In the United States alone, there were 36 million prescriptions for glaucoma eye drops in 2016, according to the health data tracking service IQVIA. The medical principle behind these agents is simple: apply the drug to the target organ to maximize the therapeutic effect and minimize the impact outside of the eye. After the medication is applied, it mixes with the tear film and some portion is absorbed through the cornea.1 The excess drug then leaves the eye with the tear film through the nasolacrimal duct or, in cases where the excess overwhelms the capacity of the duct, spills out of the eye onto the surrounding skin. This greatly reduces the time during which medication is in contact with the cornea. In fact, of an applied dose, ≤1% will reach the intended target. The rest is either absorbed via the conjunctiva or transported away via the nasolacrimal mucosa within a few minutes.2
Today’s drops are still delivered using the century-old pipette. This conventional eye dropper delivers large and highly variable drops containing between 30 microliters and 50 microliters of an ocular medication, yet the reservoir and absorptive capacity of the eye is just 6 microliters to 8 microliters. This means the traditional eye drop volume overdoses the eye by 300% or more, especially when patients mistakenly take extra drops.3-5 Excess medication leads to ocular and systemic toxicity not only from the active drug but also from exposure to preservatives and excipients.6,7 These adverse events can range from nuisances to permanent changes; common side effects associated with prostaglandin analogues, for example, include hyperemia, contact dermatitis, pigmentary changes, and periorbitopathy.8
In the case of cardiovascular medications like the beta-blocker timolol, systemic absorption due to extra drops flowing into the nasolacrimal duct has been associated with bradycardia, respiratory depression, fatigue, and impotence.6,7 Systemic bioavailability through this route is more immediate, and nonselective beta-blocker drops significantly affect lung function and increase asthma morbidity.9
Successfully instilling eye drops requires fine-motor skills, and it is not an easy task, particularly for older patients and those with poorer vision. In an analysis of more than 800 videos showing patients attempting to self-administer drops, they made many mistakes:10
- Not keeping their eyes open,
- Not using gravity to their advantage,
- Not bracing the bottle,
- Not looking at the bottle,
- Letting the bottle touch their eyes, and
- Putting in too many drops.
In one study, glaucoma patients on average used about 2 drops when attempting to self-administer 1.11 Wonder no more why it is that patients often complain about running out of medication before their monthly prescription can be refilled. More evidence that drops are problematic: patients were only accurately delivering the correct number of drops in 7% to 39% of attempts.12-14 Even after having used them daily for more than 6 months, studies show that a majority of patients cannot accurately self-administer eye drops.13-16
Other things can go wrong: anywhere from 33% to 76% of patients touched their eye with the tip of the bottle in studies.10,13,15 This issue, like myriad others related to self-administration of topical medications, is more pronounced in the elderly. One-third of patients who were 75 years of age and older and living alone had poor success administering their drops.15,16
There Has To Be a Better Way
If we were to reimagine the eye dropper, we would seek to reduce the reliance on a patient’s physical ability to instill eye drops as well as address the excess volume of topical ocular medications by improving the precision with which they are delivered. A microdosing strategy could improve tolerability and eliminate the side effects associated with drug overflow and overdosing.
One attempt at a solution to this problem has been introduced by Eyenovia. The company’s handheld Optejet container is a novel, high-precision, microdosing delivery technology that incorporates breakthrough piezo-print technology. It allows lower volume therapies to be applied directly to the ocular surface, coating the eye the way an ink-jet printer coats paper. The Optejet container sends drug to the eye in less than 80 milliseconds — faster than the eye’s 100-millisecond blink reflex. The container’s integrated smart electronics allow for dose monitoring. More efficient, effective, and “smarter” glaucoma drop delivery may mean improved compliance and, ultimately, better patient outcomes.
Traditional Pipette Drops: Macrodosing 30-50 µL
Overdoses the eye by more than 300%
Causes ocular toxicity (drug/preservative/excipient exposure)
Cardiopulmonary and neurologic risks with common topical ocular medications
Elderly are at particularly high risk of systemic adverse events
Triggers reflex blinking and tearing
Piezoelectric Delivery: Microdosing 6-8 µL
Horizontal drug delivery (no head tilting and aiming)
Medication delivered directly to primary site of ocular drug absorption
Lower drug and preservative exposure may lead to fewer ocular and systemic side effects
Smart technology may increase compliance
My colleagues and I evaluated microdosing of commercially available latanoprost in a proof-of-concept study. We undertook the EYN PG21 clinical investigation to look at the effectiveness of the administration and the IOP lowering effect of microdose latanoprost 0.005% (Optejet) in 60 eyes of 30 healthy volunteers.
After a brief training, investigators successfully administered microdose latanoprost with a single spray 95% of the time. In a separate evaluation of patient self-administration, we found an 88% success rate after limited training. Each single medication administration was within 1 microliter of the prescribed dose and the tear capacity of the eye.
The drug volume administered was reduced by 75%, yet microdose latanoprost showed a 29% reduction in diurnal IOP compared with baseline unmedicated IOP. We found this to be consistent with the reported reduction of up to 26% achieved with the same concentration of standard latanoprost eye drops.
Our work adds to a growing number of reports showing that clinically meaningful therapeutic effects can be obtained with fractional doses of topical medications. Microvolumes as low as 2 microliters to 5 microliters have demonstrated pharmacodynamic effects similar to that of conventional eye drops that are too large.17-22
One study showed that, after a single 3-microliter drop of 0.5% timolol compared with a 40-microliter standard drop, plasma levels of timolol were reduced by a factor of 17, and the aqueous humor levels were reduced by a factor of 3.3. The authors concluded that, systemic exposure of timolol can be reduced by installing smaller eye drops while quantifiable levels of timolol remain in the aqueous humor.19
Another investigation compared microdrops of tropicamide with standard drops. Tropicamide 1% in microdrop formulation (50 micrograms tropicamide) gave almost identical mydriasis to that of standard drops (250 micrograms tropicamide). The microdrops used in the study were effective, were easy to administer, and caused less patient discomfort, the authors found.21
Microdosing drugs can produce the same biologic effect as macrodosing with the legacy eye dropper while at the same time improving the accuracy, precision, and success of drop administration. By lessening exposure to drugs such as topical prostaglandin analogues, we may also have the opportunity to truly optimize therapy for glaucoma. GP
- Morrison PW, Khutoryanskiy VV. Advances in ophthalmic drug delivery. Ther Deliv. 2014;5(12):1297-1315.
- Abdulrazik M, Beher-Cohen F, Benita S. Drug-delivery systems for enhanced ocular absorption. In: E Touitou, BW Barry, eds. Enhancement in Drug Delivery. Florida: CRC Press; 2007:489-525.
- Washington N, Washington C, Wilson CG. Ocular drug delivery. In: N Washington, C Washington, CG Wilson, eds. Physiological Pharmaceutics: Barriers to Drug Absorption. 2nd ed. Florida: CRC Press; 2001;249-270.
- Mishima S, Gasset A, Klyce SD Jr, Baum JL. Determination of tear volume and tear flow. Invest Ophthalmol. 1966;5(3):264-276.
- Scherz W, Doane MG, Dohlman CH. Tear volume in normal eyes and keratoconjunctivitis sicca. Albrecht Von Graefes Arch Klin Exp Ophthalmol. 1974;192(2):141-150.
- Izazola-Conde C, Zamora-de la Cruz D, Tenorio-Guajardo G. Ocular and systemic adverse effects of ophthalmic and nonophthalmic medications. Proc West Pharmacol Soc. 2011;54:69-72.
- Quaranta L, Gandolfo F, Turano R, et al. Effects of topical hypotensive drugs on circadian IOP, blood pressure, and calculated diastolic ocular perfusion pressure in patients with glaucoma. Invest Ophthalmol Vis Sci. 2006;47(7):2917-2923.
- Novack G, O’Donnell M, Molloy D. New glaucoma medications in the geriatric population: efficacy and safety. J Am Geriatr Soc. 2002:50(5):956-962.
- Morales DR, Dreischulte T, Lipworth BJ, et al. Respiratory effect of beta-blocker eye drops in asthma: population-based study and meta-analysis of clinical trials. Br J Clin Pharmacol. 2016;82(3):814-822.
- Hennessy AL, Katz J, Covert D, et al. A video study of drop instillation in both glaucoma and retina patients with visual impairment. Am J Ophthalmol. 2011;152(6):982-988.
- Gupta R, Patil B, Shah BM, et al. Evaluating eye drop instillation technique in glaucoma patients. J Glaucoma. 2012;21(3):189-192.
- Gomes BF, Paredes AF, Madeira N, Moraes HV Jr, Santhiago MR. Assessment of eye drop instillation technique in glaucoma patients. Arq Bras Oftalmol. 2017;80(4):238-241.
- Stone JL, Robin AL, Novack GD, Covert DW, Cagle GD. An objective evaluation of eyedrop instillation in patients with glaucoma. Arch Ophthalmol. 2009;127(6):732-736.
- Davis SA, Sleath B, Carpenter DM, Blalock SJ, Muir KW, Budenz DL. Drop instillation and glaucoma. Curr Opin Ophthalmol. 2018;29(2):171-177.
- Burns E, Mulley GP. Practical problems with eye-drops among elderly ophthalmology outpatients. Age Ageing. 1992;21(3):168-170.
- Geyer O, Bottone EJ, Podos SM, Schumer RA, Asbell PA. Microbial contamination of medications used to treat glaucoma. Br J Ophthalmol. 1995;79(4):376-379.
- Lindén C, Alm A. The effect on intraocular pressure of latanoprost once or four times daily. Br J Ophthalmol. 2001;85(10):1163-1166.
- Larsson L. Intraocular pressure over 24 hours after single-dose administration of latanoprost 0.005% in healthy volunteers. A randomized, double-masked, placebo controlled, cross-over single center study. Acta Ophthalmol Scand. 2001;79(6):567-571.
- van der Heiden H, Amar T, Lichtenauer WF. Plasma and ocular pharmacokinetic study comparing 3 µL micro-drop to typical 40 µL drop volume of timolol 0.5% in pigmented rabbits. Invest Ophthalmol Vis Sci. 2014;55:453.
- Elibol O, Alçelik T, Yüksel N, Caglar Y. The influence of drop size of cyclopentolate, phenylephrine and tropicamide on pupil dilatation and systemic side effects in infants. Acta Ophthalmol Scand. 1997;75(2):178-180.
- Gray RH. The influence of drop size on pupil dilatation. Eye (Lond). 1991;5(5):615-619.
- Brown RH, Wood TS, Lynch MG, Schoenwald RD, Chien DS, Jennings LW. Improving the therapeutic index of topical phenylephrine by reducing drop volume. Ophthalmology. 1987;94(7):847-850.