Originally Published MPMN April 2008

SPECIAL FEATURE: DRUG DELIVERY

Injecting New Ideas into Drug-Delivery Systems

Advancements in active drug-delivery technologies hold promise for precisely controlled, targeted treatments

To get effectively from point A to point B, you need a safe and reliable mode of transportation. If your brakes are shot or your radiator is on the fritz, a faulty vehicle can break down and leave you stranded on the side of the road. Likewise, drug-delivery devices are the vehicles ensuring that critical treatments safely reach their destinations and their reliability is equally—if not more—important. Because if these delivery systems fail, you may find yourself in a dire situation where even AAA can’t help.

Luckily, drug-delivery technology appears to be advancing at a rapid clip. Baby boomers with longer life spans are placing a demand on the drug-delivery market for products that are convenient, safe, targeted, and user-friendly. Furthermore, a distinct trend toward home care and self-administration, as well as a more vocal and involved patient base, are requiring that drug-delivery OEMs step out of their comfort zones. Heeding these demands, researchers are delving into new territories as they strive for targeted and controlled-release drug delivery through innovative active systems.

At the Microscale

Microelectromechanical systems (MEMS) technology has influenced seemingly every aspect of the medical product realm, and active drug-delivery systems are no exception. MEMS enable low power consumption, reproducibility, cost-effectiveness, precise control, and, of course, miniaturization.

Pioneering MEMS work in drug-delivery applications is MicroChips (Bedford, MA; www.mchips.com), an MIT spin-off that has blazed a path in intelligent drug-delivery systems. The company demonstrated that it is possible to actively control the release of drugs in the body over a prolonged period using an implanted microchip and wireless technology.

Striving for the creation of a device that could both protect a therapy and keep it stable for long periods of time, the company engineered a microchip featuring an array of drug-containing silicon reservoirs. Depending on the prescribed dosage, an external control can trigger active release of the drug at desired intervals using MEMS electronics, according to Maggie Pax, vice president of business development. She stresses that the ability to change the dosage and the timing from the chip is the core technology on which the company thrives.

“You can take all the benefits of microarrays, MEMS, electronics, and small-scale manufacturing and you can combine that with the pharmaceutical world,” Pax says. “These things never come together; they’re really different worlds. To take the drug formulation from what we could do in the pharmaceutical area and marry that with MEMS, and do an in vivo study that actually worked was very much a breakthrough.”

The company’s initial system is designed to deliver a parathyroid hormone to treat osteoporosis. In order to be effective and build new bone, the drug must be delivered daily in a precisely controlled pulse, Pax says. But, if the drug trickles out of the system instead, bone can be resorbed—a dangerous consequence. Through its controlled delivery capabilities, the MicroChips systems can help build bone in people who may otherwise have to undergo daily injections.

In addition to developing its own drug-delivery systems, MicroChips can apply some of its packaging, hermetic sealing, and control mechanisms to existing OEM products. “For most people, there’s not an ability to think about working with highly concentrated doses of drugs in very tiny reservoirs and being able to fabricate those in a way that is repeatable and reliable,” Pax says. She points out that orthopedic devices could benefit from therapeutic capabilities made possible by the company’s technology. Controlled drug delivery in these instances can aid in healing, reducing local pain, or minimizing infection potential. The reservoir system also allows for controlled release of multiple therapies.

On the Surface

Researchers at Massachusetts Institute of Technology (MIT; Cambridge, MA; www.mit.edu) have redefined the use of thin films in drug delivery by turning a traditionally passive approach into an active one. Using layer-by-layer deposition techniques, the team engineered degradable thin films that enable controlled drug delivery.

“You build up a film literally one molecular layer at a time,” explains Kris Wood, a postdoc at the Whitehead Institute (Cambridge, MA; www.wi.mit.edu) who began this project as an MIT graduate student. “As a consequence, you can very precisely control the properties of the films that result, such as thickness, surface properties, porosity, and chemical groups present.”

Working along with Paula Hammond, a professor of chemical engineering at MIT, Wood sought to apply this established technique to drug-delivery applications. To do so, the team incorporated the pigment Prussian blue as a component in the film, alternating layers of a drug and the compound. In the presence of an applied voltage, the pigment undergoes a redox state change and, as a result, the film destabilizes. “The film’s integrity is based on the charge interaction,” Wood says. “And, if you suddenly take that away, the film has no reason to stick together anymore and bursts apart.”

The researchers envision coating these films onto an implantable material and attaching it to a radio-frequency (RF) detection device and battery. A physician or remote operator could trigger controlled release of the drug embedded in the film by simply pressing a button that would start a chain reaction. Activating this remote control would theoretically send a signal to the RF detector, which would then prompt the battery to turn on, resulting in the application of the voltage and, consequently, the release of a layer of the drug, according to Wood.

Electrochemically activating a drug-delivery system coated onto a device could be beneficial for a number of applications, including stents, knee implants, sutures, and a range of controlled-release therapeutic devices. Wood cites the treatment of diseases that require irregular dosing—such as Parkinson’s disease—as potential areas in which this type of system could enhance treatment.

But this is not the first time that drug-delivery systems have been able to release drugs in response to a remote signal. During the past seven or eight years, researchers have developed microchip-based systems, using lithographic processes to create gold-coated silicon reservoirs whose coating dissolves when exposed to a voltage, Wood notes. Furthermore, companies such as MicroChips are making progress in remote activation of reservoirs as well. Despite the potential for these systems, Wood points out that it is difficult to machine nonplanar surfaces—which is the case for most implants. The MIT team’s film, however, can be coated onto any surface, as well as any size, shape, or chemical composition.

Through the Skin

Skin, the largest organ in the human body, acts as a protective barrier, shielding our bodies from harm. Yet it also serves as an obstacle that must be overcome in order to effectively treat patients.

The term transdermal drug delivery encompasses a range of drug-infused patches, perhaps most notably represented by the nicotine patch that helps wean smokers off of their addiction. Transdermal products serve as effective means of passively introducing many small-molecule treatments into the body without the physical or emotional discomfort associated with squirm-inducing injections. Painless delivery methods can increase patient compliance—an important attribute as self-administration and home care slowly become more widespread. However, this drug-delivery method faces distinct limitations because large-molecule drugs cannot permeate the skin and must usually be injected instead.

Recent university research may influence the future of drug delivery, however. A great deal of research has centered on overcoming the limitations of transdermal drug delivery through the use of microneedles. Microneedle arrays assembled on patch technology allow active delivery of many large-molecule drugs by creating micropores in the skin through which the drugs can pass into the body.

Hypodermic needles, for example, inject large-molecule drugs into the body by penetrating beyond the 10- to 20-µm-thick outer layer of the skin called the stratum corneum. However, hypodermic needles can cause pain because they cross beyond the outer layer of the skin and hit nerves located in the inner layers of the skin and in deeper tissue. Microneedles, on the other hand, are so small that they are virtually painless. Typically measuring several hundred microns at the base and tapering to a tip with a radius of curvature of 10 µm, microneedles are just large enough to pass through the stratum corneum, but not long enough to disturb nerves, according to Mark Prausnitz, a professor at the Georgia Institute of Technology’s School of Chemical and Biomolecular Engineering (Atlanta; www.gatech.edu).

“Once you get most drugs across that layer and into the next layer, the viable epidermis, the drugs can then diffuse their way into the bloodstream and you’ve achieved systemic delivery of the drug,” Prausnitz explains. Prausnitz and his team at Georgia Tech, in collaboration with researchers at the University of Kentucky (Lexington, KY; www.uky.edu), demonstrated that microscopic needle-based patches can facilitate transdermal delivery of drugs that cannot pass through the skin in what is believed to be the first peer-reviewed study of its kind.

In this study, the researchers pressed a small patch containing 50 stainless-steel microneedles into the skin of human test subjects to create micropores. Then, they applied a gel containing naltrexone, a drug that is too large to be absorbed through the skin, to the micropore site and covered it with a protective dressing. Monitoring the drug in patients’ bloodstreams for 72 hours, the team found that the microneedles were successful; levels of the drug reached pharmacologically active concentrations.

Feeding off of the advancements made in MEMS technology, early research used silicon-based microneedles. But silicon proved to be fragile and the needles were prone to breakage. Further deterrents were the cost and lack of established safety in medical products. Other material options were explored because the semiconductor properties of silicon were not necessary for microneedles. Prausnitz’s team settled on stainless steel owing to its reputation for being biocompatible, inexpensive, and strong.

With both universities and companies exploring the possibilities of microneedles, Prausnitz predicts that the first microneedle-based drug-delivery systems could hit the market within the next few years, and, within 5 to 10 years, companies could be offering multiple microneedle products. He notes that although there are no approved microneedle drug-delivery systems on the market yet, Becton Dickinson, in collaboration with Sanofi Pasteur, is making strides with millimeter-scale needles, which are in Phase III clinical trials for an influenza vaccine and have been submitted to European regulatory authorities.

“The reason why microneedles have come of age now, I think, has to do with a number of factors, one of which is that the technology has been advanced in large part by the microelectronics industry, spinning off from the Intels and Motorolas of the world and adapting that technology to enable the fabrication of microstructures,” Prausnitz posits. “And, the increasing recognition that the intersection of engineering and medicine is a valuable one is a nice example of how engineering tools can be brought to a medical problem and offer a solution.”

Copyright ©2008 Medical Product Manufacturing News