For most of the industrys existence, pharmaceuticals have primarily consisted of simple, fast-acting chemical compounds that are

dispensed orally (as solid pills and liquids) or as injectables. During the past three decades, however, formulations that control the rate and period of drug delivery (i.e., time-release medications) and target specific areas of the body for treatment have become increasingly common and complex. Because of researchers ever-evolving understanding of the human body and the explosion of new and potential treatments resulting from discoveries of bioactive molecules and gene therapies, pharmaceutical research hangs on the precipice of yet another great advancement. However, this next leap poses questions and challenges to not only the development of new treatments but also the mechanisms with which to administer them. The current methods of drug delivery exhibit specific problems that scientists are attempting to address. For example, many drugs potencies and therapeutic effects are limited or otherwise reduced because of the partial degradation that occurs before they reach a desired target in the body. Once ingested, time-release medications deliver treatment continuously, rather than providing relief of symptoms and protection from adverse events solely when necessary. Further, injectable medications could be made less expensively and administered more easily if they could simply be dosed orally. However, this improvement cannot happen until methods are developed to safely shepherd drugs through specific areas of the body, such as the stomach, where low pH can destroy a medication, or through an area where healthy bone and tissue might be adversely affected. The goal of all sophisticated drug delivery systems, therefore, is to deploy medications intact to specifically targeted parts of the body through a medium that can control the therapys administration by means of either a physiological or chemical trigger. To achieve this goal, researchers are turning to advances in the worlds of micro- and nanotechnology. During the past decade, polymeric microspheres, polymer micelles, and hydrogel-type materials have all been shown to be effective in enhancing drug targeting specificity, lowering systemic drug toxicity, improving treatment absorption rates, and providing protection for pharmaceuticals against biochemical degradation. In addition, several other experimental drug delivery systems show exciting signs of promise, including those composed of biodegradable polymers, dendrimers (so-called star polymers), electroactive polymers, and modified C-60 fullerenes (also known as buckyballs). Polymers, polymers, everywhere The earliest drug delivery systems, first introduced in the 1970s, were based on polymers formed from lactic acid. Today, polymeric materials still provide the most important avenues for research, primarily because of their ease of processing and the ability of researchers to readily control their chemical and physical properties via molecular synthesis. Basically, two broad categories of polymer systems, both known as microspheres because of their size and shape, have been studied: reservoir devices and matrix devices. The former involves the encapsulation of a pharmaceutical product within a polymer shell, whereas the latter describes a system in which a drug is physically entrapped within a polymer network. Or, put differently, if a medication is analogous to a piece of solid chocolate, a reservoir device is like a wrapped Hersheys Kiss, and a matrix device is like a chocolate chip cookie.

The release of medications from either category of polymer device traditionally has been diffusion-controlled. Currently, however, modern research is aimed at investigating biodegradable polymer systems. These drug deliverers degrade into biologically acceptable compounds, often through the process of hydrolysis, which subsequently leave their incorporated medications behind. This erosion process occurs either in bulk (wherein the matrix degrades uniformly) or at the polymers surface (whereby release rates are related to the polymers surface area). The degradation process itself involves the breakdown of polymers into lactic and glycolic acids. These acids are eventually reduced by the Krebs cycle to carbon dioxide and water, which the body can easily expel. Early research into biodegradable systems focused on naturally occurring polymers (collagen, cellulose, etc.) but has recently moved into the area of chemical synthesis. Examples of such polymers include polyanhydrides, polyesters, polyacrylic acids, poly(methyl methacrylates), and polyurethanes. As a result of extensive experimentation with these materials, several key factors have emerged to help scientists design more highly degradable polymers. Specifically, a fast-degrading matrix consists of a hydrophilic, amorphous, low-molecular-weight polymer that contains heteroatoms (i.e., atoms other than carbon) in its backbone and is grown either stepwise or through condensation reactions. Therefore, varying each of these factors allows researchers to adjust the rate of matrix degradation and, subsequently, control the rate of drug delivery. In addition to research on carrier systems composed of single polymeric networks, researchers are investigating the properties of block copolymers (networks formed through the joint polymerization of two or more different monomers). These supramolecular networks, when composed of cross-linked combinations of hydrophilic and hydrophobic monomers, are called polymer micelles, and they self-arrange in shell-like structures with their hydrophilic and hydrophobic ligands aligned on opposing sides; in an aqueous medium, the hydrophilic portions form the outer shell. These micelles are only tens of nanometers in diameter and are thus ideally sized for enclosing individual drug molecules. Further, their hydrophilic outer shells help protect the cores and their contents from chemical attack by the aqueous medium in which they must travel. Finally, drug release is achieved via common polymer degradation mechanisms, with the specificity of the delivery (e.g., cell-specific drug targeting) controlled by the synthetic design. For example, micelles containing attached sugar-group ligands have been shown to specifically target glyco-receptors in cellular plasma membranes. Most micelle-based delivery systems are formed from a poly(ethylene oxide)-bpoly(propylene oxide)-b-poly(ethylene oxide) triblock network or a polypeptide and poly(ethylene oxide) combination. The results of these and other micellizations have proved quite promising. For example, in one investigation, researchers at the University of Tokyo, led by Kazunori Kataoka, have investigated the use of micelles as a means of delivering doxorubicin (a hydrophobic anticancer agent). Preliminary results have shown that, when dosed intravenously, the system can withstand the bodys normal blood circulation and effectively deliver the medication to a solid cancerous tumor. Other promising investigations into the use of polymer matrixes as drug transport devices have also been studied. For example, one method uses conducting, electroactive polymers

as a medium-sensing, bioactive molecule-releasing system. Drug delivery with these conducting polymer membranes is achieved through the controlled ionic transport of counterions (dopants) in and out of the membranes. Specifically, redox reactions regulate the necessary electrochemical switching, thus allowing electrostatically entrapped, anionic dopants (such as the biological molecule ATP, which has been investigated for various cardiovascular therapies) to be either retained or released. In fact, initial studies involving a polypyrrole-based polymer membrane have proved quite promising, with results indicating that the drug delivery rate, chemical sensing, and electrochemical triggering can all be synthetically and precisely controlled. Finally, recent research has shown that hydrogel-type materials can be used to shepherd various medications through the stomach and into the more alkaline intestine. Hydrogels are cross-linked, hydrophilic, three-dimensional polymer networks that are highly permeable to various drug compounds, can withstand acidic environments, and can be tailored to swell, thereby releasing entrapped molecules through their weblike surfaces. Depending on the gels chemical composition, different internal and external stimuli (e.g., changes in pH, application of a magnetic or electric field, variations in temperature, and ultrasound irradiation) may be used to trigger the swelling effect. Once triggered, however, the rate of entrapped drug release is determined solely by the cross-linking ratio of the polymer network. An example of a novel drug delivery system In 1997, chemical engineers at Purdue University in West Lafayette, IN, under the direction of Nicholas A. Peppas, reported the synthesis of a glucose-sensitive hydrogel that could be used to deliver insulin to diabetic patients using an internal pH trigger. This system features an insulin-containing reservoir formed by a poly[methacrylic acid-g-poly(ethylene glycol)] hydrogel membrane into which glucose oxidase has been immobilized. The membrane itself is housed between nonswelling, porous molecular fences. Unlike hydrogel systems that release their entrapped drug entities upon swelling, this system works oppositely by shrinking the membrane gates. The exact trigger for this mechanism involves creating an acidic environment around the gel. This is accomplished when a body produces high sugar levels; glucose interacts with the immobilized glucose oxidase in the gates, yielding gluconic acid, which in turn lowers the bodys pH and triggers the gate opening.

An individuals own glucose levels thus determine and direct the insulin delivery. At present, researchers are studying ways to precisely control the drug delivery rate by considering the effects of varying the size of the gates, the concentration of the entrapped insulin, and the rate at which the gates can open and close. Reference: Dorski, C. M.; Doyle, F. J.; Peppas, N. A. Polym. Mater. Sci. Eng. Proc. 1997, 76, 281. During the past two decades, research into hydrogel delivery systems has focused primarily on systems containing polyacrylic acid (PAA) backbones (see box at right for an example). PAA hydrogels are known for their super-absorbency and ability to form extended polymer networks through hydrogen bonding. In addition, they are excellent bioadhesives, which means that they can adhere to mucosal linings within the gastrointestinal tract for extended periods, releasing their encapsulated medications slowly over time. Looking to the horizon Chemists, biochemists, and chemical engineers are all looking beyond traditional polymer networks to find other innovative drug transport systems. Two of the more interesting cutting-edge technologies involve the use of dendrimers (highly branched, globular, synthetic macromolecules) and modified buckyballs to deploy medications capable of providing targeted drug delivery. Dendritic macromolecules make suitable carrier systems because their size and structure can be controlled simply by synthetic means, and they can easily be processed and made biocompatible and biodegradable. In addition, while they can be used to encapsulate individual small drug molecules in the manner of polymer micelles (a unimolecular nanocapsule, if you will), they can also serve as hubs onto which large numbers of drug molecules can be attached via covalent bonds. The practical result of this latter ability, distinct from the micelle-based systems, is that a single dendrimer may transport extremely high densities of drug molecules. To date, these delivery systems remain largely unexplored, but researchers have demonstrated the usefulness of attaching the anticancer agents 5-fluorouracil to polyaminoamine dendrimers and methotrexate to hydrazideterminated dendrimers formed from poly(aryl ether). A team of inorganic chemists led by Lon Wilson at Rice University in Houston, TX, where the C-60, soccer ballshaped fullerene was first discovered, is studying metallofullerene materials (all-carbon fullerene cages that enclose metal ions) for various applications, including the treatment of cancer tumors. In this particular application, the goal is to use selected metallofullerenes to deliver radioactive atoms directly to diseased tissues. The hoped-for result is an increased therapeutic potency and a decreased adverse effect profile for radiation treatments. Fullerenes, in fact, are ideally suited for this goal because of their size and resistance to biochemical attack from within the body. Thus, radioactive atoms

may readily be transported within the balls, and any fear of stray radiation damaging otherwise healthy tissue is minimized. At present, the Wilson group has successfully shown that modified soluble metallofullerenes will preferentially bind to human bone while slowly being cleared from other tissues. (As an interesting side note, the systems may also have application as contrast agents for magnetic resonance imaging because of the presence of an unpaired electron that renders magnetic the as-synthesized metallofullerenes.) A cursory review The technologies described here obviously represent little more than the tip of the iceberg for the development of drug delivery systems, and few of these even extend beyond the realm of benchtop experimentation. Although these approaches are the focus of intense, ongoing research, other processes are also under consideration, including aerosol inhalation devices, transdermal methodologies, forced-pressure injectables, and biodegradable polymer networks designed specifically to transport new gene therapies. Many of these advances are at the very least predicated on the technologies just described. The need for research into drug delivery systems extends beyond ways to administer new pharmaceutical therapies; the safety and efficacy of current treatments may be improved if their delivery rate, biodegradation, and site-specific targeting can be predicted, monitored, and controlled. From both a financial and a global health care perspective, finding ways to administer injectable-only medications in oral form and delivering costly, multiple-dose, long-term therapies in inexpensive, potent, and time-releasing or self-triggering formulations are also needed. The promise of administration methods that allow patients to safely treat themselves is as significant as any other health care development, particularly in developing countries where doctors, clean syringes, sterile needles, and sophisticated treatments are few and far between. Further reading Bodor, N. S. Chemical Aspects of Drug Delivery Systems; Karsa, D. R., Stephenson, R. A., Eds; Royal Society of Chemistry: London, 1996. Eisenberg, A. Bioconjugate Chem. 1998, 9, 564. Han, J. H., et al. J. Agric. Food Chem. 2000, 48, 5278. Langer, R. Macromolecules 1996, 29, 5279. Controlled Drug Delivery: Challenges and Strategies; Park, K., Ed.; American Chemical Society: Washington, DC, 1997. Reynolds, J. R. J. Phys. Chem. B 2000, 104, 4080. Wu, C. Science News 1999, 155, 292.

Cullen T. Vogelson is an assistant editor of Modern Drug Discovery. Send your comments or questions regarding this article to mdd@acs.org or the Editorial Office by fax at 202776-8166 or by post at 1155 16th Street, NW; Washington, DC 20036.

Tomorrow's rural populations may be saved from deadly diseases like malaria, typhoid, and whooping cough with a dose of freezedried medicine painlessly pushed directly into the skin by a friend or family member. UC Berkeley bioengineering professor Dorian Liepmann and postdoctoral researcher Boris Stoeber have developed a microelectromechanical system (MEMS) syringe, the size of a fingernail. MEMS are fabricated cheaply and in bulk using processes similar to those used in manufacturing integrated circuits. Called a chiclet for its resemblance to a square of gum, the MEMS syringe delivers the freeze-dried drug stored inside through up to 100 microneedles. Fortunately, the targeted site in the skin is out of reach of sensitive nerve endings, making the drug delivery completely painless. According to the World Health Organization, malaria kills more than one million people yearly while seventeen million are hit with typhoid. These and other diseases are tough to contain in developing nations where clean water and medical help are scarce. "By finding an alternative way to deliver drugs, we can open the door to more effective treatment of life-threatening illness," says Liepmann, who is also a professor in the Department of Mechanical Engineering. The MEMS syringe is designed to be shipped pre-loaded with a lyophilized, or freeze-dried, drug stored in its silicone rubber reservoir. Keeping the drug in its lyophilized state, Liepmann explains, ensures a long shelf life and negates the need for sterile water or electrically powered refrigerators to cool antibiotics like penicillin that are temperature sensitive once reconstituted.
Boris Stoeber (right) gently presses the MEMS chiclet on Dorian Liepmann's hand, all it takes to deliver a life-saving dose of antibiotics. Stoeber fabricated the 10 mm x 10 mm MEMS syringe prototype in the Berkeley Microfabrication Lab, a project funded by the Defense Research Projects Agency, and Becton, Dickinson & Company. Peg Skorpinski photo

The "shot" is delivered simply by pressing the device against the skin for a few seconds. The dry drug is pushed through the microneedles and into the skin where the body's own interstitial fluids assist in rapidly absorbing the drug directly into the bloodstream.
This neon-lit, transparent microfluidic device, seen here on an inverted stage microscope, allows Stoeber to visualize the route particles travel as they enter a small channel, much like the microneedle channels in the chiclet-sized syringe. Peg Skorpinski photo

"The MEMS syringe will be attractive to developed countries too," Stoeber says. "It could make drugs available that have been avoided because taking them orally causes liver and kidney damage. Drugs delivered through the MEMS syringe would bypass the liver, directly entering the bloodstream." Early stage tests on chicken breast tissues have been successful, and preliminary clinical trials are scheduled for spring at the University of California, San Francisco Medical Center. Someday, the technology could also be used in emergency rooms or in space for astronauts to administer emergency treatments. The fast-and-easy drug delivery system would also be a godsend during a bioterrorist attack when a large number of victims are in need of immediate treatment. "We've proved the principle," Liepmann says. "Now we have to move on to clinical trials with specific drugs the final validation of the drug delivery concept." Melinda Levine contributed to this story.