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Self-Injecting Pill Could Allow Oral Delivery of Monoclonal Antibody and Other Protein Drugs

The new pill can inject large quantities of monoclonal antibodies and other drugs into the lining of the stomach after being swallowed. [Giovanni Traverso]

MIT engineers, in collaboration with scientists from Brigham and Women’s Hospital and Novo Nordisk, are developing a drug capsule technology that could allow the oral delivery of monoclonal antibodies, or other large protein-based drugs that normally have to be injected, for diseases ranging from cancer, to rheumatoid arthritis, to Crohn’s disease. The new technology is a type of self-injecting capsule, called a liquid-injecting self-orienting millimeter-scale applicator (L-SOMA), which is swallowed, and then effectively injects the liquid medication directly into the stomach wall. In large animal preclinical models, investigators used the technology to deliver four commonly injected medications, including a monoclonal antibody.

“Although it is still early days, we believe this device has the potential to transform treatment regimens across a range of therapeutic areas,” said Ulrik Rahbek, vp at Novo Nordisk, who, together with Giovanni Traverso, PhD, the Karl van Tassel career development assistant professor of mechanical engineering at MIT and a gastroenterologist at Brigham and Women’s Hospital, is co-senior author of the team’s published paper in Nature Biotechnology. “The ongoing research and development of this approach mean that several drugs that can currently only be administered via parenteral injections (non-oral routes) might be administered orally in the future. Our aim is to get the device into clinical trials as soon as possible,” Rahbek noted.

The new L-SOMA technology is described in a paper titled, “Oral delivery of systemic monoclonal antibodies, peptides, and small molecules using gastric auto-injectors.”

While oral drug delivery is a simple, noninvasive way for patients to take their medicines, most large protein drugs can’t be given orally because enzymes in the digestive tract break them down before they can be absorbed. This means that monoclonal antibody therapeutics, and other biologic drugs commonly have to be injected, which isn’t so convenient, the authors noted. “Oral administration provides a simple and noninvasive approach for drug delivery. However, due to poor absorption and swift enzymatic degradation in the gastrointestinal tract, a wide range of molecules must be parenterally injected to attain required doses and pharmacokinetics … their injection-based method of administration often causes healthcare professionals to delay their initiation in favor of less effective oral medications.” And patients themselves generally prefer pills, and say their quality of life can be affected when they are prescribed an injectable medication.

Although new technologies for oral delivery of biologic drugs are in development, they have their limitations, which means that they can’t be used for some widely used biologics, such as pre-prandial insulin. “We recognize today that pills are the preferred route of drug administration, not only for patients, but also for health care providers,” Traverso said. “If we can make it easier for patients to take their medication, then it is more likely that they will take it, and healthcare providers will be more likely to adopt therapies that are known to be effective … Our group focuses on developing systems that make it easier for patients to receive their medications.”

Traverso and colleagues have been working on different strategies to deliver biologic drugs orally. In 2019, they developed a capsule that could be used to inject up to 300 μg of insulin. The pill, about the size of a blueberry, has a high, steep dome inspired by the leopard tortoise. Just as the tortoise is able to right itself if it rolls onto its back, the capsule is able to orient itself so that its needle can be injected into the lining of the stomach. In the original version, the tip of the needle was made of compressed insulin, which dissolved in the tissue after being injected into the stomach wall.

The new L-SOMS technology described in the Nature Biotechnology report maintains the same shape, allowing the capsule to orient itself correctly once it arrives in the stomach. However, the researchers redesigned the capsule interior so that it could be used to deliver liquid drugs, and in larger quantities—up to 4 mg. This contrasts with their original version, the SOMA, which injects solid medications, but does not work with liquid drugs.

The L-SOMA technology would allow the delivery of liquid medications that need to be absorbed more quickly, or that are challenging to formulate as solids. Delivering drugs in liquid form can also help them to reach the bloodstream more rapidly, which is necessary for drugs like insulin and epinephrine, which is used to treat allergic responses.

The researchers designed their device to target the stomach, rather than later parts of the digestive tract, because the amount of time it takes for something to reach the stomach after being swallowed is fairly uniform from person to person, Traverso suggested. Also, the lining of the stomach is thick and muscular, making it possible to inject drugs while mitigating harmful side effects.

“We recognized the potential of liquid injections to readily distribute within the stomach’s submucosal plane, thereby accommodating larger dosing volumes than solid dosage forms,” the authors commented. “Additionally, the increased surface area of interaction between the formulation and the tissue when compared to a solid-dose pellet enables accelerated drug pharmacokinetics and pharmacodynamics. Moreover, by targeting the stomach rather than the small intestine, the capsule circumvents the 1–4 h required for gastric emptying.”

The new delivery capsule is filled with fluid and also contains an injection needle and a plunger that helps to push the fluid out of the capsule. Both the needle and plunger are held in place by a pellet made of solid sugar. When the capsule enters the stomach, the humid environment causes the pellet to dissolve, pushing the needle into the stomach lining, while the plunger pushes the liquid through the needle. When the capsule is empty, a second plunger pulls the needle back into the capsule so that it can be safely excreted through the digestive tract.

To evaluate the pill’s efficacy, researchers tested the L-SOMA devices in pigs, dosing each with one of four treatments, including insulin, epinephrine, adalimumab (a monoclonal antibody used to treat rheumatoid arthritis, Crohn’s disease, and other autoimmune diseases), and a semaglutide-like GLP-1 analog (an anti-diabetic medication). They then collected blood samples from each of the animals and found that the L-SOMA pill delivered medications at comparable levels to those given with an injection. “Delivery of monoclonal antibodies orally is one of the biggest challenges we face in the field of drug delivery science,” Traverso said. “From an engineering perspective, the ability to deliver monoclonal antibodies at significant levels really transforms how we start to think about the management of these conditions.”

They also found that repeated treatments with the L-SOMA dosed with insulin induced the same results, suggesting it may be effective to give multiple, subsequent doses using L-SOMA. “The pill achieves a maximum drug plasma concentration similar in magnitude to the standard-of-care subcutaneous injection as quickly as 30 min after dosing and delivers with a calculated absolute bioavailability of up to 80% within a timespan of hours,” the team continued. They also found no signs of damage to the stomach lining following the injections, which penetrate about 4.5 mm into the tissue.

The MIT team is now working with Novo Nordisk to further develop the system. Going forward with a view to human testing, the researchers acknowledged that significant clinical development will be required to evaluate safety and effectiveness. Nevertheless, they concluded, “These multi-day dosing experiments and oral administration in awake animal models support the translational potential of the system … Here we show that the L-SOMA can carry and deliver a broad range of drugs across a range of molecular weights via an oral capsule. In doing so, it can provide a less intrusive route of administration for drugs that are otherwise limited to injectables.”

The investigators anticipate that in the future, patients may be able to orally take a diverse array of medications that were once only available via needle. Additionally, because of the L-SOMA’s injectable nature, scientists believe that it has the potential to administer vaccines, including the COVID-19 vaccine as well as potentially others.

Traverso and his collaborators continue to explore what’s possible with the device. “Through the application of fundamental engineering, the type of drugs we can deliver orally is being transformed,” Traverso said. “It changes how we think about managing different conditions. This technological advancement could apply to chronic conditions that require regular dosing or to systems that are more episodic. Mass administration of an otherwise injectable drug also becomes much easier if it can be given orally.”

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