Robotic screening speeds testing of oral drugs
The oral route is usually the most convenient way to take a medication. Oral drugs must be easily absorbed in the small intestine, but some don’t dissolve well in the small intestine because their chemical structure repels water. Others dissolve in the intestines but aren’t able to overcome the mucus layer to cross the gut wall.
It’s been difficult to develop models of the human gastrointestinal (GI) tract to test oral drugs because the cells die soon after removal from the intestines. Researchers often use cancer cells from the colon or intestine because they survive for longer periods outside the body. However, these models lack bile, mucus, and other factors that alter drug absorption in the GI tract. The current models are also time-consuming to produce.
At a Glance
Researchers at MIT and Brigham and Women’s Hospital, led by Drs. Robert Langer and Giovanni Traverso, set out to develop a better model of drug absorption in the human gut. Their work was supported in part by NIH’s National Institute of Biomedical Imaging and Bioengineering (NIBIB). Findings appeared in Nature Biomedical Engineering on April 27, 2020.
The research team decided to use intact sections of pig intestine for their screening system. Pigs have similar anatomy to humans, and scientists have studied the pig genome extensively. The researchers first tested many compositions of growth media to keep the pig’s intestinal tissue viable and functioning.
Taking GI tissue from younger animals and keeping the supporting layer, or stroma, intact yielded the best results. Tests of gene and protein expression showed that the cultured intestinal cells remained functional for up to a week.
Next, the researchers developed a device with the cultured tissue sealed between two plates. The drug is added to the upper plate. Intestinal absorption can then be assessed by measuring how much of the drug passes through the tissue to the lower plate. The fully automated process uses a robotic arm to analyze and move the plates. This GI tissue robotic interface system, or GI-TRIS, can analyze several thousand samples each day.
The team next tested how well their screening predicted oral absorption. They analyzed 55 FDA-approved drugs with available data on absorption. GI-TRIS performed much better than methods using colorectal cancer cells.
Finally, the researchers used their system to test new oral formulations of the drug oxytocin, which currently must be given intravenously. When taken orally, oxytocin has poor bioavailability—the amount of drug able to circulate in the body. To enhance oral absorption, oxytocin was mixed with various stabilizing compounds called excipients. Using GI-TRIS, the scientists were able to screen more the 2,900 formulations of oxytocin.
After identifying the two most promising formulation, the team tested them in pigs. The most effective formulation increased oxytocin absorption in the GI tract 11-fold compared to non-formulated oxytocin.
“This new system really opens up the possibility of accurately predicting, for the first time, drug transport in the gastrointestinal tract in a high-throughput manner,” Langer says. “This will allow us to test ways to greatly improve oral drug bioavailability.”
—by Erin Bryant