Eyeworld

EW NEWS & OPINION 26 September 2017 the only one that provided sufficient antimicrobial effects for the micro- organisms tested. There are many papers, howev- er, that note the negative side effects associated with BAK. The authors of a paper published in 2010 said that it "has consistently demonstrated its toxic effects in laboratory, exper- imental, and clinical studies. As a quaternary ammonium, this com- pound has been shown to cause tear film instability, loss of goblet cells, conjunctival squamous metaplasia and apoptosis, disruption of the cor- neal epithelium barrier, and damage to deeper ocular tissues." 3 The alternative to preserved eye drops in a multi-dose vial are single-dose packaged units. These are said to be more expensive. German research published in 1994 compared the cost of single-dose, non-preserved glaucoma therapy to preserved multi-dose medication and found it was 161–1,169% more expensive. 5 Dr. Lindstrom said these single- drop ampules are also inconvenient for the patient to use. Then there's the plastic waste. "There's a whole environ- mental movement in the U.S. and Europe where people want preser- vative-free," said Kevin Hershfield, CEO of TearClear. "But you can imagine all the packaging and plas- tic and waste that comes with that. I think doctors and patients would agree that a multi-dose solution is better for both the patient and the environment." Striving for the best of both worlds Research devoted to reducing the impact of preservatives while maintaining sterility has been going on for decades, from container and filter designs to adding other agents to decrease corneal damage to other preservatives with lower toxicity. 6–9 Dr. Lindstrom pointed out that the U.S. Food and Drug Adminis- tration approved preservative-free Restasis MultiDose (cyclosporine, Allergan, Dublin, Ireland) in 2016 after the company developed a bot- tle with a unidirectional valve and air filter that prevents contaminants from entering the bottle. "Our technology captures the BAK prior to the drop going into the eye," Mr. Hershfield said of the TearClear filter. "That's where the breakthrough takes place. Our efforts now are to advance our de- velopment and get it into the hands of the patients where it belongs." Research published in the Eu- ropean Journal of Pharmaceutics and Biopharmaceutics involving the filter describes the material as having "excellent biocompatibility and high partition coefficient for BAK," as well as a "specific selectivity for BAK." 10 Incorporation of the hydrogel filter "into an eyedrops bottle can virtually eliminate the exposure of the eyes to the preservatives with- out compromising the sterility," the study authors wrote. "Our novel design can eliminate the preserva- tive induced toxicity from eyedrops thereby impacting hundreds of millions of patients with chronic ophthalmic diseases such as glauco- ma and dry eyes." "Our technology is being de- signed so that it will perform for the life of the drug," Mr. Hershfield said. "It's being designed so that what's in the tip capturing the BAK is trans- parent to the patient. … The squeeze pressure is identical, the drop size is identical, everything is going on as if it were in a traditional bottle system." Mr. Hershfield said the company is currently focusing its efforts on glaucoma, conjunctivitis, and over- the-counter dry eye medications, but as the platform is built, they'll be expanding to other ophthalmic solutions. Key steps from a regulato- ry standpoint are still being worked out, said Rick Heinick, chairman of the board, TearClear. Dr. Lindstrom said they will need to show that the active ingre- dient and its efficacy are not in any way modified or distorted by the filter. "We don't expect to find it, but we could find there are some active ingredients where we have trouble separating the benzalkonium chloride from the active ingredient," Dr. Lindstrom said. From the pharmaceutical company's perspective, Mr. Heinick said the filter will be "very simple to integrate" into current bottle sys- tems. Mr. Hershfield said the goal is to have the filter in the marketplace within 2 years. "We are working very aggres- sively on the development side and making sure all aspects of the technology are being thoroughly assessed," he said, adding later, "Not only are we improving the quality of life for patients, we're addressing a need that ophthalmologists have been asking for, and it's a very re- warding process for our team. We're extremely motivated to get this into the hands of the people for whom it matters most." EW References 1. Rahman MQ, et al. Microbial contamination of preservative free eye drops in multiple application containers. Br J Ophthalmol. 2006;90:139–41. 2. McPherson SD, et al. Self-sterilizing ophthalmic solutions. Am J Ophthalmol. 1949;32:675–8. 3. Baudouin C, et al. Preservatives in eye- drops: the good, the bad and the ugly. Prog Retin Eye Res. 2010;29:312–34. 4. Charnock C. Are multidose over-the-counter artificial tears adequately preserved? Cornea. 2006;25:432–7. 5. Hertel F, et al. Single dose administra- tion in therapy of glaucoma. Comparison of costs with multiple dose. Ophthalmologe. 1994;91:602–5. 6. Teping C, et al. The COMOD system. A preservative-free multidose contain- er for eyedrops. Klin Monbl Augenheilkd. 1994;205:210–7. 7. Wilson LA. To preserve or not to preserve, is that the question? Br J Ophthalmol. 1996;80:583–4. 8. Nagai N, et al. Decrease in corneal damage due to benzalkonium chloride by the addition of mannitol into timolol maleate eye drops. J Oleo Sci. 2015;64:743–50. 9. Cristaldi M, et al. N-hydroxymethylglycinate with EDTA is an efficient eye drop preservative with very low toxicity: an in vitro comparative study. Cutan Ocul Toxicol. 2017 Jul 18:1–6. Epub ahead of print. 10. Hsu KH, et al. Rapid and selective removal of preservative from ophthalmic formulations during eyedrops instillation. Eur J Pharm Biopharm. 2015;97:30–8. Editors' note: The sources have finan- cial interests with TearClear. Contact information Heinick: jzimmerman@theruthgroup.com Hershfield: jzimmerman@theruthgroup.com Lindstrom: rllindstrom@mneye.com Eye drops continued from page 25

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