New method of oral insulin delivery patented

Syracuse University researchers have designed, tested and patented a new method of oral insulin delivery that can potentially help reduce daily insulin injections for millions of people with diabetes who require therapy for optimal glycemic control.

The pharmaceutical journal ChemMedChem will publish in its December issue this research conducted by Robert Doyle, assistant professor of chemistry in SU's College of Arts and Sciences; Timothy J. Fairchild, assistant professor of exercise science in SU's School of Education; and Amanda Petrus and Anthony Vortherms, both chemistry graduate students in Doyle's laboratory.

The non-invasive, basal delivery of insulin has been a major goal for the treatment of diabetes mellitus (DM), which affects more than 21 million individuals in the United States. Basal therapy describes a low, continuous dosage of insulin (commonly administered through a slow-acting insulin injection) that replaces the lack of insulin output by the pancreas in diabetics. This works together with bolus therapy, which is a dosage of insulin intended to replace a meal or to make a large glucose-level correction.

Up to this point, basal oral insulin deliveries have not been possible due to proteolytic degradation (digestion of proteins by cellular enzymes) and inefficient enteric uptake, meaning that free insulin delivered orally is never effectively delivered to the bloodstream because it is destroyed as it passes through the gastrointestinal tract (GIT), before it reaches its necessary receptors.

The team of SU researchers has now developed a method of oral insulin
delivery that eliminates the breakdown of insulin in the GIT, allowing for the transport of insulin to the bloodstream. This was accomplished by binding an insulin peptide to vitamin B-12, which acts as a carrier for the insulin and protects it as it is transported through the GIT. Because the insulin peptide is still intact as it enters the blood stream, it can be carried throughout the body as continuously as the B-12 vitamin is. This is a Trojan horse strategy, as the B-12 hides the insulin and carries it across the GIT's “walls.”

Mammals have an active transport mechanism in their GIT for the absorption and uptake of the relatively large vitamin B-12. Because of this, the length of this linkage is optimized so that the biological activity of both the B-12 and the biologically active substance (in this case, insulin) is maintained. At this point in the research, the SU team has focused on one insulin peptide carried by one B-12, which has a residence time in rats of about eight hours. However, they are now investigating whether more insulin can be attached to the B-12, which would provide a longer residence time—optimally 12 hours—so that potentially diabetics could take one insulin pill in the morning, and one at night for greater metabolic control throughout 24 hours.

This basal approach also helps prevent the continuous, unstabilized glucose uptake that is related to the development of metabolic-related complications in diabetics, including retinopathy and blindness, kidney failure, nerve damage, heart disease and stroke. Right now, the only options for this type of basal therapy are multiple injections of pre-prandial, short-acting insulin taken throughout the day. By providing long-lasting insulin analogues through this oral delivery, coupled with an inhalation bolus insulin therapy, diabetics in the future may rely on an entirely non-evasive delivery system for insulin using a basal/bolus regime.

Doyle believes that human investigations into the effectiveness of the team's oral insulin delivery therapy may be a few years away, with new derivatives to be assembled and extensive further testing to be performed. “We have been interested in the oral delivery of insulin and also certain neuro-peptides, and have been exploring a variety of ways to achieve our goals,” says Doyle. “In the case of insulin, we had a hypothesis, we set about testing our hypothesis, and we were rewarded for the effort. Having things go your way doesn't happen in science often enough, so when it does it's very rewarding.”

Fairchild, in collaboration with the team, conducted the testing in diabetic rat models, focusing on the experimental protocol—dosage, methods of blood sampling and frequency—that should be used. “This is a very exciting time in diabetes-related research,” says Fairchild. “There are many research groups approaching potential treatment strategies for diabetes using a number of avenues, but the possibility of having an oral insulin medication has tremendous feasibility, particularly with children and in less-developed countries where sterile needles and adequate training—for injection site and frequency, as well as needle disposal—may not always be available.”

Petrus, a third-year graduate student studying inorganic chemistry in Doyle's lab, served as the principal researcher. This research on oral insulin is her doctoral degree project and will be the bulk of her dissertation, which she will defend in two to three years. She carried out the synthesis of B-12/insulin and is currently working with new derivatives of it to try to gain improvement on its activity. “I am very honored to be contributing to a project with the potential to help people,” says Petrus. “It means a great deal to me that my dissertation will be addressing an issue that touches so many people. Diabetes runs in my family, and several of my friends are dealing with the early stages of the disease.”

“It is great to be a part of something that has the potential to help so many people,” says Vortherms, also a third-year chemistry graduate student at SU. “It is always exciting when you take something and you can do the unexpected with it. That kind of science turns heads and is what gets talked about years down the road.”

The journal, ChemMedChem , called these findings by Doyle, Fairchild, Petrus and Vortherms “pharmacologically and clinically highly relevant.” The article is now available online at ChemMedChem 's website http://www.chemmedchem.com.