May 2016




Device focus

Drug delivery systems for glaucoma

by Michelle Dalton EyeWorld Contributing Writer


Bimatoprost SR in the anterior chamber Source: Allergan

The expanding options will help glaucoma specialists manage patients IOP better

For years, the mainstay of glaucoma treatment has been topical eye drops, laser angle treatment, and surgery (trabeculectomy, mostly) when patients can no longer be medically managed. But in the past few years, researchers and companies have begun to explore how to deliver intraocular pressure (IOP)-lowering drugs with sustained delivery systems. The majority of drug delivery system studies are in their infancy, and its not yet clear which devices will be successful. In considering whether sustained delivery will make an impact, its vital that they are applicable to the vast majority of glaucoma patients. Otherwise, the development cost wont be worth it, said Harry Quigley, MD, director, Glaucoma Center of Excellence, Wilmer Eye Institute, Johns Hopkins University, Baltimore. And there are pros and cons to delivering the drugs on the surface of the eye or into the anterior chamber. Devices on the external part of the eyesuch as punctal plugsmay not be obvious to the patient, and that means patients may not notice if theyve fallen out. Others, such as contact lenses, are more easily monitored for retention by the patient, but could be uncomfortable.

Delivering drugs internallyeither through an implant or via an injectionmeans that patients will almost invariably have temporarily blurred vision, either from the implant itself, the drug, or from the process of prepping and injecting the eye, Dr. Quigley said. And injections run a potential risk of endophthalmitis. Put simply, sustained-release is at the top of our wish list to improve patient compliance, said E. Randy Craven, MD, Wilmer Eye Institute.

Sustained delivery instantaneously improves the efficacy of any glaucoma drug because of that increased adherence, Dr. Quigley agreed. With most patients on 2 different agents, delivering the drug subconjunctivally or intraocularly not only reduces reliance on patients to comply with instillation, but removes the preservative (and the toxicity associated with it), as well as topical allergies or irritation associated with eye drops.

Glaucoma delivery systems in the future

When it comes to sustained delivery devices, Dr. Quigley said the device material is as important as the drug its delivering. Whatever is being placed into the vitreous or anterior chamber has the potential to damage the corneal endothelium or to block outflow. It has to dissipate entirely and do so benignly, he said.

With 7 prostaglandin drug delivery systems in clinical development, how they deliver the drug is going to become more than just a marketing issue, said Gary Novack, PhD, PharmaLogic Development, San Rafael, California. These are not devicesfor regulatory purposes, thats a mandatory distinction from true devices. These deliver drugs and will be regulated as such. Currently, companies investigating drug delivery systems for the treatment of glaucoma include Mati Therapeutics (Austin, Texas), ForSight Vision5 (Menlo Park, California), Graybug (Baltimore), Ocular Therapeutix (Bedford, Massachusetts), Peregrine Ophthalmic (Singapore), Envisia Therapeutics (Morrisville, North Carolina), Allergan (Dublin), and Glaukos (Laguna Hills, California). Two of these companies, Allergan and ForSight Vision5, are developing delivery systems with bimatoprost as the active ingredient. Down the road, companies will likely only continue to develop products that are potentially cost-effective, Dr. Quigley saidand that means injections have to be quick and easy to deliver, and delivery systems have to be comfortable enough for patients to continue to use them.

With so many companies developing these systems, all in different stages of development, its hard to make a scientific judgment at this point about which is the best delivery system, Dr. Novack said. We dont have data yet on which ones will find the right balance of efficacy and safety and long enough delivery.

Bimatoprost in sustained delivery devices

ForSight Vision5 is developing an ocular insert to allow for continuous administration of bimatoprost for up to 6 months. Dubbed Helios, the insert is constructed as a polymer/bimatoprost matrix in a soft, compliant ring about 26 mm in diameter. The ring is applied to the ocular surface in the clinic and maintained under the eyelids, according to the company. At 6 months, there was a mean diurnal IOP reduction of 4.76.5 mm Hg from washout with no unexpected safety events.1 A phase 2 study (n=130) was designed to determine if the insert is non-inferior to timolol 0.5%. Results presented last year found over a 6-month period, the single dose of the bimatoprost insert (OU) lowered IOP by an average of 1 less mm Hg than the 360 drops of timolol applied to each eye in the other arm of the study.2 A phase 3 study is expected to start this year.

Allergan is developing bimatoprost SR, where the amount of drug thats in one of those implants is the equivalent of one drop of bimatoprost, Dr. Craven said, but that one drop lowers IOP for 36 months with one implant. Its a safer ideadrug exposure is less, the risk of side effects is reduced, he said. The biodegradable implant is placed intracamerally using a prefilled, single-use applicator system. Following washout and assessments at baseline (day 3 to 1), on treatment day 1, bimatoprost SR (6-, 10-, 15-, or 20-g generation 2 formulation) was administered intracamerally in the study eye, and the fellow eye began topical bimatoprost 0.03% QD in a phase 1/2 prospective, 24-month, dose-ranging, paired eye comparison study. Study eyes that met retreatment criteria were allowed to receive a second administration of bimatoprost SR after a minimum of 90 days and at most 12 months after the first administration.

After delivery, the implant settles on the lower angle, Dr. Craven said. At 12 months, theres a bit of the implant still in the bottom of the eye, but by 2 years its completely gone. The drug has been depleted before the implant dissolves. Over 16 weeks, the implant reduced IOP 7.29.5 mm Hg from baseline, depending on which version was used; topical bimatoprost reduced IOP 8.4 mm Hg from baseline. Both arms reported conjunctival hyperemia as the most common side effect, but within 2 days only 5 eyes in the implant group (of 75 overall) were still reporting hyperemia, compared to 13 eyes (of 75) in the topical group.

While its still early, Dr. Craven said this looks like its going to give us an expanded treatment option for a delivery platform that is very close to, if not as good as, what we saw with the drops with much less drug exposure and fewer side effects. Its promising.

Subconjunctival injections

Dr. Novack (with the Singapore National Eye Centre) investigated the use of a nanoliposome drug delivery system for the longer term delivery of latanoprost.3 In that pilot study, a single subconjunctival injection of liposomal latanoprost was well tolerated by the 6 subjects and produced a mean IOP decrease of 13.03 mm Hg (about 47%) from the baseline of 27.55 mm Hg. Both a clinically and statistically significant IOP reduction held through 3 months. Dr. Quigley is working with colleagues to develop a microparticle-encapsulated version of dorzolamide and other drugs that can be delivered subconjunctivally. With the average glaucoma patient living about 16 years past onset, that could lead to numerous injections. If youre injecting through the cornea 32 times in that 16 years, whatever youre leaving behind better be benign, Dr. Quigley said. There isnt as much space in the anterior chamber and vitreous as there is in the subconjunctiva. In the rabbit studies on the encapsulated dorzolamide, the subconjunctival histology does not suggest that theres any remaining particle material there by 90 days. The material is largely being absorbed by macrophages, Dr. Quigley said. One thing is certainthere are numerous new drugs and drug delivery systems being explored. Maybe it was the science that changed interest levels, Dr. Novack said. Were fortunate that companies are investing in this area again. Its better for our patients in the long run.


1. Goldberg I, et al. Maintenance of IOP-reduction for 6 months with a single dose of a novel topically applied bimatoprost ocular insert in patients with open-angle glaucoma or ocular hypertension. Poster presented at the 2015 World Glaucoma Congress.

2. Brandt JD, et al. Six-month IOP reduction with a single dose of a novel topical bimatoprost ocular insert: A phase 2 randomized double-masked, controlled study. Paper presented at the 2015 American Academy of Ophthalmology meeting.

3. Wong TT, Novack GD, et al. Nanomedicine for glaucoma: sustained release latanoprost offers a new therapeutic option with substantial benefits over eyedrops. Drug Deliv Transl Res. 2014;4:3039.

Editors note: Dr. Craven has financial interests with Allergan, Alcon (Fort Worth, Texas), Pfizer (New York), Transcend Medical (Menlo Park, California), and Ivantis (Irvine, California). Dr. Quigley has financial interests with GrayBug, Alcon, Allergan, and Genentech (South San Francisco). Dr. Novack has no financial interests related to this article.

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