In ophthalmology, the administration of topical medications is a cornerstone for glaucoma management. However, commercially available drop sizes (30+ µL) exceed the eye’s capacity to retain the medication (7-10 µL), leading to excessive dosing, overflow, periorbital irritation, and drainage by the nasolacrimal ducts causing systemic absorption. The increased risk of systemic adverse effects (AEs), particularly with drug classes like beta-blockers, has additional implications for patient safety.
Over the years, numerous studies have explored the potential of smaller droplet volumes to enhance the bioavailability of ophthalmic drugs and reduce systemic and local AEs to improve eyedrop tolerability. This article discusses the data from key studies on this subject, with a special focus on clinical implications, particularly considering the recent advancements in microvolume delivery with the Nanodropper Adaptor eyedrop dispenser.
Historical Perspective and Key Findings
Initial investigations into the impact of drop size on the efficacy and safety of ophthalmic medications began in the late 1970s. Researchers like Brown and Hanna (1978) demonstrated that smaller drops of less concentrated mydriatic and cycloplegic agents could achieve similar therapeutic effects as larger, more concentrated drops while reducing ocular side effects.1 This foundational work challenged the necessity of large commercial drop sizes, setting the stage for further exploration.
During the 1980s and 1990s, studies on intraocular pressure (IOP)–lowering medications further highlighted the benefits of smaller drops. For example, in 1992 Vocci et al showed that microdrops of apraclonidine were as effective as larger drops in reducing IOP, with fewer local and systemic AEs.2 Similarly, studies evaluating beta-blockers conducted by Charap et al in 1989 and Montoro et al in 1990 indicated that reducing drop size did not compromise IOP-lowering efficacy but did minimize AEs like decreased heart rate.3,4
Research on mydriatics and cycloplegics in the early 1990s, such as the work by Craig and Griffiths (1991) and Gray (1991), demonstrated that microdrops could provide effective pupil dilation with less discomfort compared to standard drops.5,6 These studies confirmed that smaller drop volumes could maintain therapeutic efficacy while enhancing patient comfort and reducing systemic absorption, particularly in sensitive populations like premature infants.7
Modern Clinical Trials and the Nanodropper
The introduction of the Nanodropper, a device that reduces the volume of ophthalmic drops, represents a significant advancement in this field. Recent studies have shown that the Nanodropper not only increases the number of usable drops per bottle but also maintains consistent droplet sizes, which is crucial for dose accuracy.8 Clinical trials, such as those conducted by Hoppe et al (2023) and Steger et al (2024), have validated the efficacy and safety of microdrops administered with the Nanodropper, demonstrating its potential to optimize mydriatic9 and IOP-lowering10 therapies by reducing AEs to potentially enhance patient adherence.
Overall, the narrative of drop size optimization in ophthalmic applications reflects a continuous effort to improve patient outcomes by balancing efficacy, safety, and tolerability. The consistent findings across decades of research underscore the importance of tailored medication delivery in achieving these goals.
Tips for Nanodropper Use
My experience with Nanodropper has been focused on reducing hyperemia and ocular irritation with the rho kinase inhibitors. I’ve found the device helps keep patients on the medications by reducing the AEs. Additionally, the reduction in wasted meds means patients are less likely to run out before the next refill is due. These factors are directly linked with adherence to glaucoma medication regimens.
As with all new technology, there is a small learning curve with introducing the Nanodropper. First, the device is a sterile, single-use product. Using a new Nanodropper with a new bottle of patient medications to minimize contamination risk has been an important part of the discussion. Nanodropper has its own cap, so once installed, the device should not be removed from the bottle.
Only medications that contain preservatives are currently compatible with the Nanodropper. I found it to be a good safety measure that the device will not fit onto preservative-free (PF) bottles, so patients can’t accidentally use it with PF medications. While I have limited experience with my patients using Nanodroppers with compounded glaucoma medications, they are compatible with some of the major compounding pharmacy medications and there is a search bar on their website (Nanodropper.com/comp) to check for compatibility.
Overall, my patients have embraced the Nanodropper as a tool to help reduce ocular side effects from glaucoma drops and extend the life of the bottle. Some patients were initially concerned about the added cost, but I found in most cases that the device pays for itself by reducing the frequency of medication refills. If you carry the units at the office, the price can be adjusted to a level that makes sense for your patients. Some of my colleagues have told me that they use Nanodroppers in-clinic for their phenylephrine; they believe what they save from not wasting diagnostic drops justifies offering the dispensers to their patients at a lower price.
Conclusion
My experience with the Nanodropper has been very positive. It is easy for patients to use, and it has significantly reduced ocular side effects with rho kinase–inhibiting glaucoma medications. This has allowed many of my patients to avoid more rigorous and/or more expensive drop regimens or even avoid more invasive procedures. I strongly feel that having Nanodropper available in my office has been a great asset to my practice and has helped improve adherence and quality of life for my patients. GP
References
1. Brown C, Hanna C. Use of dilute drug solutions for routine cycloplegia and mydriasis. Am J Ophthalmol. 1978;86(6):820-824. doi:10.1016/0002-9394(78)90129-0
2. Vocci MJ, Robin AL, Wahl JC, et al. Reformulation and drop size of apraclonidine hydrochloride. Am J Ophthamol. 113(2):154-160. doi:10.1016/s0002-9394(14)71527-2
3. Charap AD, Shin DH, Petursson G, et al. Effect of varying drop size on the efficacy and safety of a topical beta blocker. Ann Ophthalmol. 1989;21(9):351-357.
4. Montoro JB, Lalueza P, Cano SM, Escobar C, Linares F. Drop size and systemic adverse effects in timolol ophthalmic solution. DICP. 1990;24(4):439-440. doi:10.1177/106002809002400421
5. Craig EW, Griffiths PG. Effect on mydriasis of modifying the volume of phenylephrine drops. Br J Ophthalmol. 1991;75(4):222-223. doi:10.1136/bjo.75.4.222
6. Gray RH. The influence of drop size on pupil dilatation. Eye (Lond). 1991;5(Pt 5):615-619. doi:10.1038/eye.1991.107
7. Lynch MG, Brown RH, Goode SM, Schoenwald RD, Chien DS. Reduction of phenylephrine drop size in infants achieves equal dilation with decreased systemic absorption. Arch Ophthalmol. 1987;105(10):1364-1365. doi:10.1001/archopht.1987.01060100066027
8. St Peter DM, Steger JS, Patnaik JL, Davis N, Kahook MY, Seibold LK. Reduction of eyedrop volume for topical ophthalmic medications with the Nanodropper bottle adaptor. Med Devices (Auckl). 2023;16:71-79. doi:10.2147/MDER.S397654
9. Hoppe CB, Yonamine S, Kao BW, et al. Randomized trial to evaluate the efficacy of the Nanodropper device for pupillary dilation and cycloplegia in children. Ophthalmology. 2023;130(3):324-330. doi:10.1016/j.ophtha.2022.10.016
10. Steger JS, Durai I, Odayappan A, et al. An evaluation of the efficacy and safety of timolol maleate 0.5% microdrops administered with the Nanodropper. Ophthalmology. 2024;131(9):1045-1055. doi:10.1016/j.ophtha.2024.03.012
