Manufacture Small Molecules, Drug Delivery

Go for the Gut: A Dose of Enteric Innovation

The team of dreamers and achievers behind the 2023 Innovation Awards winner, Lonza’s Enprotect Capsule, discuss their technology.

09/16/2024 | 11 min read | Discussion

When the call for nominations for the 2023 Innovation Awards went out, I cannot say I expected something as seemingly ordinary as a capsule to be named the grand winner. Innovation, however, can be present in all things – given the right amount of time, hard work and partnerships. And if we are neglecting to innovate in the everyday, then we are failing altogether.

In a hotly contested list of entrants that included AI accelerators, nanoparticle analysis, cell therapy robots, and microfluidic chips, Lonza’s Capsugel

Enprotect capsule emerged as the winner. The capsule – as the name suggests – provides enteric drug delivery. It is a bi-layer capsule that consists of hydroxypropyl methylcellulose (HPMC) and hydroxypropyl methylcellulose acetate succinate (HPMC-AS) polymers.

Lonza’s chemical engineers and material scientists found a way to enhance the performance of a seemingly ordinary drug delivery product whilst simultaneously saving time, effort, and costs for pharmaceutical manufacturers; improving efficacy and easing the treatment burden for patients; and keeping in mind the company's sustainability targets. It is all too easy to hold an everyday capsule between one’s fingers without considering the R&D efforts that got it there. Here, I speak with the team of dreamers and achievers behind the Enprotect Capsule to get the story behind its development.

Christian Seufert is the President of the Capsules and Health Ingredients Division at Lonza. The Division’s aim is to enable a healthier world by giving formulators the opportunity to find innovative, targeted drug delivery solutions.

Ljiljana Palangetic is a chemical engineer/material scientist who heads Lonza’s Hard Capsules research and development team. Her role involves working alongside other R&D teams to deliver novel solutions for unmet needs for pharma and nutritional applications. Through material selection, lab and pilot scale testing, and industrial scale-up, the contributions made by Ljiljana’s team to Enprotect capsules was indispensable.

Vincent Jannin is the Director of R&D, heading a research group focusing on capsule applications. A trained pharmacist and drug delivery scientist with over 25 years of experience in the pharmaceutical excipients industry, his mission is to solve customer drug delivery challenges through innovation.

Jannin: Enteric targets delivery into the small intestine, which means the payload API must be protected from the acid and enzymes of the stomach. Developing an enteric formulation is a delicate process that can be time-consuming and expensive. And most of the time, the manufacturing process involves steps that are detrimental to certain APIs – particularly monoclonal antibodies, peptides, nucleic acids, and other fragile drug modalities, making the oral delivery an unviable delivery form.

We wanted to develop a solution that could make enteric formulation an option for these drug modalities. The result is the Enprotect capsule. It is a bi-layer capsule that is ready to use; you just need to fill the API or formulation into the capsule and close it. No post-filling treatment is required, and the bi-layer technology ensures the API is released in the small intestine.

We hope we have prepared the ground for many more new developments in enteric drug delivery. These capsules can be used for many classes of APIs that could not traditionally be delivered orally.

Palangetic: Looking into how oral enteric delivery is achieved today, coating capsules after filling them becomes the lead, if not the only, technology available to reach the goal. It is a lengthy, laborsome process that can also have a negative impact on the APIs. The key question for us was, how can we make a capsule that would be truly enteric but that would at the same time keep all the simplicity and advantages of using a capsule for oral dosages? This led to the concept of an enteric pre-coated or a bi-layer capsule and the great question of how to make it. As a technical person, you imagine a few different technologies that could be used; the advantages and disadvantages of those; the materials selection challenges and whether they will generate the right capsule quality or the right enteric performance. And while a lot of these can be relatively easily explored at the lab level, it was definitely a challenge to achieve this on an industrial scale.

We selected HPMC as the basis or the inner layer of the capsules, which has the right properties for forming a hard capsule. The outer layer uses HPMC acetate succinate (HPMC-AS), which ensures the capsule opens in the small intestine rather than the stomach. Both polymers are established cellulose derivatives well-known in solid dosage formulations. The materials offer good compatibility and long-term stability, which is important for both the capsule and the API within it.

When it came to manufacturing, we stuck with what we know best – the standard process for manufacturing capsules – the dip molding process. Thanks to our technology R&D group, we were able to modify machines to allow the creation of the right process window for both layers and ensure that we could perform a subsequent dipping to create the two layers.

We overcame key challenges in the drying process by combining our knowledge of polymers and years of experience in standard capsules. Extensive in vitro testing by our research group and by our customers gave us good insights to move forward. Then, we conducted in vivo tests that showed the capsule’s content delivery to the intestine. The list is long, but with every challenge we faced, we learned to improve and innovate further.

We also did all of this while maintaining the standard size of the capsules, which means that customers can use them with any filling machine without a need to upgrade or purchase new instruments. Because they are filled directly into the capsule with no additional processing to follow, there is no stress on the APIs.

Jannin: HPMC can dissolve in any part of the gut, stomach, or intestine. We selected this material to give the capsule its shape, and it allows us to produce it on a large scale. Our customers are happy with the compatibility with the classic fill materials, which we checked with a range of solid fill excipients. The trick for enteric delivery is to then have an outer layer composed of an enteric polymer.

The final Enprotect capsule contains an enteric polymer that is unable to dissolve in acid up to pH 6.0. It protects the payload from releasing in the stomach but will readily dissolve in the intestine when reaching pH 6.2. There is no additional excipient or plasticizer that can negatively affect the properties of the capsule. The capsule is ready to use with no need to seal, band, or coat them after filling.

Seufert: Innovation depends on inclusive and empowering teamwork. Enprotect

capsule was a cross-functional effort between different R&D teams, operations, engineering and other functional experts at Lonza. In only 18 months, the team brought this innovation to life, from conceptualization to the first capsules in our hands, all under the constraints of the COVID-19 pandemic. From our perspective, the dual layer capsule technology enables us to reimagine capsule properties and functionalities for the future.

Palangetic: This project shows our dedication as an organization to offering formulators new solutions. Enprotect capsule was our baby, and it takes a village to raise a baby. All the stakeholders came through to make sure it was delivered in the fastest possible way. I truly believe that our team has moved a mountain and created solid ground for new developments. It is a new technology, using old knowledge – and it will certainly be a catalyst for future innovation in solid dosage form delivery.

One could already imagine the Enprotect capsule playing a role in helping drug manufacturers with sustainability – replacing the traditional process of filling capsules and then coating them could be a game changer for some products. Furthermore, this capsule could be an enabling tool for the conversion of certain vaccines into oral dosages, which would not just improve patient comfort but eventually even allow better access to vaccines where the cold supply chain is a great challenge. It has been shown that enteric capsules are well suited to replace the traditional method of fecal microbiota transplant (FMT) and greatly improve patient’s experience. And we believe that these examples are just scratching the surface.

Jannin: We collaborated with academic partners to develop an in vitro test that mimics the cystic fibrosis condition in the stomach and small intestine to ascertain that the capsule can withstand this condition and release the payload exactly where it should be. We also designed two in vivo studies in human volunteers – in fasted and fed conditions – and in both cases, the capsule was able to tolerate the stomach conditions, even the higher pH and shear of the fed stomach. In fact, it remained intact even after more than four hours in the stomach. These studies demonstrate the robustness of the capsule in very harsh conditions. Our academic partners said they had never seen this with enteric delivery before!

This solution is also good for many new drug modalities, such as proteins, enzymes, LBPs, and drugs that are not acid-sensitive but need to be delivered specifically in the small intestine.

We are also collaborating with hospitals on FMT. We have shown that the capsule is compatible with FMT and able to deliver the payload while reducing the number of capsules a patient must take. We also think it could be a transformative treatment for patients with Crohn’s disease by enabling the development of targeted-release Enprotect capsules that can deliver RNA-loaded nanoparticles.

This solution is also good for many new drug modalities, such as proteins, enzymes, LBPs, and drugs that are not acid-sensitive but need to be delivered specifically in the small intestine.

Seufert: Formulators have responded very positively to the launch of Enprotect capsules, and, as a result, many new projects have already been initiated with our customers. We have seen a wide range of applications, from small molecules and proteins to medical devices. We are always looking ahead at further improvements and new applications, and as a first next step, we are planning to provide formulators with more color and capsule size options.

Seufert: I would like to see the industry pushing the limits of oral solid dose delivery. Innovative capsule technology could play a big role in the delivery of oral and inhalable biologics. It is not only about formulating such products for oral delivery but how we can provide access to cost effective solutions in a more sustainable way. This is something that will require a lot of work and much more innovation. But if you ask me to dream a little, that is what I would aim for.

Palangetic: I am convinced that the capsule’s potential in solid dosage forms has been unjustly underestimated for a very long time.

A capsule was originally an excipient/container intended to mask/cover badly-tasting contents, but it has evolved, and it has so much more to offer. The Enprotect capsule is a good example; pushing the boundaries with delivering products to the intestine and opening the possibility to deliver actives that previously could not be envisioned in oral dosage forms. I hope that capsules will be given more consideration within new drug development projects because of the benefits in functionality, customization possibilities, patient preferences, and so on. We are keen on exploring new innovation paths and are ready to partner with customers so we can generate new ideas to help patients.

Jannin: For me, the dream for the next couple of years would be to have another capsule that targets a specific segment in the intestine. We are working with GeneGut to help Crohn's disease patients. These patients have a very poor quality of life, and the standard treatment has many side effects. A drug with a local effect could change lives – and so a capsule that can deliver APIs deeper into the intestine is next on the wish list. I hope to have the opportunity to work with many customers on adaptations involving Enprotect capsules. Whether it is earlier, later, quicker, or slower release, there is a clear need in the market for oral biologics, and the potential for further innovation is certainly there.

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