Mechanical engineers at Penn State have developed the first computer-generated stomach to study the path of ingested medication in the form of extended-release tablets.

James G. Brasseur, professor of mechanical and bio-engineering and leader of the project, said he had been studying the relationship between physiology and mechanics in the stomach for four or five years when drug companies began to contact him recently to research extended-release tablets.

"The company that has sponsored our project, AstraZeneca Pharmaceuticals of Sweden, was interested in applying techniques to study extended-release tablets that are continuously absorbed over a long period of time," he said.

Extended-release tablets are designed to remain in the stomach for hours and release medicine slowly, said Jonathan Borowski, a pharmacist at University Health Services.

He said the tablets use "ALZA technology," named for the corporation that pioneered this pharmaceutical method.

"There is a layer inside the tablet that absorbs water as stomach fluid enters the membrane, causing the tablet to swell and eventually to push the medication out," he said.

The first drug designed to use this technique was Pfizer's Procardia XL, a calcium-channel blocker for relief of high blood pressure, he said.

"Extended-release tablets are [used] when you need constant medication all day," said Anupam Pal, a postdoctoral fellow and research associate on Brasseur's team who has been instrumental in the development of the virtual stomach.

"It's not something like Advil that works right away," he said.

Reasons

While pharmaceutical re-searchers knew extended-release tablets worked over long periods of time, they were not sure exactly how the medication worked once in the stomach, which hindered their ability to improve the design of the tablets, Brasseur said.

"You can't measure any of this information in a real stomach," he said. "The only other thing you could do is put a radioactively traced liquid into the stomach, but even with that method, you'd get no detail."

With the virtual stomach, however, simulations of the stomach's processes can be calculated and minute details can be observed, Pal said.

"The stomach is a muscular bag, and it is the contractions of these muscles that force the movement and mixing of the chyme, or partially digested food," Brasseur said.

He explained that the upper part of the stomach is called the fundus and the lower part is called the antrum. Almost all of the mixing occurs in the antrum because its muscle contractions, or compressions, are the strongest. The compressions form waves that move along the antrum, mixing the chyme and pushing it toward the pylorus, the valve between the stomach and the small intestine.

"With [the virtual stomach], we can study the coordination between the pylorus and the stomach contractions," he said.

Today's stomach

Brasseur said he and Pal started out using a much simpler virtual stomach than the one they work with now. Later, Pal developed the model further, and using more complex geometry, Magnetic Resonance Imaging (MRI) videos and the university's massive parallel computers, created a simulation that had its timing consistent with that of an actual human stomach.

Brasseur also said the virtual stomach only represents one possible situation.

"It is modeled after a particular idealized stomach," he said. "It is a healthy stomach, and the 'person' has just eaten a fairly high caloric meal with high nutrient content."

With the virtual stomach already in operation, it was not long before AstraZeneca contacted the researchers to find out if the simulations could be applied to study the breakdown of extended-release tablets, he said.

Pal then designed a tablet into the simulation, although he said this was a difficult task because it required even more complex geometry.

"The simulations are so huge that [the numerical methods] must be really efficient," Pal said.

With the new simulation, Brasseur and Pal said they discovered that the way a tablet releases its medication is ultimately related to its buoyancy, or its density compared to the density of the fluid in the stomach.

"The tablet's buoyancy drives it to a certain area of the stomach," Brasseur said.

What happens

He said a tablet that is denser than the stomach fluid, called a "heavy tablet," sinks down into the antrum. The vigorous mixing of the fluid caused by the antral muscle compressions drives the tablet forward toward the pylorus and causes friction with the tablet's surface.

As the surface wears away, it allows fluid into the tablet, causing the medication to be released more quickly.

On the other hand, he said a tablet that is less dense than the stomach fluid, called a "floating tablet" or "buoyant tablet," remains in the fundus where it does not experience much mixing. Since there is less friction between the fluid and the tablet's surface, the medication is released only by diffusion, a much slower process.

"What you get is either no drug in the bloodstream or a lot of the drug at one time," Pal said.

Results

Brasseur said the virtual stomach's simulations provided them with results they had not predicted and information they could not otherwise have learned.

"When we programmed the buoyancy of the tablet into the simulation, we made it just slightly different from the buoyancy of the fluid," he said. "We were surprised to learn that this slight difference has such a great effect [on the release of the medication]."

Brasseur and Pal said they concluded that a tablet's buoyancy determines its location in the stomach, which determines the rate at which the medication is released.

"We haven't finished all the experiments yet," Brasseur said. "The information we have is just qualitative; we still have to quantify it."

Still, drug companies can use this evidence to improve the design of extended-release tablets, which was the main objective in the research, he said.

"It will probably be years before AstraZeneca uses [the information], but we've had inquiries from other drug companies as well," he said.

He said they have had a number of abstracts published, and they plan to submit their findings to scientific journals when the research is complete.

Pal presented the results last month in Germany at a meeting of the European Society of Neurogastroenterology and Motility. He received the Society's Young Investigator Award for his work on the project.

The usefulness of the virtual stomach doesn't end there. Brasseur said the model can also be used to study the causes of hunger pains, the way solid and semi-solid foods break down into smaller pieces, and the causes and effects of diseased stomachs.

"The virtual stomach is an evolutionary thing," Brasseur said. "It's like [research] in a laboratory, but instead it's on a computer."