Transient

did a little experiment looking at the size of eye drops in about 1999, and I thought I'd dust it off and share it here.  A couple things to keep in mind:

  • This isn't a peer-reviewed paper
  • Some time has passed and I wouldn't recommend looking too closely at the raw data.  After all, I suspect the dropper tips used in my experiment have been redesigned several times in the last 13 years and measurements of drop size would not apply to today's bottles.  
  • It's hard for me to believe, but the medical treatment of glaucoma has greatly changed since I did this experiment: Prostaglandins were not even available at the time of my study.

However, the overall conclusions are still valid. There can be considerable differences in drop sizes, which can make the length of time a given drop will last quite variable.

So, without further adieu,

[insert dramatic 20th Century Fox movie music here] 

 

Days of therapy expected from promotional samples of antiglaucoma medication based on drop number and size.

Todd M. Zarwell OD FAAO

Abstract

Objective: To evaluate the duration of therapy of five antiglaucoma promotional samples.

Methods: Five different antiglaucoma medication promotional samples were obtainedfrom laboratory representatives. Three subjects dispensed 10 drops each onto ananalytical scale. The mean drop volume of each medication was calculated. In addition, the fill volume and amount of medication wasted by the patient was calculated. Fromthis data the expected days of therapy for each medication was determined This was then compared to what an accepted "rule of thumb" equation would have predicted. Results: This study found that four medications (timolol maleate, dorzolamide, brimonidine tartrate, and a timolol / dorzolamide combination) provided a longer duration of therapy than the "rule of thumb" would have predicted while one (betaxolol) providedless than predicted. The Alphagan bottle had the most wastage while Trusopt had the least.

Conclusion: There is considerable variation in the duration of therapy of glaucoma medications in sample form. This may be due to differences in sample size as well as differences in drop size between the medications. The professional providing these promotional samples should be aware of the duration of therapy of each medication toensure continuous treatment until further follow up or additional medication can be obtained.

Key words and phrases: Antiglaucoma medications, ophthalmic promotional samples, timolol maleate, dorzolamide HC1, brimonidine tartrate, betaxolol HCl.

Introduction

When attempting to determine the drop volume of commercially available glaucoma medications, clinicians sometimes use the "rule of thumb" equation that every milliliter of medication will yield approximately twenty drops. 

Using this formula the medical vision care provider can estimate the number of drops that a container of medication will yield by multiplying its volume in milliliters by 20. Furthermore, the number of days of expected therapy from that medication can be determined by dividing the number of drops by the number of drops used per day, taking into account the dosing schedule and the number of eyes that are receiving drops.

Assuming 20  drops per millimeter assumes a 50 microliter drop size. However, a study of 20 antiglaucoma medications by Lederer and Harold found a mean drop size of 39.0 microliters and a range from 25.1 to 56.4 microliters.1 This indicates that assuming the 20 drops per millimeter rule will greatly underestimate the number of drops and consequently the duration of therapy that can be expected from antiglaucoma medication. In addition, it is apparent that any one formula is not adequate to determine the drop size of all antiglaucoma medications as considerable variation exists. 

A number of studies have been performed to determine the duration of therapy of commercially available antiglaucoma medications. 2,3 Stewart and associates considered duration of therapy, average cost, and wastage of product in determining the expected yearl cost of glaucoma therapy.2

To the author's knowledge there has been no investigation of the duration of therapy expected from promotional samples of antiglaucoma medication. This is likely due to the fact that these samples are free of charge and are of no direct expense to the patient or the clinician. However, the knowledge of how long a promotional sample of medication will last may provide useful information to both the medical vision care provider and the patient.

The purpose of this paper is to determine the amount of medication that is provided in these promotional samples. The quantity of each of five commonly distributed sample products was determined from which the days of therapy was extrapolated, taking into account drop size and wastage of product.

Methods

Five promotional antiglaucoma medication samples were obtained from local laboratory representatives. The medications included a 5 ml bottle of Alphagan(brimonidine tartrate .2%), 2.5 ml bottles of Trusopt (dorzolamide HC12%), Cosopt (a dorzolamide HCl and timolol maleate combination product), and Betoptic S (betaxolol HCL.25%), and a 1.25 ml bottle of Timoptic XE (timolol maleate .5%).

Three subjects, all optometry students, instilled 10 drops of each medication at room temperature onto an analytical scale. To prevent fatigue, subjects were instructed to pause ten seconds between drops, at which time the size of the drops was recorded in grams. Subjects were asked to use the method of instillation they were most comfortable with. Because previous research has indicated that the dropping angle can significantly affect drop size, the analytical scale was elevated to a height of five feet to best estimatethe technique of instilling drops into the eye.4 The scale used was a Viscount Plus Series II sensitive to 0.001g.

For each medication the mass of the individual drops was measured, from which an average and a standard deviation were calculated. Calculations for wastage of medicine and percent usability were performed using formulae identified by Stewart and associates, as described below.2 Total mass of medication was calculated by finding the difference between the empty and full bottles. This value was compared to the actual amount of fluid dispensed to arrive at the amount of medicine wasted using the following formula:

Medicine wasted - total bottle mass - mass of dispensed medicine-unused medicine

Sources of wasted medicine include the fluid that rolled down the dropper tip alter dispensing and any extra drops that leaked out of the bottle after dispensing the intended drop.

The percent usability (percent dispensed correctly versus wasted) of a medicine was calculated by the following formula:

% usability formula

Number of days of bilateral therapy was calculated by the following formula:

days of therapy formula

Statistical analysis included a two-sample t-test comparing the difference between the drop size of each medication with each of the other four medications. In addition, a two-sample t-test was also calculated to compare the difference between the three different subjects.

Results

The results of the mean drop size are shown in Graph 1.  No significant difference was found between the mean drop size of Cosopt and Trusopt or between Betoptic and Timoptic XE, but a significant difference was found between all other medications (p<0.005). The largest mean drop sizes were observed with Betoptic (49 mg) and and Timoptic XE (47 mg), while the smallest drops were observed with Cosopt (31 mg) and Trusopt (31mg). Alphagan had a 37 mg drop size.

Graph 1

Graph 1

The percent usable value for each medication can be seen in Graph 2. The largest percent usable drug (least waste) was Trusopt (97.7%), while the least percent usable drug (most waste) was Alphagan(83.2%).

Graph 2

Graph 2

Graph 3 shows the expected days of therapy for each medication. A twice-a-day therapy was assumed for every medication except Timoptic XE, which was assumed to be once-a-day. As would be expected due to the larger bottle, the 5 mL Alphagan sample provided the most days of therapy: 30.1 days. Among the 2.5 mL, bottles Trusopt (23.9 days) and Cosopt (22.1 days) had a similar length of duration while Betoptic, which had the largest drop volume, yielded less days of treatment (9.9 days) than the 1.25 mL Timoptic XE (15.6 days).

Graph 3 also illustrates the expected days of therapy using the 20 drops/mL rule. All but Betoptic yielded more than the predicted duration of therapy.

Graph 3

Graph 3

No significant difference in drop size was found between the three subjects (p<0.001). 

Discussion

Oftentimes clinicians determine how long a medication will last for a patient based upon the number of drops that can be expected per milliliter of medication. It is often assumed that 20 drops of medication will amount to a volume of 1 mL.

The results of this study indicate that such assumptions may lead to errors in the estimation of duration of therapy. Of the five promotional samples tested, this assumption underestimated the duration of treatment of four of the medications (Timoptic XE, Alphagan, Trusopt, and Cosopt) and overestimated the duration of treatment of one (Betoptic S). 

Other studies have found similar results for commercially available (not promotional samples) antiglaucoma medications. Ball and Schneider point out that the differences in duration of treatment may result in a wide variation in cost of treatment for the consumer. As some physicians assume the potency of many glaucoma medications to be equivalent, cost may be a prime consideration when deciding upon a treatment for an ocular hypertensive patient.5 Because promotional samples are free to the consumer, cost of therapy is not a major concern when beginning treatment with these products. However, knowledge of how long the medication will last is useful for informing the patient how much time he or she has to obtain more so that no treatment is missed. In addition, it may be particularly useful in a system that provides medications for the patient, such as the Veterans Affairs or a managed care group. Comparing how long a sample of medication lasts a patient to how long it is expected to last based on this study's results may be useful in determining a patient's compliance. 

Promotional samples come in a variety of different volumes, which, as expected, results in a variation in the duration of therapy provided. In addition, there is also a variation in drop size for each of the medications. As current research indicates that a larger drop does not necessarily have a therapeutic advantage over a small drop, the main consequence of an increased drop size may be a decreased number of days of treatment.6,7 According to Brown, the factor most responsible for drop size is the diameter of the bottle's dropper tip.8 Other determinants may include the temperature and the viscosity of the fluid, which may offer an explanation as to why a suspension such as Betoptic S has a different mean drp size than a solution such as Alphagan. 

Obviously, an increase in drop size will decrease the number of drops and therefore the days of therapy a medication will provide. For example, in this study both Betoptic S and Cosopt had a 2.5 ml volume. However, Betoptic had a 58% larger drop than Cosopt, which consequently yielded 55% less days of therapy. 

There are several clinical considerations that may interfere with extrapolation of this stud's results.  For instance, the amount of medicine wasted can be much higher when instilled into the eye as compared to an analytical scale due to the increased difficulty with this process.  In addition, because the mean of a glaucoma patient is significantly older than the subjects of this study, there is a greater likelihood of decreased fine motor control and therefor a greater amount of wastage.

Conclusion

Promotional samples of antiglaucoma medications come in a variety of sizes. The samples in this study came in quantities ranging from 1.25 mi to 5 ml. In addition, there is also considerable difference in the mean drop size of these medications. In this study,the wide range of both these variables resulted in durations of therapy ranging from 9.9 days to 30.1 days.

When dispensing promotional antiglaucoma samples, the medical vision care provider should be aware that this range exists. Knowledge of the duration of treatment will enable the clinician to either provide enough medication to supply the patient until he or she can obtain more or to schedule follow-up before the patient's supplies are exhausted.

References

1. Lederer, CM., and Harold, RE.: Drop size of commercial glaucoma medications. Am. J Ophthalmol. 101: 691, 1986.

2. Stewart, WC., Sine, C., Cate, E., Mirmo, G.E., and Hunt, RH.: Daily cost of beta-adrenergic blocker therapy. Arch. Opthalmol. 115: 853, 1997.

3. Meyer, M.A. and Savitt, M i . : A comparison of timolol maleate and levobunolol. Length of use per 5-ml bottle. Ophthalmol. 101: 1658, 1994.

4. German, E., Hurst, A., and Wood, D.: Eye drop container delivery: A source of response variation? Ophthalmol. Physiolol. Opt. 17: 196, 1997.

5. Ball, S.F., and Schneider, E.: Cost of beta-adrenergic receptor blocking agents for ocular hypertension. Arch Ophthalmol. 110: 654, 1992.

6. Shell, J.W. : Pharmacokinetics of topically applied ophthalmic drugs. Surv. Ophthalmol. 26: 207, 1982.

7. Petursson, G., Cole, R., and Hanna, C.: Treatment of glaucoma using minidrops of cionidine. Arch Ophthalthol. 102: 1180, 1984.

8. Brown, RH., Hotchkins, M.I., and Davis, E R : Creating smaller eyedrops byreducing eye dropper tip dimensions. Am. J Ophthalmol. 11: 460, 1985.

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AuthorTodd Zarwell