Medical researchers have developed a new drug-delivery method meant to ease constipation by lubricating the colon with bile acid while slowing the delivery enough to avoid painful cramps. The company they founded has planned to fund human clinical trials involving irritable bowel syndrome patients by next year.
Scientists from the Massachusetts Institute of Technology and Brigham and Women's Hospital are seeking a patent for their two-layer bile-acid medication, which promotes secretion of intestinal fluids. The medication's initial targeted application is to make bowel movements easier and more frequent for people with constipation, though it has potential uses for other conditions such as metabolic disorders, including diabetes and obesity.
Their patent application was published by the U.S. Patent and Trademark Office on Feb. 4. Among the patent's co-inventors is Robert Langer, an institute professor at MIT who has more than 700 granted or pending patents and is one of the most cited researchers in the world.
Bile is a fluid produced by the liver, and the acids it contains make fats easier to absorb during digestion. Bile acids are also important for helping materials move through the intestines. An imbalance in bile acids can result in bowel issues: Too much can cause diarrhea, while a deficiency can lead to constipation.
A 2010 trial tested one bile acid, chenodeoxycholic acid, or CDC, as a constipation reliever on 36 women with irritable bowel syndrome. Although the subjects' bowel movements improved compared to placebo, nearly half of those receiving the treatment reported abdominal cramps and pain. This adverse side effect led to the treatment being shelved.
The scientists behind the pending patent had hypothesized that the cramps were caused by very high levels of CDC in the colon. The experimental treatment they developed employs the same bile acid, but was designed to release the acid more gradually to circumvent abdominal pains caused by "dose dumping," co-inventor Giovanni Traverso, a gastroenterologist at Brigham and Women's Hospital and an assistant professor of mechanical engineering at MIT, told The Academic Times.
"What we recognized is that we would have an opportunity to develop a system that could provide the bile acid — in this case, chenodeoxycholic acid — in a way that was sustained over the course of the travel in the colon," said Traverso, who is also a part-time assistant professor of medicine at Harvard Medical School.
As detailed in a paper published in December in Clinical Translational Gastroenterology, Traverso and his colleagues created 1-gram tablets with two parts: a quickly dissolving layer made almost entirely of CDC that initially triggers the intestinal fluid secretion, and a slowly dissolving layer that contains a mixture of CDC and hypromellose, an inert polymer that has been used to prolong the release of other drugs in the body. The tablet's acid-resistant coating also delays the release until it reaches the neutral-pH conditions of the large intestine, surpassing the bile acid-absorbing last section of the small intestine.
Tests in pigs showed that the bilayer tablet caused only one large rectal contraction, while pigs administered tablets with only fast-acting CDC experienced several such contractions. The authors said that their swine study had limitations, such as not observing the full colon for contractions or measuring levels of abdominal pain, but it still demonstrated the treatment's ability to deliver CDC while strongly reducing painful cramps.
"We show that we could mitigate some of those giant contraction events, and that we could control the release of the bile acids using these systems," Traverso said.
This targeted treatment with bile acid could eventually be used for other maladies, Traverso said. The acid could interact with the endocrine system in the colon and treat metabolic disorders, according to the gastroenterologist, and it also shapes the gut microbiome, which has been tied to several digestive issues when out of balance.
Traverso, Langer and some of their co-authors have also created a company, Bilayer Therapeutics, to continue developing the treatment and test it in humans. Founded last year, Bilayer Therapeutics is led by President and CEO Thomas Collet, who has worked with numerous other pharmaceutical startups.
A self-described "serial entrepreneur in the life sciences," Collet first met co-inventor Christoph Steiger when they were neighbors in Cambridge, Massachusetts, before becoming one of five co-founders of Bilayer Therapeutics.
"He told me that he's doing research on a way to treat constipation, and I find this interesting because I like product-focused early-stage companies where the product can provide value," Collet said. "We just decided not to let COVID stop us and start a company around this."
Using the pending patent, Bilayer Therapeutics is currently working to raise funds to prepare for human clinical trials, Collet said. The trials are planned to begin about 18 months after the company receives funding, which he expects to happen by May.
The application for the patent, "Articles and methods for administration of therapeutic agents" was filed Aug. 12, 2020, to the U.S. Patent and Trademark Office. It was published Feb. 18, 2021 with the application number 2021/0046011. The earliest priority date was Aug. 12, 2019. The inventors of the pending patent are Carlo Giovanni Traverso, Brigham and Women's Hospital, Harvard University and Massachusetts Institute of Technology; Joshua Korzenik, Brigham and Women's Hospital and Harvard University; Robert Langer, Massachusetts Institute of Technology; and Christoph Steiger, Brigham and Women's Hospital and Massachusetts Institute of Technology. The assignees are the Massachusetts Institute of Technology and Brigham and Women's Hospital.
Parola Analytics provided technical research for this story.