PROVIDENCE, R.I.--In the current issue of the journal Nature, a team of Brown University scientists reports the production of drug-filled microscopic polymer spheres that when taken orally enter the bloodstream by crossing the intestinal lining, travel body-wide and degrade, releasing their therapeutic load. The process dramatically increases the oral effectiveness of several drugs. It suggests a new oral delivery system for compounds, such as insulin, which until now could not be delivered orally.
Editors: This news release is distributed in advance of publication for your information only. Please respect Nature's embargo by withholding publication or broadcast until 2 p.m. EST Wednesday, March 26.
The researchers describe the enhanced absorption of three therapeutic compounds with widely different properties encapsulated in microspheres 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 spheres are engineered from biodegradable plastics, which become more adhesive to body tissues as the plastics degrade in water. The spheres range in size from 0.1 to 5 micrometers. For purposes of comparison, one thousand 1-micrometer spheres could fit end-to-end on a pinhead. A novel proprietary process, dubbed PIN for "Phase Inversion Nanoencapsulation," was used to produce the spheres and efficiently enclose the drugs.
In the study, microspheres made of the bioadhesive or "sticky" plastics stayed in contact with the intestines longer than spheres made of other materials. The microspheres 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.
After the microspheres 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 microspheres 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 microspheres after feeding. Usually, when dicumarol is administered orally, very little of it is absorbed. In the study, the dicumarol also remained in plasma for much longer periods 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.
Edith Mathiowitz, who led the study, 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 microspheres 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.
Mathiowitz is an associate professor of medical science and engineering in the Brown University School of Medicine. Other scientists on the Brown team were Jules Jacob, Yong Jong, Gerardo Carino, Donald Chickering, Camilla Santos and four undergraduates. Funding support for the research came from the National Institute of General Medical Sciences in the National Institutes of Health.