Hold in Your Stomach
How controlled release can lead to better compliance
Giovanni Traverso is a practicing gastroenterologist and biomedical engineer at Brigham and Women’s Hospital and Harvard Medical School in the US. His research focuses on the development of novel technologies for drug delivery and sensing via the gastrointestinal (GI) tract. In particular, Traverso has an interest in developing extended release technologies, which could allow gastric residence times in the order of months. We speak with Traverso to find out more.
How did you get into gastroenterology?
While I was at medical school in Cambridge (UK), I did a summer research rotation at Johns Hopkins with the cancer biologist Bert Vogelstein. A PhD followed, during which we developed tests for colon cancer (incidentally, these were recently approved by the FDA). My thesis was very successful; I was awarded the grand prize in the Collegiate Inventors Competition, recognized by the MIT Tech Review as one of the top innovators under the age of 35, and published my work in the Lancet, New England Journal of Medicine, and Nature Biotechnology.
After my PhD, I completed my medical training back in Cambridge (I was a Fellow at Trinity College, Cambridge and a student at the same time, which was wonderful!), before moving back to the US for my internal medicine residency at Brigham and Women’s Hospital and specialization in gastroenterology at Massachusetts General Hospital, both affiliated with Harvard Medical School. GI disorders include immune diseases, infectious diseases, cancer, and more, which makes the area very satisfying from both a clinical and an intellectual perspective. I’ve never regretted specializing in this field.
And what made you focus on drug delivery?
After my PhD, I wanted to explore something new, and the postdoctoral research component of my specialty medical training seemed like my last opportunity to dive into a completely different field. I was intrigued by the prospect of new technologies for GI drug delivery, so I joined Bob Langer’s lab as a post-doc, working on systems for drug delivery and sensing in the GI tract. That relationship has grown into a long-standing collaboration, and although I’m now a Harvard faculty member, I still work closely with Bob. We jointly run a group of about 40 people, funded by parties including the Gates Foundation, Novo Nordisk, and the NIH. Our aim is to exploit the GI system’s incredible capacity to accept materials and objects across a broad range of compositions and shapes, enabling extended release dosage formats which can be accommodated for over weeks or months. We’re also developing GI-located sensors that can detect a range of analytes from vital signs to toxins.
Why is extended-release drug delivery technology so important?
In early 2012, representatives of the Gates Foundation – including Bill Gates – visited the lab, and subsequently we discussed the challenge of developing a system that could provide a full course of treatment with a single administration. This kind of development could not only minimize emergence of resistance, but also potentially minimize non-compliance with medication regimens. Only about 50 percent of patients in the developed world, and maybe 30 percent in the developing world, actually take medication as prescribed, so non-compliance is a big problem. Administration frequency has a significant effect – compliance rises as the interval between each dose increases – for example, once weekly dosing regimens are associated with higher compliance than once daily.
We decided to develop an orally delivered system that resides in the stomach and releases drug over many days. Our recent paper is one of a series of planned publications on this topic (1). Basically, we have developed a novel gastric resident dosage form that can easily be compressed into a capsule for swallowing. Once in the stomach, it changes shape, and it is this shape and its mechanical properties that ensure it remains in the gastric cavity, releasing drug for several days or weeks. Key to this was the development of a safe material for the dosage form; we wanted to avoid risks, such as the dosage form exiting the stomach and entering the small intestine, where it might cause a blockage. Therefore, we devised linkers that are stable in the gastric cavity, but that selectively dissolve in the small intestine environment. We are also working on systems to aid medication adherence in the pediatric population – although this is at a much earlier stage of development.
These new dosage forms have tremendous potential to combat non-compliance. Our start-up, Lyndra, intends to get this technology to humans as safely and as quickly as possible – human trials are approximately 6-12 months away.
What are the obstacles facing extended release dosage forms?
The primary obstacle was evolution! Human GI tracts have evolved into very effective transit systems – if you eat something, it will be out of you in about a day. One way the body does this is through muscular compression waves that expel material from the stomach into the small intestine. Overcoming transit physiology requires dosage forms to be larger than the pylorus (the exit from the stomach) and have physical properties sufficient to withstand the compressive forces of the stomach. This is difficult to achieve, but essential if we are to develop a system that remains in the GI tract for long periods. Another challenge was to enable the dosage form to differentiate between stomach and small intestine; for example, by responding to alterations in pH, enzymatic profiles, or compressive forces. Exploiting these differences enables development of dosage forms that remain intact in one environment, but dissolve in another. Also, the GI environment itself raises challenges for extended release. It is difficult for drugs to remain stable for days or weeks at 37 degrees centigrade in very low pH and 100 percent humidity. The situation is further complicated by dietary diversity. It took a lot of work, and a multi-disciplinary team, to develop a dosage form that kept the drug stable in all such environments and released it in a controlled way.
What else might the future of drug delivery hold?
Other big challenges we are addressing include oral delivery of macromolecules, such as proteins. Protein therapeutics are digested after oral delivery and so are usually delivered via injection. Parenteral delivery, however, is associated with a significant delay in commencing treatment; for insulin, the delay between ideal and actual treatment initiation is about eight years! Delivery systems that don’t require conventional needles could change how patients engage and comply with medication regimens. Hence, we are developing systems to circumvent this problem, such as a microneedle injection inside the GI tract, as well as ultrasound-mediated drug delivery to the GI wall or into the bloodstream.
We are also working on ingestible electronics. A swallowable capsule that could measure vital signs in real time would be valuable for individuals such as burn victims, where applying sensors to the skin may not be feasible. Currently, we can detect signals sent from within the GI tract and treat accordingly. Next, we will progress to ingestible closed-loop systems that monitor relevant parameters and automatically release medication as required.
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- S Zhang et al., “A pH-responsive supramolecular polymer gel as an enteric elastomer for use in gastric devices”, Nature Materials, 14, 1065-1071 (2015). PMID: 26213897