OREGON STATE UNIVERSITY

OSU researchers develop first time-release, chewable pills

03/31/1998

CORVALLIS, Ore. - Researchers at Oregon State University have developed the first delivery system for sustained or "time-release" drugs that can be chewed, crushed or compacted into tablets.

The university has received notification of patent approval for the breakthrough, which will make it easier and more efficient for children and elderly patients to take certain drugs, according to James Ayres, a professor of pharmacy at OSU and principal investigator in the study.

Ayres said there are about 150 controlled release or extended release drug products on the market and none can be crushed or chewed and remain effective.

"There are a lot of elderly people in nursing homes who cannot swallow time-release capsules," Ayres said. "So they are forced to take medicine four to six times a day which is not only inconvenient, it results in an uneven delivery of the drug product."

Chewable time-release products have never worked because the polymer coating around the drugs which controls their release is broken down when cracked by chewing or crushing. Likewise, chewing the tiny pellets inside time-release capsules is ineffective because it immediately activates the drug agent.

The OSU researchers solved the problem through a unique combination of alternating polymer coatings that surround inner cores of sugar and the drug. Ethylcellulose - the same coating used on bowling pins - is used to control the release rate of the drug. A second "hydrophilic" polymer, polyethylene oxide, forms a gel-like substance that acts like a glue when combined with fluids from the intestinal tract, Ayres said.

When the tablet is chewed, cracks form around the ethylcellulose polymers, then gastric juices inside the body combine with the polyethylene oxide to form the glue-like substance to seal the cracks.

The rate of release can be controlled by the number and thickness of the polymer layers.

In fact, the technology works so well that the time-release mechanisms are effective even when dosages are broken into little pellets that could be sprinkled on food, Ayres said.

Commercial development of the product likely will take four to five years to reach the market. The university must reach an agreement with a drug manufacturer, which will conduct its own research and then seek approval from the FDA before marketing a product. OSU's Office of Technology Transfer is seeking major pharmaceutical firms to license the technology.

For Ayres, the achievement caps a 16-year effort that saw numerous attempts at creating such a revolutionary delivery system show promise, but ultimately fail.

He was not alone.

For years, researchers around the world have attempted to develop a time-release delivery agent that could be chewed or crushed without effecting the efficacy of sustained release. All of those efforts, however, focused on finding ways to keep the polymers from breaking. Some researchers even dabbled with creating flexible polymers, which turned out to release the drugs too rapidly.

"We finally decided that this wasn't an issue of preventing the polymer from breaking," Ayres said. "It's going to break; let it break. We'll just seal it up."

Working with Ayres on the project were Syed A. Altaf, a doctoral student at OSU, and Stephen W. Hoag, an OSU faculty member in the College of Pharmacy who since has moved to the University of Maryland.

Ayres said the delivery system would be advantageous for "short half-life" drugs, or those that clear out of the body quickly, where a sustained release is necessary. Among the possible uses: antibiotics, pain control medicines and fever-reduction compounds.

The system also works on drugs that don't clear out of the body quickly, though it isn't really necessary, Ayres said. Even on those drugs, however, a chewable, sustained release formula can minimize the peak release of the active ingredients and could offset undesirable side effects, like drowsiness, nausea or dizziness.

"Each individual drug needs its own release pattern," Ayres said.

Inspiration for the creation of the new drug delivery system came to Ayres on the highway.

"I was driving down the road thinking of self-sealing tires and wondering how they repair themselves when you get a flat tire," Ayres said. "Do they have some kind of liquid glue that fills the hole and mixes with oxygen to make it seal? I suspect that isn't how it works at all. But it did get me thinking about different ways to approach the problem."

In 1993, an Ayres-led research team developed the first time-release formula for acetaminophen designed for administration to children and infants, an important breakthrough in allowing a sustained release of the fever-fighting drug that lasts as long as 12 hours.