The soluble option — putting the patient first when manufacturing OSD forms

Do you encounter difficulties when swallowing tablets? Head of product development at Catalent Pharma Solutions, Ralph Gosden, reveals why the Zydis platform is still a game changer, and what is on the cards for the near future.

Around 35% of the general population have difficulty swallowing! Initially, I found this statistic hard to believe but actually having met people who do struggle, not just with the larger tablets but the smaller ones like paracetamol and even the contraceptive pill, I came to the realisation that there are many healthy, middle-aged people — as well as the usual sensitive patient groups — who cannot easily take pills.

Digging deeper, there are other factors that must be considered from a patient perspective when looking at swallowability. For example, in certain diseases, such as cancer, the treatment can cause a patient to suffer from a dry mouth, which makes taking tablets extremely uncomfortable.

Furthermore, for some patients who have mental health disorders, such as schizophrenia and bipolar disorder, side effects of these disorders (e.g., paranoia) can be a barrier to them adhering to their treatment schedules. If a pill tastes bad or sticks in the throat, for example, they may feel like someone is trying to poison them and will stop taking the drug.

So, Catalent’s commitment to putting the ‘patient-first’ is important when manufacturing an oral solid dosage form, as these popular delivery methods must also ensure a satisfactory level of patient adherence.

Why Zydis?

Zydis technology is an orally disintegrating tablet (ODT) form that has been around for about 30 years now. It allows us to load an API onto a disintegrating tablet, effectively taste-masked, that disperses within the mouth in as little as three seconds.

Now, for patients who struggle to swallow or perhaps need a product that has a pleasant ‘mouth-feel’ to ensure adherence to a medication regime, this disintegrating technology offers great benefits and this is probably why we have seen growth in the full R&D pipeline of Zydis ODT.

How do we make it?

We start off with a suspension or solution, we dissolve polymer in water, add the active ingredient — at this stage with Zydis ODTs we are limited to 25% loading for a suspension, for a solution product it’s much lower because that can have impact on downstream processes. This gives us our batch, which can then be dispensed directly into the primary packaging pockets via metered dosing pumps.

But, the true magic of Zydis technology is in how we freeze it. It is flash frozen using nitrogen. Through this freezing process we actually drive off the water leaving the API adhered to the polymer matrix. It’s those gelatine strands that are left behind with the active material impregnated on it that gives us the fast dissolve.

What about the taste?

This is a commonly asked question, can a Zydis ODT be effectively taste-masked? When you pop the tablet onto your tongue and it dissolves, without taste-masking essentially all of that bitter tasting API would drop straight onto the taste buds, which is not going to give a great patient experience!

In fact, there is a lot we can do to help in this area. So, the first port of call is flavours — which, for many drugs, is effective. Sweeteners can also be used to mask bitter taste but more and more we are finding that there is a need to modify the pH.

pH modification

Through this type of modification, we can adjust the form of the drug — so, we can make it less soluble in the mouth and the tablet simply dissolves in the stomach instead and is absorbed in the usual way. Equally, we can employ more advanced approaches, such as ion-exchange resins and cyclodextrins — binding the drug so that it is not available to the taste receptors, which again prevents dissolution in the mouth and the drug is absorbed in the usual way.

I would also like to point out that pH modification can be effective for areas where we need buccal absorption as well. The pH in the mouth is naturally around about seven, if you want a lower pH to aid buccal absorption, we can add additional pH modifiers into the formulation to change the saliva pH and help the drug get absorbed.

Advantages and challenges

The advantages of Zydis technology include rapid disintegration, bioavailability enhancement, smooth mouth feel and, a key thing, improved compliance — which is a result of quality of the product and the ease of administration.

This is a well-known product now, but we have encountered some challenges, including masking the taste of very bitter APIs and restrictions of drug loading.

These challenges are associated with the big sellers too such as paracetamol, and let’s take ibuprofen as our example here. With ibuprofen the usual dose in a tablet is 200 mg so trying to put that into a Zydis ODT, we would end up with a tablet that is about 20 mm across and that doesn’t even take into consideration the extra weight we would need for taste-masking! Let’s face it, even if the tablet dissolves in the mouth that will be a daunting prospect, let alone the size of the blister packs that we would need on the supermarket shelves.

The solution?

So, we were faced with the challenge to effectively taste-mask ibuprofen and I can say that we’ve done it with Zydis Ultra. So, we’ve proactively developed this, we’ve got it to a great phase and are currently working towards commercial manufacture with customers.

We’ve achieved this by investing in some technology from the New Jersey Institute of Technology — acoustic coating. Essentially what we’ve been able to do with this technology is to take a polymer, which we then place in with the powder (completely dry), we subject the mix to intense vibrations and that coats each individual API particle. The polymer is transferred into a coating and it is seamless — so no cracks or deficiencies.

Something that we have been faced with in the past with the Zydis platform is that the coating can be knocked off. Basically, when we have put the coated particle into a tank full of suspension or solution and stirred it the coating has been disrupted.

To overcome this, we looked at a continuous manufacturing process where instead of making a tank and drawing off the individual doses and over the next 24–48 hours we’re filling off pockets from the batch, now what we’re doing is we’re taking our powder blend and mixing it with the liquid part of the Zydis formulation and literally at the point of dose they get mixed and go into the pocket and that allows us to overcome this issue with the coating being knocked off. So, the taste-masking is not affected.

An added benefit of mixing at the source too is that the drug loading restriction has also disappeared, and we found that we can go up to about 50%, so it brings the size of the tablets down by about half.

Future prospects?

When asking ourselves what would be great for the industry to achieve in the next five to ten years, we would all say a cure for cancer probably as our number one. That really would be great but for the foreseeable future a major area I can definitely envisage Catalent having some sway is in oral vaccines and the Zydis platform has the potential to remove the need for end-to-end cold-chain storage of vaccines.

With Zydis technology, being able to process the product cold, just plays into the hands of being able to develop oral vaccines. We’ve currently got more than one development programme going on at the moment on oral vaccines and we’re building up a body of data on what we need to do to get these things to work, so watch this space!