New Ways to Deliver Drugs

by Food and Drug Administration (FDA)

If, 25 years ago, someone tried to sell you an adhesive patch, telling you to stick it behind your ear and it would keep you from getting sick on the high seas, you could make a safe bet that you were being sold up the river by a modern-day snake oil salesman.

Today, however, a similar patch can be legitimately prescribed by your doctor. Technological advances over the last 20 to 30 years have enabled scientists to develop new forms of delivering drugs to our bodies, including a transdermal patch containing the drug scopolamine to prevent motion sickness.

Drug dosage forms are keeping pace with the high-tech times. Indeed, the ubiquitous tablet of 1990 may one day become obsolete, going the way of the spirits, powders and tinctures of a century ago.

What might replace the tablet? How about pills that are pumps and implanted drug-filled devices with or without tiny computers to regulate the time and amount of drug dispensed? These and other unconventional dosage forms already exist, heralding advances in drug delivery that promise even safer and more effective treatments.

One of the most active areas of research and development in drug delivery involves "controlled-release" products. Rather than develop new drug entities at great cost, some drug therapies already on the market can be improved simply by controlling the rate at which they enter the bloodstream.

"Virtually all the delivery systems marketed are initially in what we would call 'immediate-release preparations' — things that disintegrate and dissolve in 5 or 10 minutes," says FDA visiting scientist Gordon Amidon, Ph.D. "For some drugs, dissolution may take longer because of drug or dosage form properties, but the controlled release is not designed in."

Timing Is Everything

"Drugs that are released rapidly produce a relatively rapid and high concentration in the body, followed by a sharp decline — a peak and valley effect," says Amidon. "We know that at too low a blood level the drug is not effective, at optimum level it's effective, and at too high a level undesirable effects are produced. The objective is to try to maintain the range in between."

Controlled-release systems deliver a drug at a slower rate for a longer period. The dosage form contains more drug than a conventional tablet or injection, for example, but delivers the medication far more slowly — over a period of hours, days, or even years, rather than seconds or minutes.

Depending on the mechanism, the delivery system may simply release the drug at a variable, but slower, rate, or release it at a constant rate over the period of release. Sometimes, by decreasing the variability of blood levels, it may reduce side effects.

The Ways to Delay

Milo Gibaldi, Ph.D., dean of the University of Washington's School of Pharmacy in Seattle, writes in Biopharmaceutics and Clinical Pharmacokinetics: "The early history of the prolonged-release oral dosage form is probably best forgotten. Products were developed empirically, often with little rationale, and ... problems were common. Today, the situation has improved; many of the available products are well-designed drug delivery systems and have a defined therapeutic goal. In some cases, the prolonged-release dosage form is the most important and most frequently used form of the drug."

Prolonged-release preparations usually require less frequent dosing. Being able to take a pill once a day instead of four times or more, for example, can help improve patient compliance. That is, it's often easier and less bothersome for patients to remember to take fewer doses of medications.

There are a number of ways of controlling the rate of delivery of oral medicines. One system uses the principle of osmosis to release the drug. The drug and an osmotic agent are surrounded by a semipermeable membrane pierced by one or more small, laser-drilled holes. As water from the digestive tract is drawn through the membrane, the osmotic layer expands, pushing the drug through the holes.

In other systems, the drug simply diffuses through a polymer coating of the pill. The drug may be contained in a reservoir surrounded by a polymer film, or it may be uniformly distributed through the polymeric material.

"Most of the polymers used in human pharmaceuticals are derivatives of natural products such as gelatin and cellulose, or the synthetic polymer silicone," says Amidon. "When designing a drug delivery system, you select the polymer best suited for that particular system based on the properties of the specific polymer."

An erosion-controlled release system uses a polymer that is relatively water-soluble with the drug incorporated in it. As the polymer dissolves, it releases the drug. The formulation of Contac's "tiny time pill" capsules is based on an erosion system. It consists of coated and uncoated granules that erode at various rates, thus releasing the drug at varying rates and providing relief for an extended period.

Skin Patches

Some drugs that have the right properties to penetrate the skin and are potent enough to be effective at low doses can be delivered transdermally (through the skin). The first transdermal patch was approved by FDA in 1979. It contained the drug scopolamine, used to treat motion sickness.

Scopolamine can cause dry mouth, drowsiness, blurred vision and other eye problems, and sometimes more serious side effects, including dizziness and confusion, hallucinations, difficulty urinating, and rashes. Delivered through the skin at a slow rate in small amounts over three days, however, the drug can protect against motion sickness with fewer or less severe side effects.

One patch design consists of four layers of thin, flexible membranes: an impermeable backing, a drug reservoir, a rate-controlling membrane, and an adhesive. When the patch is applied, the drug begins flowing through the skin into the bloodstream at a rate regulated by the membrane, pre-programmed to keep the drug at levels that provide effectiveness with acceptable adverse effects.

Another transdermal preparation is a nitroglycerin patch for patients with angina pectoris (chest pain). Unlike nitroglycerin tablets placed under the tongue at the onset of an attack to relieve pain, the patch is applied once a day (usually to the chest) to help prevent angina attacks. As with scopolamine, a goal of delivering a steady concentration of nitroglycerin was to provide the lowest effective blood level of the drug while minimizing adverse effects, such as headaches in the case of nitroglycerin.

About the Author

www.fda.gov
FDA is A United States government body that oversees medical devices, including contact lenses, intraocular lenses, excimer lasers and eyedrops. In the US, these products must be approved by the FDA before they can be marketed.