Researchers closer to delivering new insulin pill for diabetics

August 26, 2001

WEST LAFAYETTE, Ind. -- Chemical engineers are getting closer to developing a method for taking insulin and other medications orally instead of by injection, research that would benefit hundreds of thousands of diabetics in the United States alone.

Purdue University researchers, in findings to be discussed Aug. 26 during a national meeting of the American Chemical Society, have demonstrated that the method works in a chemical environment that mimics the stomach and upper small intestine.

The method might be used to treat insulin-dependent diabetes and other conditions for which medicines, such as insulin, currently cannot be administered orally because they are broken down in the acidic environment of the stomach.

To get around this complication, the engineers have made microscopic particles for drug delivery about a millionth of a meter in diameter, or roughly one-hundredth the width of a human hair. The particles protect medicines from the harsh environment of the stomach until they can be released in the intestines and absorbed into the blood.

In the most recent lab experiments, and in animal research, when the particles enter the less-acidic environment of the upper small intestine they expand and use chemical tethers to latch onto "mucosal" areas and cells that line the intestine.

The tethers serve two roles: They help prevent stomach enzymes from breaking down the particles. And once the particles enter the intestines, the tethers keep the particles anchored long enough for the medication to be released into the upper small intestine, where the medication is absorbed by capillaries into the blood.

"If we don't have these 'anchors' to stick in the upper small intestine and hold the particles for a little while, they will pass through and the medication will never release in the upper small intestine," said Nicholas A. Peppas, Purdue's Showalter Distinguished Professor of Chemical and Biomedical Engineering.

Aaron Foss, a Purdue doctoral student working with Peppas, said it's important to note that the particles would be flushed out naturally by the body's digestive system after releasing their medication.

"The mucosa in the gastrointestinal tract washes out every six to 10 hours," Foss said. "If the particles do permanently anchor to the mucosal lining, the mucosa gets washed out, so there is no permanent effect there.

"This washing out is important because we don't want to have a buildup of material."

The new findings are the result of research in which the particles were tested in a "physiological medium" that mimics the acidity found in the stomach and intestines. The particles remained constricted, protecting the insulin inside, for at least two hours in a highly acidic stomach-like environment. That would be enough time for them to pass from the stomach into the intestines. Then, when the acidity was decreased to a level comparable to the upper small intestine's, the particles expanded, enabling the insulin to escape.

"It worked beautifully," Foss said. "I decreased the acidity after two hours, and suddenly the material opened up and released the insulin out into the solution."

The Purdue research also demonstrated that the particles are not toxic to cells in the intestine.

"This lack of cytotoxicity is a major finding of the new studies because it shows that such particles can be very helpful in the development of oral delivery systems for drugs," Peppas said.

The findings will be discussed during the chemical society's national meeting, which will be from Aug. 26-30 in Chicago.

The system could bring insulin pills and other products to market within a decade, but only if the Purdue researchers can gain private industry support and begin human clinical trials, Peppas said.

About 700,000 Americans suffer from insulin-dependent diabetes, also known as type one diabetes. People who have insulin-dependent diabetes must take insulin, either by injecting themselves with a needle at least twice a day or by using a battery-operated "insulin pump." The pump is worn outside the body on a belt or in a pocket and delivers a steady supply of insulin through a tube that connects to a needle placed under the skin.

Because insulin-dependent diabetes usually afflicts young people, it used to be called juvenile diabetes. About 12,000 children in the United States are diagnosed with the disorder every year.

The Purdue researchers will continue working to improve the system and to learn exactly how insulin is transported from the particles and into capillaries in the intestinal lining, where it is absorbed into the blood, Peppas said.

"We've done animal studies already where we have seen the insulin going into the blood," he said. "But how does it go into the blood? How does it pass through tissues?

"These questions are very important to answer."

In related work at Purdue, researchers have used the system to administer a protein called calcitonin, which is used to treat osteoporosis. The system also might be used for medications used in treating cancer and other diseases.

The researchers are studying particles made of different materials to learn how to improve them.

"We've got something that works right now, but I think we might be able to find something that has more responsiveness to be able to deliver even more insulin than this particular one," Foss said. "So we are changing some parameters, looking at different ratios, looking at different compounds, not completely changing the system but varying different aspects to see if we can optimize it."
-end-
The research is supported by the National Institutes of Health, and the work is being conducted under the auspices of the recently formed Program in Therapeutic and Diagnostic Devices, which is supported by the National Science Foundation and directed by Peppas. The program brings together engineers from a broad range of backgrounds and expertise and was formed to train researchers in the field of biomedical devices, including artificial organs, biomaterials, controlled release devices and tissue-engineered materials.

esv/Peppas.drugdeliver

Writer: Emil Venere, 765-494-4709, venere@purdue.edu

ABSTRACT

Acrylic-Based Copolymers For Oral Insulin Delivery Systems

A.C. Foss and N.A. Peppas

Microparticles and nanoparticles of poly (methacrylic acid-g-ethylene glycol) and poly (acrylic acid-g-ethylene glycol) were synthesized by free radical UV-polymerization. The particles exhibited sensitivity to the pH values and having a much larger swelling ratio at high pH values. The transition point of the materials is close to the pKa values of their respective acid monomers. This behavior was used to create a pH-sensitive oral insulin delivery device. The materials were found to have a low cytotoxicity in contact with Caco-2 cell cultures. Release studies of insulin from the materials proved they would trap the loaded insulin inside the particle at low pH values and then release it once the pH was raised to neutral conditions.

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NOTE TO JOURNALISTS: Electronic or hard copies of the abstract and pre-print of a research paper about this work is available from Emil Venere, 765-494-4709, venere@purdue.edu.

Source: Nicholas Peppas, 765-494-7944, peppas@ecn.purdue.edu
Aaron C. Foss, 765-494-3331, afoss@ecn.purdue.edu

Purdue University

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