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Encyclopedia of Physical Science and Technology EN011J-141 July 31, 2001 15:14

Pharmaceuticals, Controlled Release of 799

The leading developers of oral drug delivery formu-
lations are Alza and Elan. Other important producers
are Skyepharma, which has developed a technology
called Geomatrix (a multilayer tablet with each layer
releasing the drug at a different rate), R. P. Scherer, which
has several different technologies including Zydis (a
lyophilized tablet), and Eurand, with several technologies
for controlled release, taste masking, and improved
bioavailability.

B. Transdermal Systems

Scopolamine, for control of motion sickness, was the first
drug to be marketed in the form of a transdermal patch
system. Since then the market for transdermal patches
has grown steadily. However, the number of drugs that
can be delivered through the skin is more limited than
was anticipated when the first patches were introduced in
the 1980s. The main problem limiting widespread use is
the low permeability of most drugs through the skin. De-
pending on the drug, skin permeabilities are in the range FIGURE 9 Transdermal patch designs.
2
0.01–10 µg of drug/cm · hr. Because the maximum ac-
ceptable size of a transdermal patch is limited to about
2
50 cm , drugs delivered through the skin must be effec-
tive at doses of 0.01 mg/day for a poorly skin-permeable The third type of device is the reservoir system (Fig. 9,
drug and 10 mg/day for a highly skin-permeable drug. bottom). In this case, the drug—usually in liquid or gel
Very active skin-permeable drugs are required to make form—is contained in a reservoir separated from the skin
transdermal drug delivery possible. Despite the enormous by an inert membrane that controls the rate at which drug
interest in transdermal delivery in academia and industry, is delivered to the skin. These devices offer an important
the number of drugs delivered transdermally is currently advantage over the monolithic geometry: as long as the
limited to nitroglycerin, nicotine, estradiol, clonidine, fen- drug solution in the reservoir remains saturated, the drug
tanyl, testosterone, and isorbide nitrate. Nitroglycerin and release rate through the membrane is constant.
nicotine are currently the most important drugs, but the The pattern of drug release from the device is important.
area of hormone replacement therapy is growing as a result If drug is delivered to the skin at less than the maximum
of improved estradiol and testosterone delivery patches. rate at which it can be absorbed, the device is the primary
The three main types of diffusion-controlled transder- dosage-controlling mechanism. When the drug is deliv-
mal devices are shown schematically in Fig. 9. The simple ered faster than the skin can absorb it, the skin surface is
adhesive device (Fig. 9, top) has a two-layer “Band-aid” then saturated with drug at all times, and the limiting fac-
configuration comprising the backing layer coated with tor for systematic dosage is the rate of absorption through
adhesive. The drug is mixed in the adhesive layer used the skin. Thus, at least in principle, devices for which the
to fix the bandage to the skin. These medicated bandages dosage-controlling mechanism is either the skin or the de-
bring a known quantity of drug to a known area of skin vice can be designed.
for a known period of time, but have no mechanism for To reach the systemic blood circulatory system, drug
controlling the rate at which the drug is delivered to the from a transdermal patch must cross several layers of skin,
patient. as shown in Fig. 10. The top surface layer of skin, called
Thesecondtypeofdeviceisamonolithicsystem(Fig.9, the stratum corneum, represents the main barrier to drug
middle) incorporating a backing layer, a matrix layer, and permeation. The stratum corneum is only 10–15 µm thick,
an adhesive layer. The matrix layer consists of a polymer but it consists of layers of flattened, cornified cells that are
material in which the solid drug is dispersed; the rate at quite impermeable. The interspace between these cells
which the drug is released from the device is controlled is filled with lipids, giving the structure a “bricks-and-
by this polymer matrix. With this type of system, the drug mortar” form, with the cells being the bricks and the lipids
release rate falls off with time as the drug in the skin- being the mortar. The most important pathway for drug
contacting side of the matrix is depleted. absorption is through the lipid (mortar), which dictates