There are few treatment options available to people with esophageal disorders. Because it is difficult to deliver drugs directly to this part of the body, patients are usually treated with systemic drugs, which can cause unwanted side effects.
To overcome this challenge, MIT engineers developed a gel-like oral drug formulation that coats the mucosal lining of the esophagus after swallowing, allowing the drug to pass through the tissue.
The formulation contains hydrogels and other key ingredients that promote rapid drug absorption and could be used to deliver antibodies such as infliximab, which is used to treat many autoimmune diseases, as well as other types of antibodies and small molecule drugs.
“There are a lot of people who suffer from esophageal diseases, but when you look at the drugs that address these conditions, the ability of drugs to target this part of the body is very limited and very difficult to develop. We hope that this platform will facilitate the development of systems that help patients suffering from these diseases,” said Giovanni Traverso, MIT associate professor of mechanical engineering, gastroenterologist at Brigham and Women’s Hospital, and associate member of the MIT Broad Institute. Harvard University.
Traverso is the lead author of the new study, published today natural biomedical engineering. Former MIT postdoctoral fellow Christina Karabasili, now an assistant professor at Aristotle University of Thessaloniki in Greece, is the paper’s lead author.
Direct delivery
One of the most common diseases of the esophagus is eosinophilic esophagitis. This is a type of inflammation caused by food allergies that causes the esophagus to close and prevent you from swallowing food. Crohn’s disease can also cause inflammation of the esophagus.
These diseases are usually treated with systemic drugs such as infliximab, an antibody that neutralizes an inflammatory protein called tumor necrosis factor alpha (TNF-alpha). However, because this drug is an immunosuppressant, it may increase your risk of infections and other health problems.
Delivering drugs directly to the esophageal tissue may reduce these side effects, but this is inherently difficult because orally ingested drugs pass through the esophagus very quickly. Adding to the problem, the esophagus is lined with a layer of tissue called stratified squamous epithelium, which is highly impermeable to drugs.
Another option is to inject the drug into the esophageal tissue, but this is uncomfortable for the patient and inconvenient because it must be done in the clinic. There is also at least one anti-inflammatory steroid drug formulated as a viscous mixture that can remain in the esophagus longer after being swallowed, although the drug still has some difficulty passing through the impermeable squamous layer.
In this study, the researchers set out to develop a new drug formulation containing molecules that increase the permeability of esophageal cells, allowing more drugs to pass through.
To identify molecules that increase permeability, the researchers designed a screening system that mimics the structure of the esophagus. This system contains esophageal tissue sandwiched between two vertical plates. Drug formulations can be poured into the top of the system to simulate oral ingestion. Researchers can measure how much drug passes through the tissue and is collected in one well of the plate.
Using this system, the researchers were able to measure how different excipients (inactive ingredients that help increase the effectiveness of a drug) affect the permeability of esophageal tissue. First, they tested about 100 different compounds and identified several leading candidates. They then tested pairs of these excipients and found that the most effective combination was a pair of bile salts called sodium chenodeoxycholate and sodium cholate.
These salts are thought to work together to loosen cell-cell bonds that normally act as barriers to the entry of drug molecules. The researchers added these bile salts to polysaccharide-derived hydrogels. This hydrogel has a viscous consistency that allows it to lightly coat the inner wall of the esophagus.
“The hydrogel helps the formulation stay on the surface of the esophagus longer, and the bile salts help facilitate transport across the tissue,” says Karabasiri. “Our data suggest that bile salts temporarily loosen these intercellular bonds, primarily by interacting with calcium ions that help maintain bond integrity. This creates more permissive pathways between cells, allowing larger molecules to move more efficiently into mucosal tissues.”
minimize side effects
Researchers showed in animal studies that this formulation could be used to effectively deliver infliximab to the esophagus. They also found that the loosening of the junctions between cells was temporary, and the cells returned to normal within three days.
This type of delivery could help avoid the side effects that patients sometimes experience when administering infliximab systemically, the researchers said.
“We were interested in providing an anti-TNF drug as a model drug, but we were also interested in helping people suffering from conditions like Crohn’s disease have an option that they can bring to the field,” Traverso says.
The possibility of site-specific delivery may reduce the systemic side effects of these immunosuppressants. ”
Giovanni Traverso, Massachusetts Institute of Technology
Researchers are currently working to further optimize the formulation for possible human trials. One important goal is to ensure that the gel adheres long enough to deliver the drug, but not so long that it causes discomfort to the patient. Researchers are also exploring the possibility of using this approach to administer other types of drugs.
“This is a platform that allows us to develop drug delivery systems into the esophagus, which was previously not possible because the tools did not exist,” Traverso said.
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Massachusetts Institute of Technology
