Eyeworld

EW NEWS & OPINION 30 December 2016 by Liz Hillman EyeWorld Staff Writer The researchers observed an initial "burst" release of cyclosporine A from the micelles within 24 hours, followed by a longer, slower release over an up to 14-day period. They also observed increased mucoad- hesion of LMP micelles with in- creased phenylboronic acid content, although there did appear to be a point where more phenylboronic acid stopped increasing adhesion. According to the study, some reduced cell proliferation and altered morphology was seen in vitro when the micelles were tested with human corneal epithelial cells. Negative side effects were not observed, however, in vivo in a rat model. "What we think happened in vitro is the micelles presented a bar- rier to oxygen, which doesn't allow the cells to breathe," Dr. Sheardown said, explaining that overall there were no negative side effects in vivo. "Our in vivo studies have been incredibly positive." The authors concluded that the mucoadhesive micelle drug delivery system "[shows] the potential to sig- nificantly improve the bioavailabil- ity of topically applied ophthalmic drugs." The micelles could decrease dose levels and frequency, thus re- ducing unintentional, negative side effects from systemic exposure to ophthalmic drops. For now, this micelle technique has only been tested with cyclospo- rine A because of the widespread issue of dry eye, Dr. Sheardown said, but the platform has potential for other drugs as well. To move the research forward, Dr. Sheardown said their start-up company—OptimEyes—is now rais- ing money to begin a full preclinical package to show that this drug deliv- ery method is safe and effective. EW Reference 1. Prosperi-Porta G, et al. Phenylboronic-ac- id-based polymeric micelles for mucoadhe- sive anterior segment ocular drug delivery. Biomacromolecules. 2016;17:1449–1457. Editors' note: Dr. Sheardown has finan- cial interests with OptimEyes. Contact information Sheardown: sheardow@mcmaster.ca "The difference is subtle, but we think that because of the core and shell design of our materials we can encapsulate various drugs and control the release more efficient- ly," Dr. Sheardown said, explaining that previous research has looked at mucoadhesive nanoparticles and mucous penetrating nanoparticles. "Also, we think that our materials have the advantage of being able to be prepared and encapsulate the drugs in a single synthetic step." Dr. Sheardown said the micelles are composed of hydrophilic and hydrophobic components. When put into an aqueous system, they spontaneously form into droplets with the hydrophobic components all pointing inside and the hydro- philic components all pointing outside. The hydrophobic core of the micelle is what interacts with the drug and sequesters it inside the hydrophilic shell for release. "The release is mainly diffu- sive," Dr. Sheardown said. "It's based on the concentration gradient be- tween the inside of the micelle and the outside of the micelle. We hope that all of the drug is gone—or most of it is gone—before the degradation of the polymer occurs." Restasis (Allergan, Dublin, Ireland) for delivery of cyclosporine A, an immunosuppressant that reduces inflammation, which can cause dry eye. Cyclosporine A in Restasis, however, is in an emulsion. Dr. Sheardown's team went a step fur- ther to create a mucoadhesive block copolymer micelle that would stick to the ocular mucosa. The research- ers varied the amount of phenylbo- ronic acid to see how much "muco- adhesive strength" they would need. As Dr. Sheardown explained it, other work suggests that mucoadhesion may not be the best way to increase the longevity of a drop in the eye because it could attach to mucin in the tear film, which would clear rapidly. "We wanted to optimize the amount of stickiness that we had to ensure that we got as much as we could on the surface of the eye without losing it," she said. Previous research has shown the potential for mucoadhesive nanoparticles, but the use of muco- adhesive micelles in Dr. Sheardown's research is novel. Researchers develop an eye drop formula with mucoadhesive properties to keep drugs in the eye longer T he problems with eye drops are many. The issue of patient compliance is one thing—remembering to apply them as instructed, being accurate in one's application. But there is also an inherent flaw to the drop delivery model itself: Such a small percentage of the actual medication remains in the eye be- fore washing out. A study published in the Amer- ican Chemical Society's journal Biomacromolecules states that this leads to "large frequent doses" of the drugs, which can "result in high systemic exposure and side effects." 1 "The eye has great barrier functions to keep things out of it," said Heather Sheardown, PhD, professor, Department of Chemical Engineering, McMaster University, Hamilton, Canada. "The drop is considered foreign to the eye and [the eye] essentially tries to get rid of it. … We need a better drop." Dr. Sheardown and her labora- tory set out to develop a polymer that would improve retention of a drop-delivered drug targeted for the anterior segment. They speculated this could reduce the number of drops needed by the patient, thus improving compliance and reducing dosage-related side effects. Dr. Sheardown and her team developed and tested a poly(L-lactide)-b-poly(methacrylic acid-co-3-acrylamidophenylbo- ronic acid) (LMP) block copolymer micelle—a molecular packet, if you will—which they hypothesized would remain in the eye longer to deliver medication before washout. The researchers decided to use a mucoadhesive polymer that would "stick" to the immobilized mucin layer of the tear film. "We knew boronic acids have mucoadhesive properties; that's been well-known for a long time," Dr. Sheardown said, noting that boronic acids are part of the formulation of An eye drop that sticks Researchers at McMaster University developed a "sticky" eye drop using mucoadhesive properties in the hopes of reducing compliance issues and dose-related side effects of topical medications. Source: Heather Sheardown, PhD

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