A little bit of polysaccharide helps the medicine go down
By Morgan Johnson, Lynn Davis, and Kara Williams, College of Natural Resources
It used to be that patients with HIV had to carry around a cooler of medications so they could take the frequent doses necessary to get through the day.
Drug delivery has come a long way since then. For instance, now many HIV patients can take one pill a day, thanks to the development of better drugs and delivery systems. However, despite modern advances, there are still patients who are suffering needlessly, says Kevin Edgar, professor in the College of Natural Resources' Department of Wood Science and Forest Products.
Cancer treatments provide painful examples of drug delivery problems. The poor solubility and toxicity of the active ingredient in the drug paclitaxel (Taxol), for instance, mean that the drug must be administered slowly by IV. Treatments take up to eight hours, and there is the danger that the patient will experience an allergic reaction. Edgar expresses the frustration of many when he says, “I think it’s tragic that very ill patients still have to go through treatments like this. I want to change that.”
Before joining the Virginia Tech faculty in 2007, Edgar and his colleagues at Eastman Chemical Company in Kingsport, Tenn., did research to improve the delivery of tamoxifen, an important therapeutic for the prevention of breast cancer recurrence, and the HIV drug saquinavir, so the drugs can be better absorbed by patients. He continues to work on antiviral drugs with researchers at Purdue University and on systems for improved delivery of anticancer compounds.
Edgar and his Virginia Tech colleagues also have close collaborations with other groups in the U.S. and Europe, including Rensselaer Polytechnic Institute of New York, the Complex Carbohydrate Research Center at the University of Georgia, and others from the Royal Institute of Technology in Stockholm, the University of Frankfurt, and the University of Jena. “The complementary biopharmaceutical expertise helps advance our research and provides excellent cultural experiences for our students,” he says.
“I think it’s tragic that very ill patients still have to go through treatments like this. I want to change that.” -- Kevin Edgar
Edgar’s magic ingredient to improve medicine is polysaccharides from such natural sources as trees, corn stalks, sugar cane, cotton, and sea shells. Polysaccharides are complex carbohydrates made up of many sugars joined by glycosidic bonds. Examples of these natural polymers are starch, cellulose, chitin, and molecules from human tissue, such as heparin. Nature connects a variety of carbohydrates into linear or branched structures that perform functions as diverse as providing strength to trees and nutrition to mammals, preventing blood clots, and guiding the development of the human nervous system. “To exploit the usefulness of polysaccharide derivatives in drug delivery, I need to understand how polysaccharides work in nature,” Edgar says.
“Nature has provided us with a wide variety of beneficial polysaccharides and derivatives; a rich and varied source of materials that can enhance the safety of pharmaceutical formulations,” he wrote in a guest editorial for a special issue of the journal Cellulose on polysaccharides in drug delivery. “Physicochemical properties may be finely tuned (to achieve) a particular delivery system to meet the diverse needs of different molecular entities for delivery by suitable routes to the human body.”
Today, polysaccharides are used in drug delivery in many ways and have become essential to drug development. As part of a pill, the polysaccharide helps move the drug from the gastrointestinal (GI) tract into the bloodstream and can control release times. Some medications are extended release, meaning the drug is released into the body slowly, so patients can take a pill once a day instead of once every few hours. Convenience is an important element of successful treatment, Edgar says. In the Cellulose editorial, he also identified site specificity as a critical goal so that medications will do the most good with the fewest side effects. But the first challenge is enhancement of drug solubility, and thus bioavailability.
“Almost half of possible new drugs in clinical trials fail due to poor solubility,” he says. A successful drug must dissolve, permeate the GI membrane into the bloodstream, and avoid the body’s protective mechanisms that would transport the drug out of the body, or metabolize it so it can be more easily excreted.
“If a 100-mg pill is only 10 percent bioavailable, as is the case with a number of medications, then only 10 mg of the drug enters the bloodstream. The remaining 90 mg can cause side effects or be excreted and end up in the environment, where it may impact plants and animals,” Edgar says.
Poor bioavailability also causes variability between people, or between dosage times for one person. “It’s important that doctors know what dose to prescribe, that the medications work for everyone, and whether the patient should take the pill before bed on an empty stomach, with a salad at lunch, or with a steak or a burger and fries in the evening. High bioavailability makes sure that drugs and their delivery systems perform the same way every time,” Edgar says.
Thus, he and his students are researching combinations of polysaccharide derivatives and drugs to discover solutions to overcome poor solubility and enhance drug performance.
Developing the drug delivery system begins by synthesizing polysaccharides. Before they are dissolved in a liquid or compounded into a powder to be used in the pill production process, polysaccharides are modified by attaching benign chemical groups to them, like ornaments on a tree. A suitable method is then developed for combining drug and polysaccharide; sometimes as simple as mixing and pressing a pill, sometimes more complex techniques, such as freeze-drying. Tailoring the polysaccharide to the drug in this way, they can work together to form a drug delivery system that works for the patient.
“We modify natural polysaccharides to be compatible with the target drug, to release it at the right pH, and to enhance its solubility, all while taking great care that the modified polysaccharide is itself entirely nontoxic,” says Edgar.
“In order to select the target drug, we need to know which drugs have problems; which have low bioavailability, which have toxic side effects, and which would benefit from our polysaccharide derivatives.”
At Virginia Tech, Edgar’s group decides what they want to improve. For example, they may choose once-a-day delivery as their focus to improve patient convenience. Edgar jokes, “I like to backpack, and it would be really great to have a once-a-day version of ibuprofen to treat those hiking aches and pains.”
Often Edgar’s research students find that by incorporating the drug into a polysaccharide matrix, they can improve drug bioavailability. “The combination reduces the natural crystallinity of the drug, making it easier to dissolve,” he says.
The students test many drug-polysaccharide matrices to come up with the desired solubility performance. By understanding the properties of the drug, Edgar’s students can then predict whether high solubility will guarantee high bioavailability; their prediction will be tested later in the development process. “It’s all about designing the right biomacromolecule to accomplish what we want,” Edgar says.
The matrix results are evaluated and analyzed. Understanding what worked with one compound and why helps scientists develop the ability to predict what will work next time, and solve the next problem better and faster.
The last step is to find out how well the system will work in the much more complex living systems, including in people. To do this, Edgar’s group collaborates with partners ranging from the Virginia-Maryland Regional College of Veterinary Medicine to medical schools, including the new Virginia Tech Carilion School of Medicine and Research Institute in Roanoke. The process of improving drug delivery culminates with the approval of the Food and Drug Administration (FDA).
There are three steps to the FDA approval process, which begins only after the drug has been found to be safe and effective in appropriate animal models. The first step is to run a small safety trial of the drug and delivery system on a small sample of human volunteers. Several variables are tested and monitored, such as the impact of different doses on the patient. The side effects are closely monitored to ensure that the new system is an improvement to the existing drug and does not cause unexpected harm to the patient. The second step to FDA approval is a small efficacy test to determine whether or not the drug will work and to compare it with the best therapy currently available.
The third step is a large efficacy test to prove that the drug is effective on a large population of varied ages, races, and medical conditions. For example, the drug needs to safely provide the same benefit to a 50-year-old, 100-pound Caucasian woman as to a 20-year-old, 160-pound African-American man. Side effects and interactions with other drugs are closely monitored, and the results are used to determine safe dosage, drug interactions to be avoided, and any limitations on who should take the medication.
Edgar’s goals are to increase the pipeline of effective drugs for the treatment of serious illnesses, replace injections with pills where possible, reduce dosages to once a day, eliminate dangerous and unpleasant side effects, and increase patients’ health.
“I hope my work will make drug taking more effective, safer, and convenient for patients,” Edgar says.