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Manufacture Drug Delivery, Vaccines

Sublingual Vaccines – A Taste of the Future?

sponsored by Catalent

Biopharmaceuticals have the potential to treat a range of conditions, but almost all biologic medicines must be delivered via injection, which is not the most comfortable option for patients. Here, Rosie McLaughlin gives us a taste of Catalent’s ‘Zydis® Bio’ technology and explains why the oral delivery of large molecules is the future.

How did you get involved with Catalent?

I started my career working for SmithKlineBeecham, but I’ve been at Catalent for 20 years now. I’ve always worked in product development and currently I’m Director of Scientific Affairs for Zydis® – Catalent’s technology for manufacturing orally disintegrating tablets (ODTs). In particular, I’m looking at how we can expand the applications of the Zydis technology into new areas. We’ve developed a formulation technology called Zydis Bio, which permits the oral delivery of peptide and protein biotherapeutics. It can also be used to deliver much larger structures, such as inactivated viruses. In fact, Zydis formulations of peptide therapeutics and sub-lingual immunotherapy vaccines for the treatment of allergy are on the market right now. You might think that proteins and peptides would be prone to degrade and denature during processing – for example, they are susceptible to hydrolysis in aqueous solution – but our formulation system generates robust, dry products that are stable at room temperature for 3-4 years.

What are the benefits of delivering biologics via the oral mucosa?

Sublingual delivery can enable the oral administration of molecules that are usually injected, because if you get the biologic into circulation before it reaches the acidic, proteolytic environment of the stomach, you avoid losing your drug to digestion. While it’s true that the gastric environment can also be avoided by formulating tablets with enteric coatings – which only break down and release drug once they are in the intestine – this approach is not ideal. For example, if it is to be fully assimilated, the drug has to remain on the intestine’s absorptive surface for a significant period of time, which can be difficult because of intestinal wash-through. Salivary wash-through under the tongue, however, is minimal and mucoadhesives can help keep the preparation at the absorption site; so it’s a more efficient way of getting the drug into the circulation system. In addition, delivery of antigens generate a better mucosal immune response than other vaccination routes, which means better protection against pathogens that infect via the mucosa.

And no needles are required?

Exactly. We avoid poor compliance brought on by needlephobia, since people are more likely to take tablets than injections. In addition, there is a perception in some parts of the population that injected vaccines are somehow dangerous – an attitude which has led to measles outbreaks due to a fall-off in vaccination coverage. We could bypass that perception by offering vaccines in an entirely different format. And an oral vaccine avoids not only the costs of the needles and syringes themselves, but also of their disposal, including sharps bins and associated storage, transport, and incineration costs. There is also no need for trained personnel to administer the therapy, and the dangers of needlestick injuries are eliminated. In addition, a dry preparation that is stable at room temperature avoids the cold chain issues that have dogged vaccine supply – and which also have cost implications in terms of energy, storage space, and vaccine wastage. Finally, a Zydis vaccine does not need a sophisticated healthcare infrastructure to reach the people that need it, making it easier to respond to emergency situations or pandemics, particularly where conditions are challenging, such as disaster zones or remote areas.

What kinds of vaccines will be compatible with Zydis Bio?

We’re assessing the full spectrum of marketed vaccines, including whole inactivated vaccines, split virus vaccines, subunit vaccines, and so on, to determine the best vaccine applications for Zydis Bio. In terms of market, travel vaccines might be an interesting niche because they are private sector products, which means you can achieve a good price. With a tiered pricing approach, you can also look for volume sales in emerging markets. Of course, there will be challenges to overcome; for example split virus and subunit vaccines tend to be less immunogenic than whole inactivated vaccines, but I’m confident we can manage those challenges through formulation and it’s an area the company is addressing.

Buccal and sublingual regions are predisposed to tolerization – how do you overcome that?

We’ve formulated an allergy vaccine that exploits the tolerizing effect of sublingual antigen administration, so the tolerizing predisposition of the sublingual route has its advantages. But to develop a vaccine that provokes an immune response, we had to modulate the Zydis Bio formulation. We succeeded in shifting tolerance induction to induction of immunity – I won’t say exactly how we did it, but we managed it without recourse to traditional adjuvants. In particular, we’ve shown that we can deliver a whole inactivated influenza vaccine in a Zydis Bio sublingual formulation and thereby induce good, balanced immune responses, including both antibody effects and cytotoxic T-cell effects.

And for some pathogens you need that balanced response. It is not always the case that an antibody response is sufficient. Many pathogens invade and replicate in cells, and to effectively fight the infection you need not only humoral responses, but also cytotoxic T-cell responses to help clear those infected cells. And the results so far are highly encouraging. For example, we’ve shown that a Zydis Bio influenza vaccine mediates protection in a mouse model of the disease. So, although it’s early days, data to date suggest that a sublingual flu vaccine for humans is within reach.

Are there any other advantages or challenges?

If you could mediate an effective immune response with one or two viral proteins purified from cell lines, you would have a system that can easily be modulated in response to mutations in the wild-type virus. We’re working towards that situation, and as I said we are looking at the whole field of split virus and subunit vaccines in some detail. Certainly, the Zydis Bio technology is capable of formulating a broad range of protein antigens expressed from mammalian or other cell types. We can readily prepare them in a dry, stable format suitable for sublingual administration – that aspect isn’t a challenge for us at all. The further work we are now focusing on is ensuring that the proteins we deliver in this format can induce the right magnitude and form of immune response. So although we have very encouraging data, as exemplified by the mouse model of influenza, and although we are building up the data into something quite substantial, there’s still a little way to go before we see Zydis Bio prophylactic vaccines on the market.

Is the system also applicable to other biotherapeutic molecules?

Definitely. It’s a slightly different aspect of the system, but it’s another area that we are moving into. In brief, if the biologic can be transported across the buccal or sublingual mucosa, then we can formulate it so as to accomplish delivery by that route. But often the real skill comes in optimizing the formulation to provide the desired outcome in terms of, for example, immunogenicity or dose. And that area – formulation optimization – is where a flexible platform has real advantages.

The future

Robert Smith, VP Product Development Advanced Delivery Technologies, Europe, introduces the recent advances for the Zydis® ODT technology.

Catalent has made significant progress with the Zydis ODT innovation. To address market demand for solutions that solve challenges with dose form, taste masking, bioavailability and oral biologics delivery, patient-preferred Zydis ODT technology is now available to our customers across an increasingly wide variety of products. Enhanced taste masking capabilities can provide a broader array of options for our customers with bitter or strong tasting APIs. Through formulation optimization, we can also offer a stable platform for nanoparticles within the Zydis platform, thereby improving the bioavailability of poorly soluble APIs. This capability complements our existing sublingual delivery offering for compounds exhibiting poor bioavailability due to high first pass metabolism. In addition, we are continuously improving our operational flexibility, with potential for higher speed production and streamlined printing capabilities. We believe that the flexibility and technology benefits provided by the Zydis platform have applicability to a wide variety of products, and we are having ongoing discussions with leading global OTC and Rx customers to explore development partnerships.

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