Research and Response

Research

Optimising the delivery of topical ophthalmic medication in dogs

FLORenCe CLARk (uPPeR Sixth)

Eye drops are commonly used worldwide in both humans and animals in healthy and diseased states. They are usually administered by the patient themselves or a carer and are a commonly used medication.

They deliver ophthalmic drugs for the treatment of various diseases such as glaucoma, dry eye, ocular inflammation, infection and allergies to name a few. As with all drugs, the dose of the active ingredient is important both for effectiveness and safety of the patient. The dose is determined through the volume and concentration of the drop, and the number of drops. There is a huge variety of devices used to administer these drops. Generally, they come in multi- or singledose dispensers, with a variety of different dropper tips which can have a substantial effect on the volume and hence the dose of medication administered. It is important manufacturers consider the design of the tips so that doses are administered easily, effectively and safely.

Currently the volume of eye drops dispensed is too large for the eye to hold. The average drop volume from different preparations ranges up to 56.4μl. The amount of remaining eye drop after instillation is as high as 30.3μl. This could lead to systemic side effects, such as hypotension, bradycardia, and tremors after using a local anaesthetic. A commonly used drug, Tropicamide, causes pupil dilation as its main effect in order to allow examination of the retina, but this can last for many hours, giving side effects such as blurred vision, meaning for example that patients can’t drive for hours after its use. Smaller drops may mean a faster recovery. Therefore, there is a need to develop a suitable method of delivering ophthalmic medication at an appropriate volume.

Previous studies have tried methods to reduce drop volume, but these results in impractical methods, such as the addition of a steel needle or glass capillary tube to the dropper bottle.

The aim of my research was to develop a safe and practical method to administer drops with a small and consistent volume. The hypothesis was that by attaching a Gilson pipette tip to a Minim dropper (a single-dose eye drop dispenser), the drop weight (or volume) will be significantly and consistently reduced and associated with an identical Tropicamide induced maximal pupil dilation, and earlier recovery compared to a standard Minim dropper.

methodology

Two drop methods were compared. The standard Minim (standard tip) was modified by attaching a Gilson tip to the Minim (modified tip). Both studies were conducted in a laboratory at the University of Cambridge Veterinary School.

Stage 1: Tropicamide 1.0% in a standard and a modified Minim dispenser was dispensed one drop at a time onto a weighing scales, recording the weight in milligrams). Mean and standard deviations were calculated for both sets of data, and a 2-tailed Student’s t-test was applied to test for the significance between the two means.

Stage 2: two healthy adult dogs were studied using three different conditions, sham treatment (n=1), then Tropicamide 1.0% was administered by standard (n=3) and modified (n=5) tips into one or another eye. Pupil diameter was recorded over 330 minutes.

Results

As part of the first stage of the research, n=28 drops were weighed from the standard tip and n=27 from the modified tip. The mean drop weight with the standard tip was 31.4mg and for the modified tip it was 10.0mg (see Table 1). The t-test showed that these results were statistically significantly different, with a p value of less than 0.0001.

tABLe 1: Comparison of mean and median weights, and standard deviations of drops dispensed from modified (n=27) and standard tips (n=28) (mg weight)

mEAn (mg)

STAndARd TIp 31.4

STAndARd dEVIATIon (mg)

15.1 mEdIAn (mg) p VALuE

33.0

<0.0001

Stage 2 was an in vivo pilot study to determine the effectiveness and duration of dilation using 1.0% Tropicamide dispensed from a standard Minim dispenser compared to Minim modified with Gilson tip.

The mean maximal pupil diameters induced by Tropicamide 1.0% delivered by standard and modified tip were not different. Both increased more than with sham treatment, and also to the same maximum diameter as each other (12–13mm) and recovered to baseline equally quickly (330m).

The results showed a small increase in pupil diameter for the sham treatment over the first 15 minutes, which then returned to baseline for the remainder of the experiment. The mean pupil diameters induced by Tropicamide 1.0% delivered by standard and modified tip were not significantly different. Both increased significantly more than with sham treatment, and also to the same maximum diameter as each other (see Table 2) and recovered to baseline in the same amount of time (see Figure 1).

The study tested the hypothesis that the drop weight, and hence volume, would be significantly and consistently reduced by attaching a Gilson pipette tip to a standard Minim dropper (a single-dose dispenser) and will be associated with an identical Tropicamide induced maximal pupil dilation, and earlier recovery compared to a standard Minim dropper. It was demonstrated that a drop size approximately one third of the size of that from a standard Minim dispenser could be consistently achieved using a minim modified with a Gilson D200 pipette tip. Furthermore, both methods were equally effective in achieving maximum pupil dilation, with equal time to resolution to baseline, meaning a similar therapeutic effect was achieved using a smaller drop size.

Acknowledgements

I would like to thank Dr David Williams from the University of Cambridge Veterinary School for his guidance and support over many weeks, in performing the experiments, analyzing and interpreting results. I am very grateful also to my supervisor Mrs Banks for support in helping me frame the project, and Mrs Kemp for her advice on ophthalmology.

FiguRe 1: Graph of pupil diameter in millimeters over time (mean and standard deviation) in minutes after application of drop or sham treatment using modified and standard tips.

mm I n IA m ETER d IL p up 16

12

8

4

0

0 5 10 15 20 25 30 35 40 45 50 55 60 150 180 200 210 220 240 270 300 330

TImE In mInuTES AFTER TRopICAmIdE 1.0% AppLICATIon oR SHAm TREATmEnT

sham treatment mean of standard tip results mean of modified tip results

tABLe 2: mean maximum pupil diameter and time to maximum for all conditions for n=2 subjects

SHAm TREATmEnT

modIFIEd TIp (mean) mAxImum pupIL dIAmETER (mm)

7

12 TImE To mAxImum dILATIon (minutes)

5

60 TImE To RECoVERy To BASELInE (minutes)

20

>330

& Response

dR. BeCky LOWten Bvetmed mRCvS

Firstly, congratulations to Florence Clark for producing an excellent piece of research and winning the Rouse Essay prize! An amazing achievement and very well deserved. I am slightly overwhelmed and humbled at being asked to write a response.

What is a Minim? I associate the term with the little plastic, single use eye drops that live in the bottom of my consulting room fridge. I have to admit I haven’t given them very much thought. A quick scan through my trusty Saunders veterinary dictionary revealed, quite charmingly, that it is a unit of volume of liquids used in the apothecary system equivalent to 0.0616mls. The version I use is actually 0.5mls but I like the historical provenance of its name.

I really like this study and I can see the huge benefits of subsequent application. It has confidently established that the modified tip will deliver a consistently reduced drop weight. This, I can see, could help both animals and people.

Examining the Tropicamide data sheet in a little more detail, the current recommendations are clear for adults but less so for children. “The dose for children will be decided by the doctor or eye specialist.” Could there be an application for a smaller drop size in paediatric ophthalmic medicine I wonder?

Tropicamide can occasionally cause hypersalivation as a side effect in cats and it would be interesting to see if this could be reduced or eliminated with a smaller drop size. It would also be useful to find out if any other side effects of different medications could be reduced or eliminated by using the smaller drop size too. It would be important to establish that efficacy could be maintained.

There can be species-specific variations in terms of physiological response to a particular medicine. The dose needed to produce the desired effect could vary between species irrespective of eye size.

I would like to see the second part of this study repeated with a larger sample size. This would give us more confidence in implementing changes to clinical protocols in dogs.

Sometimes changes to clinical protocols can be cost sensitive within veterinary practice but it sounds like attaching a Gilson pipette may not be too onerous both in terms of difficulty or cost.

It was interesting that the sham treatment appeared to cause an increase in pupil size in the first 10 mins. Presumably the act of putting drops into the dogs’ eyes caused a sympathetic nervous system response? I would be interested to know how the pupil diameter was measured. Possibly the dog needed a few minutes to get used to the measurement process? Or their handler? Or maybe the drops caused an unpleasant sensation? Again, it would be interesting to see if this is repeatable.

The hypothesis of maximal pupil dilation with a smaller volume has definitely been achieved which gives great hope in terms of reducing side effects for patients. I certainly think the preliminary results would enable us to start thinking about a more practical application, particularly in our smaller patients.

Unfortunately the recovery times, irrespective of drop size, do still seem to be the same. Therapeutically the standard tip and the modified tip produce the same results. Dogs will still have fuzzy vision for some time after their test. Happily dogs rely very much on their sense of smell. They don’t need to drive cars or read the newspaper and so, I suspect, the dogs won’t mind!

THE HYPOTHESIS OF MAXIMAL PUPIL DILATION WITH A SMALLER VOLUME HAS DEFINITELY BEEN ACHIEVED WHICH GIVES GREAT HOPE IN TERMS OF REDUCING SIDE EFFECTS FOR PATIENTS.