May 2018


Pharmaceutical focus
Examining the sustained front

by Maxine Lipner EyeWorld Senior Contributing Writer

The bimatoprost sustained-release ring is an example of an external guided administration of pharmaceuticals.
Source: Allergan

Placing sustained-release devices such as a bimatoprost ocular insert under the upper lid may help with patient medication compliance issues.
Source: John Sheppard, MD

Also being considered for sustained release are punctal plugs loaded with medication.
Source: Malik Kahook, MD

New delivery possibilities for glaucoma

For glaucoma patients, using eye drops is often a daily ritual. The holy grail would be an implant that could deliver the needed medication on cue. From punctal plugs to rings and implants and more, here’s the latest in this area.
Even in this era with so much attention in glaucoma on MIGS technology, there’s ample room for sustained-release devices, according to Jason Bacharach, MD, founding partner and medical director, North Bay Eye Associates, Sonoma County, California. He views these as ancillary treatment opportunities. “They’re not necessarily separate,” he said. “You could deliver a drug through a MIGS-type device that is potentially replaced over time.”
For example, practitioners could deliver one of the commonly used topical agents or even a novel agent through a MIGS device that would provide ancillary intraocular pressure reduction over what a stent without pharmaceutical products might provide, Dr. Bacharach explained. This is akin to the coated stents being regularly used in the cardiology world, which work better than the stent alone.
“I think that it’s a great opportunity,” he said, adding that using this approach in glaucoma would teach practitioners about the impact of such devices in the angle and how the eye tolerates having something small in the anterior chamber over time.
Steven Mansberger, MD, vice chair and director of glaucoma services, Legacy Devers Eye Institute, Portland, Oregon, pointed out that any MIGS devices that use the outflow tract collector system are going to require medicines. In his view, sustained delivery implants will fill an important void. “We don’t have a sustained delivery device available right now, so there’s a need for this type of treatment for those patients who can’t remember to use their eye drops every day,” he said. While not all would likely want this, sustained delivery represents a way for many of these patients to be treated for a long period without much effort on their part.

Considering the possibilities

There are a variety of possible approaches for sustained delivery, Dr. Bacharach said. He refers to these as GAP (guided administration of pharmaceuticals) therapy and breaks them into two groups, eGAP and iGAP. “The eGAP is external delivery, and the iGAP is internal,” he said. “The external group includes delivery emulsions, fornix-based rings, contact lenses, subconjunctival injections, and punctal plugs.” The internal group are placed in the anterior chamber and include biodegradable implants or a replaceable device put on an intraocular lens or a MIGS device. Examples include the iDose Travoprost implant (Glaukos, San Clemente, California) and Bimatoprost Sustained Release (Allergan, Dublin, Ireland).
Devices placed internally would need to have higher efficacy, Dr. Bacharach pointed out. “With eGAP you might give up some efficacy because of perceived benefits on the safety side,” he said. “If you place a pharmaceutical product inside the eye, one benefit would be allowing for a lower concentration or reduced amount of medicine as it is closer to the targeted tissue.”
An example of a replaceable eGAP would be the bimatoprost sustained-release ring (Allergan), which is a flexible ring placed in the fornix and barely visible, Dr. Bacharach said.
An example of the iGAP would be the iDose. “The iDose provides sustained IOP reduction over time via a delivery cartridge of proprietary travoprost oil that has demonstrated robust IOP reduction over months,” he said. Once the agent is delivered, the practitioner can remove the canister through a small microincision in the cornea and replace this through the incision.
Bimatoprost sustained-release is a dissolvable pellet that would not need to be removed, he noted, adding that the physician would need to put in a new one once it was gone.
Dr. Mansberger pointed out that there can be issues with some of the sustained-release approaches. The bimatoprost ring, for example, has had some efficacy issues, he noted. “It didn’t have as much IOP-lowering as timolol,” Dr. Mansberger said. “Also, there is a foreign body in the fornix of the eye, which can create all the issues that you might get from a contact lens-type process.” This approach is similar to one used in the past in which a silicone sack filled with pilocarpine was placed in the lower fornix where it would remain for a period of time.
Gary Novack, PhD, president of PharmaLogic Development, San Rafael, California, and visiting professor of pharmacology and ophthalmology, University of California Davis School of Medicine, cited the pilocarpine-filled Ocusert as an early iteration of these sustained-release devices. There can be pros and cons to these, Dr. Novack stressed. “Ocusert, developed in the 1970s, did a great job of delivering pilocarpine to the tear film for 1 week, but unfortunately could slide across the cornea to block the vision,” Dr. Novack said.
Dr. Mansberger said that any location in the eye is possible for sustained delivery. In his view, the punctal plugs show some promise. “You can see that they’re there,” Dr. Mansberger said, adding that these are slowly eluting medicine. The question is whether patients will be amenable to putting in such a plug and stretching the puncta, as well as whether there are any long-term side effects.
“I think that patients would look at this favorably because they don’t like taking drops every day,” Dr. Novack said, adding, however, that it’s hard to know which of the sustained-release approaches patients would prefer. There can also be unintended consequences. “By doing one thing, you perturb the system in another way,” he said.
In considering what molecules might be most likely to succeed in a sustained delivery approach, Dr. Novack stressed that this depends on the type of delivery system. “If it’s a ‘zero order,’ i.e., constant delivery with respect to time system, a molecule like brimonidine or timolol is most appropriate,” he said. “If it’s a pulsatile, i.e., peaks and troughs system, a molecule like the prostaglandins is the better choice.” The fact that the prostaglandins tend to do better with such pulsatile delivery is supported by the data that indicate that twice-a-day dosing of this drug is less effective than once-a-day dosing. For molecules such as pilocarpine, timolol, and brimonidine that have variable durations of activity, constant delivery seems to be a workable solution, Dr. Novack said.
Dr. Mansberger pointed out that investigators still don’t know the lowest amount of drug to get the highest effect with sustained delivery. “I think there are some dose-response curves that need to be done to answer the question about which molecules are going to be best,” he said. The prostaglandins are interesting because they have the most IOP lowering, they work well, and there are few side effects, he noted. “They are attractive because there are not that many systemic side effects when you compare them to something like timolol, which has more systemic side effects,” Dr. Mansberger said, adding that the carbonic anhydrase inhibitors also have minimal side effects. However, the alpha agonists are likely not of interest here because of the side effect profile.
Dr. Bacharach views the potential molecules that could be utilized here as wide open. “Most of the agents that have been looked at with these delivery devices have been the prostaglandin class because they have shown the highest efficacy,” he said. “But it’s very possible that you might be able to combine classes that are currently already marketed like beta blockers, alpha agonists, or CAIs.”

Stumbling blocks

How you get the drug into the eye is part of the sustained-release equation that must be evaluated. One possibility being considered is viral vectors, which Dr. Mansberger thinks has some potential. “I think viral vectors would be interesting if it could change the meshwork so that it starts to work better or change the outflow pathway in some way that it works better,” he said. Still, he has concerns about the approach. “I don’t think a viral vector given every 3 months would be a good way of delivering medicine because I would expect these viruses to have some sort of inflammatory response that may create untoward side effects.”
There remain other challenges as well with sustained-release implants for glaucoma. Dr. Novack pointed out that one stumbling block with internal systems has been the concept of payload. Part of the sustained-release approach is potency and determining how many milligrams of the molecule that you need.
Overall, it will likely take some time before any sustained-release systems become available, Dr. Novack thinks. “Based on public data, the most advanced program at present is the bimatoprost implant, currently in Phase 3,” Dr. Novack said. “Upon completion of Phase 3 clinical observations, it typically takes 6–9 months to prepare a submission.” It can then take 6–10 months for the FDA to review the application, then some time for the company to launch the product.

Editors’ note: Dr. Bacharach has financial interests with Allergan, Glaukos, and Ocular Therapeutix (Bedford, Massachusetts). Dr. Mansberger has financial interests with Allergan and Ocular Therapeutix. Dr. Novack has no financial interests related to his comments.

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