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New technologies offer timed, targeted drug delivery
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 Andrew Lotery, MD, said that nanotechnology drug delivery platforms may greatly enhance patient comfort and compliance and reduce injection-related complications. Image: Lotery A
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Eye drops, intraocular injections and systemic means have been the traditional ways of delivering medications to the eye. However, these methods have several disadvantages and limitations in terms of patient compliance, absorption, efficacy and side effects.
In recent years, increased attention has been given to the development of alternative systems for the delivery of ophthalmic medications. A variety of methods have been proposed, with the common aim of providing controlled, sustained release of the active agent directly into the eye, with minimal side effects.
With topical treatments, due to the barrier effect of the epithelium and to the significant loss occurring as a result of drainage and tear film turnover, only a minimal amount of the drug, typically less than 5%, permeates the cornea and reaches the ocular structures. Most of the drug is absorbed systemically through the conjunctiva and the nasolacrimal duct.
However, the main impetus for drug-eluting devices, especially in glaucoma, is patient noncompliance with dosing protocols, Steven D. Vold, MD, said.
“Compliance is just a real challenge for patients,” he said. “If we could find a way to make it so patients don’t have to put in drops on a regular basis, I think, no question, it would be one of the bigger breakthroughs in medical therapy.”
Delivery technologies for the posterior pole
Intravitreal injections are an effective and direct approach to deliver medications to the posterior segment. However, they are associated with potentially severe side effects, such as vitreous hemorrhage, retinal detachment, endophthalmitis and cataract, Paolo Lanzetta, MD, an OSN Europe Edition Editorial Board Member, said.
 Paolo Lanzetta |
“The need for repeated treatments, also in an [as-needed] regimen, multiplies the risk of these complications and is a source of stress and discomfort for the patient,” he noted.
Systemic treatment of posterior segment diseases has shown poor results in clinical trials, due to limited retinal delivery, high dose requirements and systemic side effects, he said.
Sustained-release devices provide an alternative route for delivering drugs to the eye. A number of these devices have been developed or are under development for retinal diseases and glaucoma, but also for ocular surface diseases and ocular surgery aftercare.
These devices are mainly in the form of biodegradable and erodible or nonbiodegradable inserts, punctal plugs and contact lenses, but also IOLs and micro-devices attached to IOL haptics.
A promising new method, still experimental, is the use of biodegradable polymer nanoparticles as carriers for targeted drug delivery.
Currently, two drug-delivery devices are approved by the U.S. Food and Drug Administration for retina/vitreous disorders. Ozurdex (Allergan) is a biodegradable implant for prolonged delivery of steroids, recently approved for macular edema secondary to central and branch retinal vein occlusion. It is injected intravitreally using a 22-gauge applicator. Official trials have shown encouraging results, especially in terms of safety with regards to IOP and cataract, Dr. Lanzetta said. Trials evaluating Ozurdex in diabetic macular edema with and without laser are ongoing.
Retisert (Bausch + Lomb) is approved for noninfectious posterior uveitis, is nonbiodegradable and requires surgical implantation to the sclera.
“In diabetic macular edema, despite the positive results on visual acuity, Retisert has been shown to cause secondary glaucoma with the need of filtering surgery in almost 40% of treated patients. Also, after 3 years, 96% of phakic patients received cataract surgery,” Dr. Lanzetta said.
“Research is now focused more on implants that are biodegradable or that, at least, don’t need to be explanted,” he said.
Iluvien (Alimera), a nonerodible reservoir of fluocinolone acetonide currently being studied for diabetic macular edema, holds promise. It is a miniaturized implant injectable through a 25-gauge needle and can be left indefinitely in the vitreous cavity.
A phase 2 trial for Iluvien showed efficacy, with about 30% of patients gaining three or more lines of vision at 12 months. Phase 3 trials are ongoing.
“It delivers a low dose of the drug, for a period of 18 to 36 months,” Dr. Lanzetta said.
A promising alternative to injectable devices are prodrugs — pharmacological substances administered in an inactive form and then metabolized in vivo in the active compound.
“Cortiject (Novagali Pharma) is a preservative-free and solvent-free emulsion that contains a tissue-activated corticosteroid prodrug. The emulsion is administered through a single injection and provides patient exposure to the active compound for approximately 9 months,” Dr. Lanzetta said.
A phase 1 study is currently under way in the U.S. for patients with diabetic retinopathy.
Prolonged delivery of drugs can also be provided by posterior juxtascleral infusion.
“Drug delivery through this vector takes advantage of the permeability and large 17-cm² surface area of the sclera, accounting for 95% of the entire surface of the globe. It is a much wider area for drug diffusion than the cornea, which is only 1 cm²,” Dr. Lanzetta said.
In a study, 22 eyes of 18 patients with refractory diffuse diabetic macular edema were treated by posterior juxtascleral infusion of modified triamcinolone, injected with a cannula needle through a small conjunctival and Tenon’s capsule incision.
In all eyes, a significant reduction in macular thickness and a visual acuity gain of at least one line were obtained. In more than 50% of cases, these results were achieved at 1 year with a single injection.
“Transscleral infusion seems to provide a sustained effect over 6 months, compared to the 1 to 3 months of intravitreal injections, with a significantly lower risk of complications,” Dr. Lanzetta said.
Glaucoma devices
In glaucoma treatment and disease management, an effective and safe drug-eluting device would significantly alter treatment management, according to Richard A. Lewis, MD, an OSN U.S. Edition Glaucoma Board Member.
 Richard A. Lewis |
“The goal is trying to maximize pressure reduction with minimal drugs,” Dr. Lewis said. “You’re also enhancing compliance because you’re not depending on the patient to do it. You’re going to be able to have the device do it. And then you’re trying to regulate the diurnal pressure flow so it’s not fluctuating as much.”
Drug-eluting ocular conformers with antifibrotic agents, medicines placed in a glaucoma shunt, contact lenses, punctal plugs and conjunctival drug-eluting devices are some of the ways that researchers are examining to deliver glaucoma drugs to the eye.
While not a device, anecortave acetate sub-Tenon injections are another option that could potentially offer sustained IOP lowering over several months, Dr. Vold said.
Dr. Lewis is working on a QLT-sponsored clinical trial examining a punctal plug that would deliver latanoprost from a drug-eluting core over 3 months. The plug is in a phase 2 trial; however, early results have shown that the retention rate is not optimal.
Regulatory approval also proves challenging for glaucoma drug-eluting delivery systems because of the cost involved in proving safety and efficacy, along with uncertainty that the finalized product will be market-worthy, Dr. Vold said.
A novel system designed by Mark S. Humayun, MD, PhD, would deliver glaucoma drugs through an intraocular pump implant (Replenish), which is in benchtop and preclinical testing. According to information Dr. Humayun presented at Glaucoma Subspecialty Day before the 2009 American Academy of Ophthalmology meeting, the system enables drug release to be timed, with the amount released controlled by the system’s wireless programming.
Other potential devices include a hydrogel contact lens that elutes a glaucoma drug and a device attached to the Ahmed glaucoma valve (New World Medical) that would slowly release mitomycin C for reduction of glaucoma drainage device failure.
Another possibility may be to lower pressure posteriorly instead of anteriorly, which is the topic of much current research. Neuroprotective agents could potentially deliver drugs directly to the optic nerve, making treatment highly effective, Dr. Lewis said.
QLT’s device could reach the market by 2011, but Dr. Lewis said overall research on the topic is still in early stages because of the difficulties of developing new technology.
“It’s a big challenge,” he said. “I think it’s a huge goal and would have a major impact in glaucoma management, but it’s going to be a tough one. It isn’t easy. It sounds easy when people talk about it, but there are so many hurdles along the way.”
The promise of nanomedicine
Promising new technologies are offered by nanomedicine. Nanocarriers such as nanoparticles (NPs), liposomes and dendrimers are currently undergoing intensive research as a means for ocular drug delivery.
“NPs are structures smaller than 100 nm, designed to contain the active ingredient and protect it from immediate and uncontrolled dilution or degradation. Entering into the cells by endocytosis or phagocytosis, NPs act at a cellular level, directly targeting the site of action,” Andrew Lotery, MD, said.
“Different NPs afford different drug-release kinetics, capacities and stability. Once injected into the vitreous, they provide sustained delivery of the drug, maintaining stable therapeutic drug concentrations,” he said.
Nanoparticles are relatively easy to prepare, can be sterilized and have a long shelf life. Various natural and synthetic biocompatible polymers are engineered as nanocarriers. The most commonly used natural polymer is egg albumin, which has shown high efficiency in incorporating drugs or oligonucleotides. Synthetic polymers are mainly polylactides, which degrade in vivo to form natural metabolites. Degradation rate can be customized by changing the polymer composition and molecular weight. Controlled drug release can be programmed to last from a few days to several years.
“Compared to the current schedule of intravitreal injections for retinal diseases, which entails repeated, often monthly injections, this new technology presents considerable advantages. A single procedure with extended-release drug delivery would significantly reduce the risks of injection-related complications as well as the economic burden of repeated procedures. Patient comfort and compliance would be greatly enhanced,” Dr. Lotery said.
Animal experiments have demonstrated that NPs have the capacity to migrate through the vitreous and neurosensory retinal layers, reaching the retinal pigment epithelium and choroid. This is particularly promising in the treatment of retinal degenerations that typically require subretinal injections.
“The possibility to deliver the therapeutic agent through the vitreous is very exciting, since intravitreal injections are technically less challenging and safer,” Dr. Lotery said.
Nanoparticles could also be used in the future for gene therapy, as a safer and more effective alternative to viral vectors to deliver full genes or gene-suppression agents to the eye.
“Thanks to their ability to penetrate the retinal pigment epithelium, NPs could be used clinically as carriers of anti-VEGF drugs like small interference RNA in the treatment of age-related macular degeneration,” Dr. Lotery said.
Naked small interference RNA targeted to genes for VEGF and VEGF receptors has shown safety and efficacy in phase 1 and 2 trials. If these results are confirmed by phase 3 trials, the delivery of small interference RNA through nanotechnologies may be considered as a further step to improve selectivity and targeted drug delivery.
Nanoparticles could be used in several different ways for the treatment of glaucoma.
“First of all, as carriers for the classic glaucoma medications, taking away the burden of twice-a-day drop administration and overcoming the problem of compliance, which is known to be a big issue with glaucoma patients,” Dr. Lotery said.
Another step would be the delivery of trophic factors to prevent retinal ganglion cell degeneration and the use of magnetic NPs for optic nerve repair.
“Magnetic NPs have the capability to engineer tissue by guiding cell growth. In a proof-of-principle study, magnetic cationic liposomes were added to ARPE-19 cells, and these cells were grown in presence of a magnet. After 24 hours, they formed a multilayered sheet that could be transferred to a tissue culture dish to proliferate and form a monolayer,” Dr. Lotery said.
This procedure could be used to prepare retinal pigment epithelium sheets for transplantation and also to extend an injured ganglion cell axon to the optic nerve to help neurons reconnect. This would be achieved by attaching magnetic NPs to the tip of the axon and directing them to grow in the correct orientation with the application of an external magnetic field.
“There are many other potential applications of nanotechnologies in the treatment of eye diseases. The eye is in fact a privileged organ for nanomedicine. First of all, because we have two eyes and therefore a built-in control for experimenting new treatments. Then, the eye is easily accessible and transparent; the effects of interventions can be monitored and controlled. Finally, due to its small size, the eye requires smaller doses of medications than other organs. Scientists involved in nanomedicine should develop a stronger interest in the eye,” Dr. Lotery said.
Currently, most of these new methods are theoretical or in the very early stages of development, and only a few of them have reached the stage of in vivo experiments.
“It will take another 5 to 10 years before we reach clinical stages. However, early studies suggest that NP technology might be a breakthrough in the treatment of potentially blinding diseases,” he said. – by Michela Cimberle
What technologies will
lead the way for drug delivery in eye disease?
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- Paolo Lanzetta, MD, can be reached at University of Udine, Department of Ophthalmology, Piazzale Santa Maria della Misericordia, 33100 Udine, Italy; +39-0432-559905; fax: +39-0432-559904; e-mail: paolo.lanzetta@uniud.it. Dr. Lanzetta is a consultant to Allergan.
- Richard A. Lewis, MD, can be reached at Grutzmacher & Lewis, 1515 River Park Drive, Suite 100, Sacramento, CA 95815, U.S.A.; +1-916-649-1515; fax: +1-916-649-1516; e-mail: rlewiseyemd@yahoo.com. Dr. Lewis is a consultant for QLT.
- Andrew Lotery, MD, can be reached at Southampton Eye Unit, Southampton General Hospital, Southampton SO16 6YD, U.K.; +44-238-079-5049; fax: +44-238-079-4542; e-mail: a.j.lotery@southampton.ac.uk. Dr. Lotery has served on an advisory board for Allergan in the past year.
- Steven D. Vold, MD, can be reached at Boozman-Hof Regional Eye Clinic, 3737 West Walnut St., Rogers, AR 72756, U.S.A.; +1-479-246-1700; e-mail: svold@cox.net. Dr. Vold receives research support from Alcon Laboratories and Allergan and serves on Allergan’s speakers’ bureau.
