Topical Medicines in Ophthalmology

Expert Profile

Section 1: Current Landscape

1.1. How would you describe the current state of topical medicines and how they are used?

In order to answer that you have to really look at several different categories. First let’s divide the categories into two; prescribed medications versus over the counter or let’s call them nutraceuticals. With regard to prescribed medications, predominantly those are for glaucoma or steroids used mainly pre-op, post-op, but also for various controls of ocular inflammation. I would say on the whole, and I think this has been pretty well documented, that for glaucoma, topical medications, especially when you get above two to three drops a day is not in agreement with the patient. They are used more when there is a perceived vision loss or pain and they’re used more rigorously, of course. On the whole, I think they are used much less than prescribed. Now, when it comes to nutraceutical drops, these are primarily for dry eye disease management. They’re used more commonly when the symptoms are more significant, but patients are very erratic in their use

1.2. What interesting trends/opportunities for topical medicines are you seeing at the moment?

I have to answer that with some prejudice because I’m currently working on a new topical drop that I am very interested in introducing as a nutraceutical. I think that there are a number of different things that are occurring, there are drops that are placement medications that help to adhere the medication to the surface of the eye, or penetrate better into the eye that will help to prolong the efficacy of the drop once is placed and allow for better penetration. As an example of our own drop it is a dry eye drop that uses the natural sugar xylitol.

What you may not realize is that cavities in teeth predominantly begin in the crevice between the gum line and the tooth. In that environment, it’s not washed typically by the average child. It is a relatively anaerobic environment relative the other parts of the mouth, so you get proliferation of certain pathogens such as gram-negative bacteria, and it turned out that xylitol kills those. So, it normalizes the biofilm in those anaerobic areas where it could be absorbed. This makes it highly applicable to areas of ophthalmology.

1.3. What are some advances in the use of topical medicines in Ophthalmology?

The potential applications of xylitol in the eye are large. Firstly, and this is where I think a lot of the drops are going, we have to realize that there are surface constituents in the tear film. There are the membrane-associated mucins that hold the wet tears on the surface of the epithelium, both of the conjunctiva as well as the cornea. Then there is the water tear film that contains the liquid mucins and all kinds of antibodies and enzymes that protect the surface.

Finally, there is the lipid-tear film on the surface. This film prevents evaporation and helps break down the surface tension so that tears can spread out. What we find out in dry eyes is that there is an inflammation on the back of the lids that causes meibomian-gland inflammation and distorts the meibomian production. We call it evaporative dry eye syndrome or evaporative dry eye disease where the lipids are not normally secreted onto the surface. This in turn leads to increased hydrostatic pressure. Furthermore, it leads to reduced water and to more rapid evaporation; this breaks up the tear film into little droplets because the surface tension is reduced in between the blinks.

All of this is aggravated by our looking at computers all day long, because when your eyes are stationary, such as when you are driving or looking at a screen, you’re blinking frequency decreases and your eye motions decrease. So that does not help to replenish because when you blink, you squeegee the meibomian glands and so all of these negative impacts are reduced.

It’s not just the reduced blinking rate, but it’s the effect that it has also on the meibomian. The cause of the meibomian-gland inflammation is by the mucosal inflammation on the back side, which is caused by this anaerobic bacterial proliferation, just like in the mouth. So, xylitol, has been demonstrated to reduce superficial punctate keratitis (SPK) and inflammation significantly.

There is also development of a new hyperspectral camera that will photograph the pile film so we can define what pathogens exist. To summarize, it appears that xylitol has several significant effects including reducing pathogenic bacteria, increasing and enhancing membrane-associated mucins. It increases the depth of those membrane-associated mucins so that the bacteria can proliferate on and cause these SPK.

Section 2: Pain Management

2.1. How do topical medicines currently fit into the treatment landscape for acute/chronic pain?

I think it’s a combination of the both acute and chronic. What compliance says is that the patient doesn’t really realize the significance for chronic disease management, unless he sees a deterioration; so, he sees a rationale for why he has to use the medication. The difficulties of putting in drops, what manufacturers don’t realize is it’s very difficult to judge how much a patient has put in. All of these things make it difficult on a chronic aspect. It’s hard to answer that question, but I think that they will continue because you don’t have the systemic side effects.

Can we make a chamber that will slowly release the medications, or can we use things that have been used in the past, such as the hydrogel? These are receptors that will slowly release the medication and make it better. All of these things are being investigated as ways to help the person manage their disease. However, the problem with chronic disease management is the patient fails to understand the prediction of where the disease is going.

2.2. How has an increased desire for home-setting or self-administration affected OTC / prescription habits for topical medicines?

I think COVID has pushed us a lot into tele-medicine types of management. What I’ve said worldwide is that ophthalmology and optometry are the few subspecialties that do very poorly with telehealth management. This is because we depend so much on diagnostic services such as vision checking and photography. I’m currently working with a company to develop mobile diagnostics that are going to allow for much better home diagnostic prediction. It will help the patient to much better understand, where’s he going over time as well as helping the doctor better understand the disease progression.

I believe that topical medicines are going to be used and prescribed more often for sure. However again, how is the doctor going to be able to look at the patient and assess them. We’ve got much better ways of coordinating that with home diagnostics or mobile diagnostics. How can we treat patients in elder care centers where chronic disease management is not at a high enough standard? We need to think of ways of how to better get into those centers to perform screenings, monitoring and enable management with doctors so that they can do it from home. In the US there is this reduced desire or even allowance on the part of the elder care centers to allow patients to go to the local doctor only for life-threatening emergencies.

I think it’ll make the physician feel more comfortable with being able to prescribe these and even watch a patient apply the topical medicine as they’re doing it, to see if they’re getting the drops into the eye.

Section 3: Future Landscape

3.1. How do you expect habits around topical medicines to change in the next 1-2, 3-5 years?

We’ve got to personalize this for the patients. In other words, if the patient can see what it’s doing, they’re more likely to follow and be adherent with the topical medical regimen. That’s going to be dependent upon a lot of the diagnostics.

I also think that different application medications are going to be absolutely necessary. Many of the bottles, especially the bottles that I see nowadays that are over-the-counter drops, are almost impossible for elderly patients to squeeze and get out the appropriate amount.

We need to look at the ways of applying the drop. I believe Allergan or Alcon, had an attachment to the drop lid that would spread the lid and introduce the drop at the same time. How do we do it without the patient having to either lie on their back or on the bed because most elderly people can’t put their head back far enough. The major mechanisms, as I said, are those that will preserve the adherence of the medication on the drop or improve the penetration, so it enters into the eye rather than going down into the nose.

All three are going to increase the use of topical drops, which now I think are used commonly because they are prescribed or are recommended. I’m surprised that the nutraceutical, over-the-counter eye drop in most of our pharmacies has now outnumbered the nasal sprays and the toothpaste counter.

3.2. What would drastically change this?

In my opinion I think that home diagnostics hold the key. There, what we have to think about is how do I image the eye better so that I can apply my medication at home with my iPhone for example.

Yes, we can do it in the doctor’s office, but again, what we’re realizing with a lot of the adoption of tele-medicine is that we’ve got to move in that direction. This is also affirmed by the leading medic Eric Topol who said that we need to really develop better diagnostics that’ll sit in the background and help the physician make medical decisions. What those diagnostics will offer is prediction of the disease process in the individual patient. If we can predict progression of their disease process, we’re in a much better position to treat earlier and prevent it rather than trying to pick up after the shoe falls at the end.

Eric Topol has developed this method of statistical analysis, what he calls multi-variate chronologic risk prediction for the individual. Here, we’re looking at the chronologic changes in those variables with an idea of, where are we predicting the course of this disease to go. How do we do this with regard to topical drops and surface disease on the eye? I think that we can do it either by vision testing or by imaging. Currently I’m working on developing a hyperspectral camera that will be able to photograph and detect the biofilm constituents.

Currently, that hyperspectral camera can only be done in the doctor’s office and only at periodic times, just like in Drucker pressure measurement is now done for glaucoma, which is ridiculous. You’re looking at the injectsense module that is injected into the eye and measures continuous intraocular pressure that will help the doctor and the patient realize their glaucoma medications are controlling the pressures. Elements like the injectsense module, which is undergoing FDA approval that will measure continuously Drucker pressure, or imaging the eye will definitely be new areas to look into.

I’m not sure if we will be able to detect SPK. I think that’s on the horizon, but we need to do that so that the patient can understand the source of their pain and get their compliance with the recommended regimen. We not only have to help the doctor; I think we have to help the patient to really understand the importance of compliance.

There are also a number of companies and I’m working with a small company in Switzerland, that are trying to put a little monitor on your glasses that will detect blinking rates. When the blinking rate goes way down, or hopefully it might be able to detect the meniscus in between the blink rate, it’ll tickle your eye a little bit to stimulate you to blink. All of these things, I think are factors that will help in patient understanding of their disease; with topical disease management and compliance, I think that’s absolutely necessary. On the vision side, there are all kinds of charts, programs that are out there, and they are all ridiculous because they don’t measure real-world vision. We need a way that the patient can measure real-world vision at home.

On various topical medication applications, right now, when I look at most of the 5ml drop bottles, they’re just impossible for elderly people to hold, to drop and get their head back. We’ve got to rethink how we’re going to apply those medications. This could be the hydrogel implants that slowly dissolve over several days for example. I thought that was quite an interesting application.

3.3. Where do you see the biggest growth potential for topical medicines?

One of them will be the xylitol drop, I think for dry eye disease; especially in younger people who are staring in front of a computer all day. Their dry eyes are very symptomatic and so I think people are using these much more commonly. I think dry eye disease is going to be a big area and similar to xylitol, I think it’ll be concentrated on how we reduce this inflammation on the backside of the lids that reduces the lipid production and meibomian gland production.

The other area that I think is going to become more popular are non-steroid inflammation controlling and longer controlling medications that will be able to penetrate and control various forms of uveitis. I think those are going to become much more prevalent because the side effects of steroids are glaucoma and cataract. Therefore, I think that we’re going to look for more adjunct, primary longer-term and better anti-inflammatory types of medications.