One reason that it’s so difficult to deliver large protein drugs orally is that these drugs can’t pass through the mucus barrier that lines the digestive tract. This means that insulin and most other biologic drugs that comprise proteins or nucleic acids have to be injected, or administered at a hospital. Researchers at MIT and at Brigham and Women’s Hospital have now developed a robotic drug capsule, RoboCap, that may one day be able to replace those injections. The orally ingestible drug delivery device has a robotic cap that spins and tunnels through the mucus barrier when it reaches the small intestine, allowing drugs carried by the capsule to pass into cells lining the intestine. So when ingested, the capsule’s gelatinous coating is first dissolved in the stomach. The environment of the small intestine then activates RoboCap, which vibrates and rotates to clear mucus, enhance mixing and deposit the drug payload in the small intestine where the drug is likely to be absorbed.

The team tested the device in preclinical models, delivering insulin and the antibiotic vancomycin, which is usually delivered intravenously. In a swine model, RoboCap increased drug permeability for both insulin and vancomycin by more than 10-fold. The developers hope that their device may overcome many of the challenges of the gastrointestinal environment to deliver its payload.

“Peptides and proteins are important drugs, but the degradative environment of the gastrointestinal tract and poor absorption has limited the ability to deliver these drugs orally,” said says Giovanni Traverso, MB, BChir, PhD, the Karl van Tassel Career Development Assistant Professor of Mechanical Engineering at MIT and a gastroenterologist at Brigham and Women’s Hospital. “RoboCap’s mucus-clearing and churning movements are designed to overcome these barriers and help deliver drugs to where they are needed … By displacing the mucus, we can maximize the dispersion of the drug within a local area and enhance the absorption of both small molecules and macromolecules.”

Traverso is co-corresponding author of the team’s published paper in Science Robotics, titled “RoboCap: Robotic mucus-clearing capsule for enhanced drug delivery in the gastrointestinal tract.” The paper’s lead author is Shriya Srinivasan, PhD, a research affiliate at MIT’s Koch Institute for Integrative Cancer Research and a junior fellow at the Society of Fellows at Harvard University.

Although it is the most common, cost-effective, and practical method of drug administration, oral drug delivery for macromolecules is limited by the degradative environment of the gastrointestinal (GI) tract and poor absorption,” the authors noted. “Drugs must overcome the harsh acidic environment of the stomach, dissolve in GI fluid, remain stable among dynamic intestinal microbiota and degradative enzymes, penetrate through the viscous mucus barrier, and evade efflux pumps to achieve therapeutic bioavailability.”

Insulin, for example, which is required daily by millions of people with diabetes, has an oral bioavailability of less than 1%, and so must be injected. The peptide antibiotic vancomycin, which is commonly used to treat serious Gram-positive bacterial infections, has an oral bioavailability of 0.069-4%, and so must be intravenously administered, requiring costly hospitalization, the team continued.

For several years, Traverso’s lab has been developing strategies to deliver protein drugs such as insulin orally. This is a difficult task because protein drugs tend to be broken down in acidic environment of the digestive tract, and they also have difficulty penetrating the mucus barrier that lines the tract. “Absorption, the first stage of entry, is predominantly hindered by the mucus barrier,” the investigators further explained. “Through its viscous, hydrophilic, frequent turnover, and shear-thinning gel properties, mucus serves as a dynamic, steric, and interactive barrier, preventing drugs in the lumen from reaching the epithelial surface.”

To overcome some of these obstacles, Srinivasan came up with the idea of creating a protective capsule that includes a mechanism for tunnelling through mucus, just as tunnel-boring machines drill into soil and rock.

“I thought that if we could tunnel through the mucus, then we could deposit the drug directly on the epithelium,” she said. “The idea is that you would ingest this capsule and the outer layer would dissolve in the digestive tract, exposing all these features that start to churn through the mucus and clear it.”

The team’s resulting RoboCap capsule, which is about the size of a multivitamin, capsule is coated with gelatin that can be tuned to dissolve at a specific pH. The device carries its drug payload in a small reservoir at one end, and houses its tunnelling mechanism in its main body and surface. When the coating dissolves, the change in pH triggers a tiny motor inside the RoboCap capsule to start spinning. This motion helps the capsule to tunnel into and displace the mucus. The capsule is in addition coated with small studs that brush mucus away, similar to the action of a toothbrush.

A new drug capsule developed at MIT can help large proteins such as insulin and small-molecule drugs be absorbed in the digestive tract. The capsule has a robotic cap that spins and tunnels through the mucus barrier when it reaches the small intestine, allowing drugs carried by the capsule to pass into cells lining the intestine. [Felice Frankel]
The spinning motion also helps to erode the compartment that carries the drug, which is gradually released into the digestive tract. “What the RoboCap does is transiently displace the initial mucus barrier and then enhance absorption by maximizing the dispersion of the drug locally,” Traverso explained. “By combining all of these elements, we’re really maximizing our capacity to provide the optimal situation for the drug to be absorbed.”

In tests in animals, the researchers used the RoboCap device to deliver either insulin or vancomycin, a large peptide antibiotic that is used to treat a broad range of infections, including skin infections as well as infections affecting orthopedic implants. Using the capsule, the researchers found that they could deliver 20 to 40 times more drug than a similar capsule without the tunneling mechanism. “Vancomycin (1.4 kilodaltons of glycopeptide) and insulin (5.8 kilodaltons of peptide) delivery mediated by RoboCap resulted in enhanced bioavailability 20- to 40-fold in ex vivo and in vivo swine models when compared with standard oral delivery.” Encouragingly, they further noted, “Insulin delivery using the RoboCap resulted in a more gradual uptake as compared with the pharmacodynamics of subcutaneous or intravascular injection, which may be a useful feature for various drugs requiring gradual or sustained release.”

Once the drug is released from the capsule, the capsule itself then passes through the digestive tract on its own. Through their in vivo studies the researchers found no sign of inflammation or irritation in the digestive tract after the capsule passed through, and they also observed that the mucus layer reforms within a few hours after being displaced by RoboCap.

Another approach that some researchers have used to enhance oral delivery of drugs is to give them along with additional drugs that help them cross through the intestinal tissue. However, these enhancers often only work with certain drugs. Because the MIT team’s new approach relies solely on mechanical disruptions to the mucus barrier, it could potentially be applied to a broader set of drugs, Traverso suggested. “Some of the chemical enhancers preferentially work with certain drug molecules,” he noted. “Using mechanical methods of administration can potentially enable more drugs to have enhanced absorption.”

And unlike other drug carrier systems, such as lipid-based formulations or nanoparticles, the RoboCap doesn’t present biocompatibility concerns, because the electromechanical components remain sealed off and pass through the body after the drug is delivered, the scientists stated. In their paper, they concluded, “As we demonstrated in the case of insulin delivery, the RoboCap makes it possible to achieve therapeutic absorption levels through oral ingestion for drugs that usually require more cumbersome and expensive methods such as subcutaneous injections, inhalers, and intravenous administration, requiring hospitalization.”

While the capsule used in this study released its payload in the small intestine, the RoboCap strategy could also be used to target the stomach or colon by changing the pH at which the gelatin coating dissolves. The researchers also plan to explore the possibility of delivering other protein drugs, such as a GLP1 receptor agonist for treating type 2 diabetes. The capsules could also be used to deliver topical drugs for treating ulcerative colitis and other inflammatory conditions, by maximizing local concentration of the drugs in the tissue to help treat the inflammation.

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