Drug delivery systems

Which of the sustained-release drug-delivery approaches now being developed for the treatment of glaucoma will prove to be the most successful five years? An expert panel debated this question at the 7th World Glaucoma Congress in Helsinki, Finland. James Brandt MD, of the University of California, Davis, USA, argued in favour of extraocular approaches, noting that it is the safest and most reversible means of drug delivery. In two-thirds of patients receiving IOP-lowering medications, the indication is either ocular hypertension (OHT) or early glaucoma. While some compromise in safety may be acceptable in eyes with more advanced disease, safety is the priority in eyes with early disease, particularly when one considers the generally slow rate of progression that is typical of the disease, he said. NEW EXTRAOCULAR DRUG DELIVERY SERVICE Topical medications are an extraocular approach that should work in theory. However, research indicates that around half of patients do not adhere to their regimens and identifying these patients can be difficult. An extraocular sustained-release delivery system could address the problem without sacrificing safety. One extraocular device that is currently in an advanced stage of development is the bimatoprost ocular insert. The ring-shaped device consists of a polypropylene core coated with bimatoprost-impregnated silicone. It is designed for placement beneath the eyelids in the conjunctival fornix. It is not bio-absorbable but is replaced every six months by the patient’s physician. Phase II results with the ocular insert indicate that it is safe, lowers IOP predictably and is well tolerated. In a study published in 2017 (Brandt et al, Ophthalmology, ePub in press) with 144 patient-years of data, patients had consistent lowering of IOP for up to 19 months of follow-up. An important potential advantage of the ocular insert as a drug-delivery platform is that it can be impregnated with multiple agents; an insert combining bimatoprost and timolol is already in development. “After all, half of the patients in the Ocular Hypertension Treatment Study needed two or more drugs to achieve the Study’s modest IOP-lowering goal of 20%,” said Dr Brandt. Ingeborg Stalmans MD, Catholic University KU Leuven, Belgium, maintained that an intracameral sustained-release approach is most likely to prove successful in the medical treatment of glaucoma because it delivers medication directly and reduces the amount entering systemic circulation. She noted that poor adherence is not the only problem in current medical treatments for glaucoma. Bio-availability is also an important issue. She noted that the volume of a typical eye drop is 20-to-50μl, but pre-corneal space can only hold around 7.0μl. The excess either rolls down the cheek or enters systemic circulation through the nasolacrimal duct. In fact, only 1-to-5μl is absorbed by the eye. “Alternative drug-delivery systems might achieve a longer lasting, highly localised delivery with more accurate concentrations and fewer side-effects than topical administration,” Dr Stalmans said. She noted that Allergan has developed a modified version of the intravitreal Ozurdex implant, which contains a slow-release formulation of bimatoprost rather than dexamethasone, and is designed for intracameral injection. Like the Ozurdex implant, it is biodegradable and therefore does not need to be removed. In a dose-ranging study, the bimatoprost implant provided rapid, sustained IOP lowering with an overall reduction from baseline ranging from 7.2mmHg to 9.5mmHg, depending on the dosage, for 16 weeks. In addition, a proportion of the eyes with the implant continued to have significant IOP reduction at two years. A phase III trial is now under way and is expected to be completed in 2018. Dr Stalmans noted that the injections should prove acceptable from a patient’s perspective. She cited a study showing that 75% of patients are willing to undergo subconjunctival injections every three months. That study also showed that 86% of patients surveyed were willing to accept higher costs, and that patients who do admit to non-adherence and those who were on multiple medications were the most willing to accept repeated injections and increased costs. With regard to safety, she pointed out that that intravitreal injections have been shown to carry only a very small risk of endophthalmitis and have now become routine in the treatment of retinal disease. “Humans are clumsy and forgetful, imprecise and unreliable. High-tech drug-delivery systems are not, and this is why I believe that medications delivered through a sustained-release platform may particularly the intracameral route may be the future of ophthalmology. INTRAVITREAL MAY BE THE BEST OPTION Concluding the debate was Uday Kompella PhD, University of Colorado, Denver, USA, who argued that intravitreal drug-delivery has many theoretical advantages over both extraocular and intracameral approaches. He noted that, like intracameral approaches but unlike extraocular approaches, intravitreal approaches deliver 100% of the drug into the eye. In addition, unlike intracameral approaches, intravitreal drug delivery presents no danger to the cornea. He added that there are already well-established biodegradable and non-biodegradable slow-release systems for drug delivery to the vitreous humour, including a non-biodegradable system that allows for fluocinolone acetate to be administered once every three years. James Brandt: jdbrandt@ucdavis.edu Ingeborg Stalmans: 
ingeborg.stalmans@med.kuleuven.be Uday Kompella: 
uday.kompella@ucdenver.edu