Microscopic spheres produced at Brown may revolutionize oral drug delivery

Sticky plastics appear ideal for delivering such compounds as insulin

You swallow some tiny biodegradable beads and they stick tightly to the walls of your small intestine or pass through it. Over time, the beads erode, releasing the drugs they contain into your bloodstream. The system is ideal for delivering medicinal compounds, such as insulin, that can't be taken orally. And it's not a pipe dream.

In the current issue of the journal Nature, a team of Brown University scientists led by Edith Mathiowitz reports the production of drug-filled microscopic polymer spheres that when taken orally enter the bloodstream by crossing the intestinal lining, travel bodywide and degrade, releasing their therapeutic load.

The scientists show that the process dramatically increases the oral effectiveness of several drugs. It suggests a new delivery system for compounds, such as insulin, which until now could not be delivered orally.

In the Nature article, the Brown scientists describe the enhanced absorption of three therapeutic compounds with widely different properties encapsulated in these micro-spheres made of "bioerodible" polymers. The compounds are the anticoagulant dicumarol, plasmid DNA, which is a material used in gene therapy, and insulin, used to treat diabetes.

The micro-spheres are engineered by the scientists from plastics, which become more adhesive to body tissues as they degrade in water. The spheres range in size from 0.1 to 5 micrometers. (One thousand 1-micrometer spheres could fit end to end on a pinhead.) A novel proprietary process developed by the Brown researchers, dubbed PIN for "Phase Inversion Nanoencapsulation," was used to produce the spheres and efficiently enclose the drugs.

In the study, micro-spheres made of these bioadhesive or "sticky" plastics stayed in contact with the intestines longer than spheres made of other materials. The micro-spheres moved through the intestinal wall and between individual cells as early as one hour after being fed to rats. After three and six hours, there was an intense uptake of the spheres by cells lining the intestines, liver and spleen.

The scientists can tailor the release of compounds and the "stickiness" of the polymers for specific applications. After the micro-spheres were given orally to the rats, the scientists found dicumarol first appeared in the bloodstream within two hours and persisted for three days. For insulin, blood sugar levels were reduced within two hours. The plasmid DNA was incorporated into cells of the liver and small intestine and produced an active protein within five days.

Moreover, use of the micro-spheres greatly enhanced the drugs' availability in the bloodstream. For example, the increase in activity of dicumarol could be explained by intestinal uptake of up to 47 percent of the micro-spheres after feeding. Usually, when dicumarol is administered orally, very little of it is absorbed. In the study, the dicumarol also remained in plasma much longer than other forms of the drug orally dispensed to the animals, resulting in improved availability. Insulin and plasmid DNA cannot be administered orally because they are degraded by the harsh conditions of the intestinal tract.

Potential applications of this drug delivery system - to replace therapeutic agents not taken orally today - exist in gene therapy and in the use of vaccines; in treating AIDS, cancer and diabetes; and for delivering medication to inflamed intestines. Proteins, such as insulin, growth hormone and erythropoetin (used to treat anemia) are examples of drugs that would benefit from this new form of oral delivery. The delivery of corrective gene sequences in the form of plasmid DNA could provide convenient therapy for a number of genetic diseases such as cystic fibrosis and hemophilia.

Mathiowitz, an associate professor of medical science and engineering in the School of Medicine, thinks the enhanced absorption relates in part to the small size of the spheres and the adhesive nature of the polymers. The spheres were engineered to stick tightly to and even penetrate linings in the gastrointestinal tract before transferring their contents over time into the circulation system.

"The study indicates uptake of entire micro-spheres by specific cells, particularly absorptive cells of the small intestine," Mathiowitz said. "This allows us to think that a system can be developed to deliver a variety of drugs not normally administered orally." She estimates that system will be created within 10 years, depending on drugs and uses involved.