Drug delivery devices pinpoint human bodies; inhalers, patches and other devices deliver doses...

One of the most important functions of packaging is making sure that products can get where they need to go and stay intact along the way.

Drug delivery devices perform that function to what might be the ultimate degree. For other packaged goods, the destination is inside a consumer's

Inhalers, transdermal patches, injector pens, implants and other drug delivery systems combine the functions of packaging and medical devices. They both protect the product and administer it to the patient. The most innovative ones have the potential to make the medicine they deliver more effective than ever.

Some of the most exciting advances in drug delivery systems have occurred with inhalers. New designs can help make inhaled medicine significantly more effective and versatile.

One important innovation in inhaler design has to do with the choice of propellants. Aerosol inhalers are one of the few consumer products still allowed to use chlorofluorocarbons (CFCs), which were phased out of almost all other aerosols under the Montreal Protocol, signed in 1987. CFCs were allowed to stay in inhalers because alternative propellants, like butane, were not safe for human consumption. But the clock is ticking; under a rule approved this year by the Food and Drug Administration, CFCs no longer can be used in inhalers after 2008. Inhaler developers are turning to hydrofluoroalkane (HFA) as an alternative.

"It has turned out to be a lot more difficult to shift from CFC propellants to HFAs than first thought, because you essentially have to redesign the aerosol--every component of it," says Peter Lang, a spokesperson for SkyePharma, a pharmaceutical development firm. "Also, drugs tend to behave differently with these propellants than they do with CFCs." Valves, actuators and other components have to be redone to conform to the different characteristics, such as pressure intensity and sustainability, of the new propellants.

Conventional aerosols present more problems than just the choice of propellant. Atomized liquid just isn't the most efficient format to get medicine into the lungs.

"To use that aerosol inhaler, you have to press a button on the top," Lang says. "The device emits a cloud of vapor with the drug in it. You then have to wait a fraction of a second before inhaling. Even if you do that with the best possible timing, only about 20% of the emitted dose gets into the deep lung."

How dry I am

That's a big part of the reason why dry powder applications represent one of the most significant advances in inhalers. Starting with the introduction of GlaxoSmithKline's Advair Diskus, dry powder inhalers have opened new vistas of convenience and versatility in drug delivery. (Production for the Diskus recently was shifted from Europe to the United States. See "GSK breathes easy with new inhaler line" in Food & Drug Packaging, Dec. 2004, p.40.)

The major advantage of dry powder inhalers is their efficiency. Aerosol liquids have to include many times more diluent than medicine: A formulation with 0.5 milliliters of medicine might contain 100ml or more of diluent. Powdered medicine can have a much higher proportion of active ingredient.

The implications for this efficiency extend far beyond the formulation of the medicine. Because powder inhalation is so efficient, it's possible to design delivery systems that carry many times more doses in a single load. Advair Diskus, for example, comes in a version that holds 60 doses in a single unit.

The two most common conditions treated with dry inhalers are asthma and chronic obstructive pulmonary disorder, a term that comprises chronic bronchitis and emphysema. But the efficiency of dry powder inhalers opens up potential applications for new medications.

Perhaps the most prominent new possibility for inhaled medicine is in the field of diabetes treatment. Pfizer is seeking federal approval for Exubera, a inhalable, powdered form of insulin that it fomulated in conjunction with sanofi-aventis. An advisory panel of the Food and Drug Administration voted in early September to recommend approval of Exubera.

Exubera goes with an inhaler device developed by Nektar Theraputics. Its major advantage is that it can be absorbed into the bloodstream quickly without injection, making it a good way to counter meal-related spikes in insulin. Other inhaled-insulin systems are being developed by Aerogen Inc. and MicroDose Technologies Inc.

Patching it up

Transdermal patches represent another interesting field for drug delivery devices. Recently, they've been able to deliver medicine, such as birth control hormones, to the entire system over a long period of time. Now, advances in both patch design and medicine formulation open the possibilities of using patches for more medicines, treating a greater variety of conditions.

Improvements to transdermal patches can involve making osmotic devices, which just sit on the body, into active devices that can force medicine through the skin. For example, Foster-Miller, a product and process equipment design and development firm, helped develop an electro-osmotic dermal patch. Two electrodes in the patch are connected to a tiny battery that discharges through conductive fluids or gels in contact with the skin. This temporarily enlarges the pores of the skin beneath the patch, allowing medicine to pass through.

"If you can get transmission of the drug or the molecules through the skin osmotically, then just a simple patch would be the way to go," says Bob Andrews, Foster-Miller's medical division manager. "But if the molecule is too large to pass through on its own, you can aid it by electro-osmotic delivery or ultrasonics, for example."

Similarly, 3M has developed a microstructured transdermal system that enables the delivery of vaccines without injection. The patch contains thousands of microscopic projections within a very small patch that is coated with vaccine and inserted painlessly into the superficial layers of the skin. Once in the skin, the vaccine is taken up by the immune presenting cells in the skin, provoking a very efficient immune response.

Chicken or egg?

The development of drug delivery systems depends, of course, on the development of the drugs they deliver. In some cases, devices are concocted to accommodate an existing medicine. But pharmaceutical researchers agree that the optimal method is to develop device and medication in tandem.

"Typically, the drug formulation and the delivery device are developed in parallel because they tend to behave as a system," says Tim Peterson, a 3M technical manager. "It is important to optimize the behavior of the total system to get the desired drug delivery performance. Of course, certain aspects of the delivery device do not need to be developed from scratch for each new formulation, such as the valve or canister in an inhalation device or the release liner and backing film in a transdermal delivery device. However, even the components require careful selection or modification to enable optimal performance of the overall drug delivery system."

The future holds out the prospect of ever more ingenious drug delivery devices. Improvements in nanotechnology and other technology areas give new devices the potential for "smart" delivery of medicine inside the human body. These advancing technologies enable targeted therapy and drug delivery. Additionally, advances are being made in time-release and sustained-release systems, which in some cases are being coupled to biofeedback to further improve efficacy.

For instance, a company called MicroCHIPS is developing an implantable microchip consisting of an array of tiny wells, filled with medicine, in a silicone wafer. The wells are covered with gold foil that is inlaid with circuitry. Following a preprogrammed schedule, electrical current disintegrates the foil one well (or multiple wells) at a time, exposing the contents to body fluids and allowing for a systemic, programmable release over a period of time. These chips also have the potential to be converted into sensors that could gauge glucose levels or other body chemistry, says Charles Brunner, a director at Product Genesis, a consulting firm for innovations in medical and other fields.

For more information

The following companies contributed to the research of this article:

3M Drug Delivery Systems

800-643-8086; www.3m.com/us/healthcare/manufacturers/dds

Aerogen

650-864-7300; www.aerogen.com

Foster-Miller

781-684-4000; www.fostermiller,.com

Meridian Medical Technologies

800-638-8093; www.meridianmeds.com

MicroCHIPS

781-275-1445; www.mchips.com

MicroDose Technologies

732-329-2401; www.microdosetech.com

Nektar Theraputics

650-631-3100; www.nectar.com

O-I

419-247-5000; www.o-i.com

Product Genesis

617-234-0070; www.productgenesis.com

Easier injections are the point of new devices

Parenteral (injectable) medicine is a significant growth area in health care, especially home health care, Trends like the aging Baby Boom population and the obesity epidemic will ensure a market for parenteral medications that treat chronic conditions like arthritis and diabetes.

Using a hypodermic needle is a daunting task for many patients. Devices to make the job easier have been around for decades, starting with the auto-injectors that are now standard equipment for insulin administration. A recent embellishment is Foster-Miller's development of an "injector pen" with a dosage dial that turns with an audible click, the better for vision-impaired patients.

Meridian Medical Technologies has recently developed a dual-chambered, single-needle auto-injector for military use. The idea is to help soldiers who are exposed to chemical attack self-administer a two-part antidote without having to carry two injector pens. Meridian is currently working on a dual-chamber pen that will mix dry contents with diluents or other liquids upon injection.

Another military application in development, by Foster-Miller, is a "needleless injector" system. The antidote, or an introductory stream of water, is accelerated to such a high velocity that it punctures the skin by itself, with no needle required.

As with many products, plastic is preferable to glass for injection devices because of its lighter weight and lower liability of breakage, Several years ago, O-I commercialized a multi-layer plastic called MLx for pharmaceutical vials; it is now developing that technology for pre-filled syringes.

MLx combines different resins, including polycarbonate, nylon and cyclic olefin copolymer (COC), in configurations customized to a given medicine's needs for oxygen and moisture barrier. Using MLx for syringes would make pre-filling safer and more reliable. O-I plans to have a commercialized application of MLx syringes ready by the end of 2006.