Dry powder for dry eyes – a new approach to drug delivery to the eye?

The number of people afflicted with DED is increasing. It used to be a condition suffered primarily by those over 50 – fewer than 2.7% of sufferers are 18 to 34. But there is a general increase in all proportions of the population and a significant increase in women suffering. In the US alone, 6.8% of the adult population suffer with DED.

What causes dry eye disease?

Dry eye disease can be caused by the ageing process, medical conditions including vitamin A deficiency, reactions to medications and side effects from contact lens use and laser eye surgery. The eye has a highly efficient system to keep itself lubricated and running smoothly. The exposed surface of each eye is less than 2 square centimetres, each covered by a layer of liquid – the tear film. The total volume of tear film in each eye is only ~7 µL (microlitres). To put that in context, a wine bottle contains enough fluid to rehydrate the eyes of half a million people. The tear film is extremely thin – it’s only just deep enough to submerge a single red blood cell. Another surprising fact is that the tear film isn’t just salty water, it’s actually comprised of three distinct layers; the top layer is lipid – which stops the water from evaporating, the middle layer is salty water, and the base layer is made of a mucus-like glycoprotein which acts as a lubricant.

How do you make tears?

Tears are generated in the lacrimal gland. Tears enter the eye from the lacrimal duct system and are spread across the eye by the eyelids. They exit through the ampulla and canaliculus. Trying to help this system produce tears is challenging, but treatment for DED is progressing.

Standard treatments for DED

For over 50 years, the standard way of treating dry eye disease, and delivering other drugs to the eye, was via the dropper bottle. As you will know if you’ve had to use eye drops, a dropper bottle is just a small plastic bottle which is squeezed to dispense a single droplet of liquid onto the eye. A typical droplet contains around 40 µL of fluid and, as many can attest to, the process of applying drops to your eyes is very difficult. Even if you manage to get the droplet to land on your eye without blinking (which is a tremendous usability challenge in itself), most of the liquid immediately runs down your face. This isn’t a surprise considering the surface of the eye is already covered with just the right amount of liquid (~7 µL), meaning there isn’t space for any more liquid. Adding a further 40 microlitres simply means that 40 microlitres immediately overflows out of the eye and down the face. Many attempts have been made over the years to create a better delivery mechanism than the dropper bottle.

Unfortunately, there are a number of commonly encountered problems which have brought about the demise of these attempts, including technical, economic, user related and microbial challenges.

Technically, it is quite hard to deliver small quantities of liquid into the eye, not least because the blink reflex is so fast (0.1 seconds) and the eyelids are so effective at keeping unwanted things out of the eye. Even if the technical challenges are solved, the whole device needs to be made intuitive to use, something which can be overlooked by technically focused development teams.

Cost of goods is also often a nail in the coffin for complex devices. The most widely used ophthalmic drugs, such as dry eye, anti-infectives and glaucoma medications, are mostly cheap and off-patent. Users are accustomed to relatively cheap drugs and the market is unlikely to bear the additional cost of an expensive device.

Lastly, sterility is a big problem for liquid medications. As soon as a dropper bottle is opened there’s a risk of bacteria getting into the bulk of the solution and multiplying. Preservatives are added to almost all formulations, but they can cause irritation in the eye and aren’t always compatible with sensitive drugs (particularly biologics). Various mechanical designs have also been developed to prevent bacterial ingress back into dropper bottles, but they tend to be inelegant, unreliable and relatively expensive.

It seems that drug delivery to the front of the of the eye is a great deal more difficult than it might first appear. So, what’s the answer? Let’s first look to see what new options are becoming available.

Oyster Point Pharma’s Tyrvaya (recently acquired by Viatris) was approved by the FDA in October 2021. This new treatment involves delivering a varelincline solution nasal spray. The drug stimulates the nose to produce more basal tears, not reflex tears. Other advances include gel inserts like Amorphex Therapeutics’ TODDD soft gel device, which is being used for Glaucoma and is in clinical studies.

Drug delivery to the surface of the eye

Let’s look at the challenge of drug delivery to the eye in order to get an active ingredient onto the surface of the eye. As unintuitive as it may seem, putting a dry powder drug into the eye may actually be a very smart thing to do.

We know that the tear film is a multi-layered structure and there isn’t room for any additional liquid. Some finely powdered drug sprinkled into the eye wouldn’t immediately wash away – rather, it could potentially dissolve into the tear film and reach its target destination more easily than if it were dissolved in water.

There are other benefits to using a dry formulation. The problem of microbial contamination is effectively eliminated because microorganisms cannot grow without water. A dry formulation would not need any preservative and may not even need sterile packaging. Drug stability is also often improved when the drug is stored dry rather than as a dissolved formulation. Additionally, dry formulations typically have extended shelf life and reduced need for refrigeration, because the drug is often less susceptible to degradation in powder form.

The challenges of using dry powder formulations

Whilst there are several benefits to going dry, there are also some significant challenges, specifically with the formulation and the delivery.

The drug particles would need to be smaller than the depth of the tear film (7 microns), otherwise they would feel abrasive in the eye – dry powder formulations for inhalation are already produced which are less than 5 microns, so this is feasible. Whilst powders can be milled (or micronised) to produce very small particles, handling such fine powders is a challenge because they stick together and don’t like to disaggregate. In the respiratory world, the small drug particles are often blended with relatively large (400 micron) lactose particles, to improve handling of the powder. Unfortunately, this wouldn’t be feasible for ophthalmic delivery because such granules would feel like sand in the eye. A potential alternative could be to use ‘engineered’ drug particles – spray dried particles with a hollow porous structure and a non-stick coating. Such particles look like miniature, hollow-plastic golf balls and could dissolve quickly in the eye without causing irritation.

Storage of drug and delivery to the eye is undoubtedly the biggest technical challenge in using dry powder formulations to treat ophthalmic conditions. The powder must be kept completely dry, up until the moment it reaches the eye. This is challenging enough on a macroscopic scale, but ophthalmic doses would be literally microscopic, weighing only a few micrograms, necessitating true microscale technology. It is incredibly difficult to handle such small quantities of powder. New technology would need to be developed to firstly store and then transport powder onto the eye, perhaps repurposing electrostatic technology from the printing industry. In any case, a huge amount of technology development would be required.

The future of drug delivery to the eye

There is clearly still great potential to improve methods of drug delivery to the eye. While the road to realising more radical solutions such as dry powder delivery will be challenging, there is a clear need to try new treatments and approaches to tackle this issue. It may not happen in the blink of an eye, but hopefully we can revolutionise ophthalmic drug delivery and consign the dropper bottle to history.

This article was taken from Team Consulting’s Insight magazine. Sign up for your own copy here.