg device to a 700-mcg device implanted into the vitreous cavity in 306 patients. So far, results are favorable. At 3 months, eyes implanted with the 350-mcg device show a trend toward improved visual acuity; there's definite improvement in visual acuity with the 700-mcg device.

Other researchers are testing the Neurotech encapsulated cell delivery method with encapsulated cells that produce CNTF in a phase I/II trial for retinitis pigmentosa. They should have results in 1 or 2 years.

And finally, a study is testing an adenoviral vector delivery system that's injected into the vitreous cavity. It carries pigment epithelial-derived factor (PEDF), which is a neurotrophic factor and an antiangiogenic agent. Researchers hope this system will help patients with neovascular age-related macular degeneration.


These studies showcase the great potential of sustained drug delivery systems to help patients with a variety of diseases. The implants may help us achieve new levels of success while avoiding some of the drawbacks of oral or systemic medications.

Dr. Jaffe is a professor of ophthalmology, vitreoretinal diseases, and surgery at Duke University in Durham, N.C.


1. Jaffe GJ, Ben-Nun J, Guo H, Dunn JP, Ashton P. Fluocinolone acetonide sustained drug delivery device to treat severe uveitis. Ophthalmology. 2000;107:2024-2033.

2. Jaffe GJ, Yang CH, Guo H, et al. Safety and pharmacokinetics of an intraocular fluocinolone acetonide sustained delivery device. Invest Ophthalmol Vis Sci. 2000;41:3569-75.