Sustained-release ocular drug delivery devices

The Bimatoprost Ring sustained release  insert in place. Courtesy of ForSight VISION5, Inc.

Several external sustained-release ocular drug delivery devices, including punctal plugs, fornix rings, drug-eluting contact lenses and long-acting gels, are in development with some nearing approval, presenters told Glaucoma Day at the 2016 ASCRS•ASOA Symposium & Congress in New Orleans, USA. While they are unlikely to supplant eye drops any time soon, these devices may eventually help solve problems with long-term medication adherence and diurnal drug concentration variation seen with current topical glaucoma treatment. Demonstrating the potential of sustained delivery, a polymer ring placed in the conjunctival fornix successfully lowered intraocular pressure (IOP) for up to 13 months without additional treatment, said James D Brandt MD of the University of California-Davis, USA. Inserted under the eyelid, the non-bioabsorbable ring of 24mm to 29mm diameter elutes preservative-free bimatoprost at a therapeutic level for about six months. In a six-month phase 2 clinical trial (Brandt et al, Ophthalmology, ePub in advance of publication), 63 patients treated with the Bimatoprost Ring and artificial tears twice daily saw mean IOP drop nearly as much as IOP dropped in 64 patients treated with timolol 0.5 per cent eye drops twice daily and a non-medicated insert. In a seven-month open-label single-arm trial extension, patients who received a second insert maintained IOP reductions of 4-6mmHg for the entire 13 months. A third insert was then placed, which will extend the ongoing study to 19 months. To his knowledge, this is the longest duration dataset for any of the emerging sustained-release platforms, Dr Brandt said. Adverse events were similar to those seen with bimatoprost eye drops, and mostly resolved without complications, Dr Brandt said. Nearly 90 per cent of patients retained the ring without assistance for the first six months, and 97 per cent for the second cycle of seven months (data presented at the 2016 meeting of the American Glaucoma Society). An important advantage of this platform, Dr Brandt said, is that (in contrast to punctal plugs) no patient experienced a dislodgement where they were unaware that the device had popped out of place. The manufacturer, ForSight VISION5, Inc. has received guidance from the US FDA on a trial design needed to bring the ring to market, Dr Brandt said. The phase 3 programme is planned for later this year. “My personal prediction is that within five years we are going to see a growing number of glaucoma patients who have MIGS supplemented by one of the sustained-release platforms, all in an attempt to avoid the use of daily drops,” Dr Brandt added. IN THE PIPELINE The search for extended-delivery devices goes back at least to 1976, with the Ocusert, a ring placed in the lower cul-de-sac that delivered pilocarpine for one week, noted Richard Lewis MD, Sacramento, California, USA. But delivery was uneven – too high early in the week causing side effects, and too low later reducing efficacy, and the device was not a big hit. Among current devices in clinical trials that overcome the challenge of steady elution are punctal plugs. Mati Therapeutics has latanoprost glaucoma and olopatadine allergy devices, and Ocular Therapeutix has a travoprost glaucoma device as well as a dexamethasone anti-inflammatory device, Dr Lewis said. These non-invasive devices deliver preservative-free medication for up to three months. However, medication may be flushed into the nasal passages instead of the eye, and they can dislodge, which is a major concern, Dr Lewis said. Both firms claim retention rates of over 95 per cent in clinical trials. Further out in the pipeline are drug eluting contact lenses, Dr Lewis said. A latanoprost contact lens has maintained therapeutic levels in rabbit eyes for up to 28 days, which may make it suitable for long-term drug delivery, or drugs that cannot be delivered by drops, he added (Ciolino et al. Biomaterials. 2014 Jan; 35(1): 10.1016). Eye drops that solidify into a stable gel on the ocular surface and elute medication for up to one month have been tested in rabbits, Dr Lewis said. They appear non-irritating and 100 per cent were retained for 28 days in preclinical trials at the University of Pittsburgh, USA. The SoliDrop combines a thermoresponsive hydrogel carrier with drug-loaded polymer microspheres. It is designed to be self-administered by patients, but is not yet in human trials. “This may be good for specific types of treatment, but I’m not sure it is best for glaucoma where we need years of treatment,” Dr Lewis said. Also in development are subconjunctival inserts, which have been tested in humans in a phase 1 trial, Dr Lewis said. These deliver medications for three to six months with a target of one year, but achieving therapeutic levels has been problematic. Indeed, all sustained drug delivery technologies face significant hurdles, Dr Lewis added. Unknowns include whether long-term constant level exposure to drugs, particularly prostaglandins, is good or bad for IOP control. Development, even with approved molecules, is expensive and time consuming, with punctal plugs in development for more than 10 years. Also, peer-reviewed studies of these devices are almost entirely lacking. “Compliance and adherence problems with chronic disease must be addressed, and punctal plugs, contact lenses, new gels and subconjunctival implants offer many advantages. But eye drops are not going away in the near future,” Dr Lewis concluded.