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

Pharmaceuticals, Controlled Release of 793

FIGURE 1 Milestones in the development of controlled release pharmaceuticals.

0.5 per 1000 patient-years. This product has the lowest delivered directly to the systemic blood circulation from a
pregnancy rate, that is, the highest degree of contraceptive transdermal patch, a delivery rate of only 50 µg of estra-
efficiency, of any steroidal contraceptive because it elim- diol/day is sufficient to achieve the required effect.
inates poor patient compliance, the principal reason for
drug failure. II. METHODS OF ACHIEVING
• Targeted site of action delivery. A final benefit of con-
CONTROLLED RELEASE
trolled release formulation is the ability to deliver drug
directly to the systemic circulation. Drugs taken orally are
A. Membrane Diffusion-Controlled Systems
absorbed into the blood stream in the gastrointestinal (GI)
tract. The drug then enters the portal circulation, so is first In membrane diffusion-controlled systems, a drug is
taken to the liver before entering the systemic circulation released from a device by permeation from its interior
and being transported to the site of drug action. The liver’s reservoir to the surrounding medium. The rate of diffusion
function is to deactivate toxic agents that enter the body of the drug through the membrane governs its rate of
through the GI tract. Unfortunately, the liver often treats release. The reservoir device illustrated in Fig. 3 is the
drugs as toxic agents and metabolizes a large fraction be- simplest type of diffusion-controlled system. An inert
fore the drug reaches the blood circulatory system; this is membrane encloses the drug, which diffuses through the
called the first-pass effect. For example, in the first pass membrane at a finite, controllable rate. If the concentration
through the liver, 70–90% of the hormone estradiol is lost. of the material in equilibrium with the inner surface of the
Therefore, when used for hormone replacement therapy, it enclosing membrane is constant, then the concentration
must be administered as tablets of 1–2 mg/day to achieve gradient, that is, the driving force for diffusional release
effective systemic blood levels. When the same drug is of the drug, is constant as well. This occurs when the inner