The animated shape on Anupam Pal's computer monitor is quickly recognizable: It's a human stomach, deforming and contracting around a quantity of swirling liquid, and, in this case, a small red sphere. The tumbling sphere leaves a bright green trail, winding out and mixing with the liquid. The sphere is a drug tablet, Pal explains. The trail of green is a pharmaceutical being released.
Anupam Pal
In a still image taken from a cartoon animation, a timed-release tablet breaks down in the "virtual stomach."
The animation was generated from the output of the virtual stomach—a computer model developed by Pal, a postdoctoral fellow in the gastric mechanics research group of James Brasseur, Penn State professor of mechanical and bioengineering. Although the cartoon animation gives a visual picture, the actual model is a much more sophisticated tool, useful for pinpointing how and where in the dynamic environment of the stomach an extended-release tablet—the formulation used for some antihistamines and blood-pressure medications—releases its drug.
We can quantify the forces on the tablet and its breakdown, predict the rate of medication, and analyze the entire process of mixing—including the release of drug into the duodenum, where it is ultimately absorbed into the bloodstream, Brasseur says. You can't measure these details in a real stomach, he adds. Magnetic resonance imaging scans are too blurry, and human and animal experiments are too costly and too unpredictable, since stomach behavior varies from individual to individual. With computer simulation we can control' the stomach. This may be the only way to observe in such fine detail the mechanical processes that cause tablets and food to break down .
As mechanical engineers, Brasseur and Pal are used to thinking about fluid flow and its effects. In aeronautics you specify mathematically the geometry of an airplane's wing or fuselage and then predict the fluid motions around it, Brasseur says. Here, we specify the changing geometry of the stomach and predict the fluid motions inside it—and the effects those motions have on objects such as pharmaceutical tablets. These tablets are designed to release a drug in a controlled fashion, but there is little understanding of how, why, or where this happens.
Pal developed the computer code for the model using a lattice-Boltzmann algorithm that reflects Newton's laws of mechanics, and employing sophisticated equations to specify the stomach's irregular shape and variable movement. He used M.R.I. scans of functioning human stomachs as the basis for the model's geometry and manometric pressure data to validate his code. The model can account for the effects of a pill's buoyancy and the viscosity and density of any food present. Researchers can vary the rate and size of contractions; the coordination of those contractions with the opening and closing of the pyloric valve between the stomach and duodenum; the size, shape and density of the tablet; the orientation of the stomach; and the rate of gastric emptying.
With collaborators at Astra-Zeneca Pharmaceuticals in Sweden, Brasseur and Pal are currently using the virtual stomach to analyze in detail the breakdown of extended-release tablets. As Pal explains, these tablets are designed to remain in the stomach for several hours while slowly releasing medicine. They aren't like gel caps, he says. Their surface doesn't break down quickly. Some extended-release tablets are covered with a silicone membrane to control the rate and time span of drug delivery. Others are designed to simply wear away slowly. These sorts of tablets have been around for some time, he notes, but no one has been able to study them in action until now.
Prior research has shown that, for many timed-release tablets, shear stresses have a greater effect on drug release than chemical dissolution. The virtual stomach predicts the shear stresses from fluid motion on the tablet that cause the tablet's surface to wear away. In the uppermost region of the stomach known as the fundus, these stresses are very low and the tablet experiences little wear. In the more active lower stomach, called the antrum, strong muscle contractions by the stomach wall cause much higher shear stresses, more rapid wear, and faster drug release and dispersal. The research suggests that, to improve their effectiveness, extended-release tablets should be designed to spend just the right amount of time in each of these very different environments.
Brasseur and Pal found that adjusting a tablet's density can alter its buoyancy in a way that controls this important balance. If a tablet is lighter than the stomach's contents, Pal explains, it tends to float to the upper stomach, and remain there for long periods. If the pill is denser than the gastric contents, it will tend to sink to the lower stomach, where intense contractions may break it down rapidly. With more detailed understanding from this research, we hope to learn exactly how altering tablet buoyancy changes the rate of breakdown, drug release, and mixing, Brasseur says. This knowledge could be the basis for improved designs of extended-release tablets in the future.
Pal and Brasseur are also using their virtual stomach to better understand basic gastric function. They're particularly interested in the mechanical consequences of diseases such as gastroporesis and hyperactive stomach, conditions that cause slowed or accelerated gastric emptying. When the release of nutrients into the duodenum is too fast, nutrients cannot be properly digested in the small intestine, Brasseur says. If it is too slow, again the body does not receive enough nutrients.
The current research is in collaboration with Bertil Abrahamsson of AstraZeneca Pharmaceuticals. Abrahamsson's group has been conducting laboratory experiments to measure the rate of mass degradation of extended-release tablets using a stomach-like vessel that is also simulated numerically at Penn State. The two groups have developed a unique approach to combine their experimental and numerical data in a mathematical model that will soon be applied in the virtual stomach.
After five years of development, the virtual stomach has finally come on line as part of a virtual gastrointestinal tract that Brasseur, his research team, and colleagues at other institutions have been developing for nearly 20 years. As a graduate student in Brasseur's group, Pal developed a computer model of the human pharynx. You might say I've moved downstairs, Pal laughs.
Anupam Pal, Ph.D., is a post-doctoral research fellow in mechanical engineering in the College of Engineering, 335 Reber Building, University Park, PA 16802; 814-865-3726; apal@psu.edu. James G. Brasseur, Ph.D., is professor of mechanical and bioengineering in the College of Engineering, 205 Reber Building, University Park, PA 16802; 814-865-3159; brasseur@psu.edu. Their collaborators include Bertil Abrahamsson, Ph.D., of AstraZeneca Pharmaceuticals in Mölndal, Sweden, and Werner Schwizer, M.D., of University Hospital, Zürich, Switzerland. AstraZeneca Pharmaceuticals supports the current gastric research program. Initial funding was provided by Janssen Pharmaceuticals.