Page 215 - Academic Press Encyclopedia of Physical Science and Technology 3rd BioTechnology

P1: ZBU Final Pages
Encyclopedia of Physical Science and Technology EN011J-141 July 31, 2001 15:14

792 Pharmaceuticals, Controlled Release of

degrades in the body. Drug delivery is then controlled by the drug nifedipine, a widely prescribed antihypertensive.
a combination of diffusion and biodegradation. Other important products launched in the last 15 years
include Prilosec, a diffusion-controlled microparticle oral
formulation system for the drug omeprazole, and Lupron
I. INTRODUCTION/HISTORY (leuprolide) and Zoladex (goserelin), polypeptide drugs
delivered from biodegradable intramuscular and subcuta-
The pharmaceutical industry has produced long-acting neous implants. Since the first controlled release product
oral medications since the 1950s. Enteric coated tablets was launched, the controlled release industry has grown
were the first long-acting medication to be widely used. to a $10–20 billion industry with more than 30 major con-
In 1952, Smith Kline French (SKF) introduced Spansules, trolled release products registered with the U.S. Food and
or “tiny time pills,” an over-the-counter cold medication Drug Administration. A time-line showing some of the
consisting of millimeter-sized pills containing the drug important milestones in the growth of controlled release
and covered with a coating designed to delay its disso- technology is shown in Fig. 1. Development of the tech-
lution. By varying the thickness of the coating, different nology has been reviewed in a number of monographs.
drug release profiles were achieved. These early products Controlled slow release of drugs to the body offers sev-
are best called sustained release systems, meaning that the eral important benefits to the patient.
release of the drug, although slower and more controlled
than for a simple, fast-dissolving tablet, was still substan- • More constant drug blood levels. In controlled re-
tially affected by the external environment into which it lease products, drug delivery to the body is metered slowly
was released. In contrast, the release of drug from con- over a long period, avoiding the problems of overdos-
trolled release systems is controlled by the design of the ing and underdosing associated with conventional med-
system and is largely independent of external environmen- ications. These problems are illustrated in Fig. 2, which
tal factors. shows the blood levels achieved when a relatively rapidly
The founding of Alza Corporation by Alex Zaffaroni metabolized drug is given as a series of conventional fast-
in the 1960s gave the development of controlled release dissolving tablets. Immediately after the drug is ingested,
technology a decisive thrust. Alza was dedicated to de- blood levels begin to rise, reaching a peak value, after
veloping novel controlled release drug delivery systems. which the concentration falls as drug is metabolized. In
The products developed by Alza during the subsequent Fig. 2 two important concentration levels are shown: the
25 years stimulated the entire pharmaceutical industry. minimum effective concentration, below which the drug
The first pharmaceutical product in which the drug regis- is ineffective and the toxic concentration, above which un-
tration document specified both the total amount of drug desirable side effects occur. Maintaining the concentration
in the device and the delivery rate was an Alza product, of the drug between these two levels is critical for safety
the Ocusert, launched in 1974. This device was designed and effectiveness. Controlled release systems meter deliv-
to delivery the drug pilocarpine to control the eye dis- ery of the drug to the body at a rate equal to the rate of
ease glaucoma. The device consisted of a thin, elliptical, drug removal by metabolization, so that a prolonged con-
three-layer laminate with the drug sandwiched between stant blood level is maintained. Because controlled release
two rate-controlling polymer membranes through which products use the drug more efficiently, the total amount
the drug slowly diffused. It was placed in the cul de sac required to produce the desired effect is often very much
of the eye, where it delivered the drug at a constant rate reduced, frequently by a factor of 10 or more.
for 7 days, after which it was removed and replaced. The • Improved patient compliance. A second benefitof
Ocusert was a technical tour de force, although only a lim- controlled release formulations is improved patient com-
ited marketing success. Alza later developed a number of pliance. Many studies have shown that few patients take
more widely used products, including multilayer transder- their medications in complete accordance to physician
mal patches designed to deliver drugs through the skin. instructions, and that the degree of noncompliance in-
The drugs included scopolamine (for motion sickness), creases significantly as the complexity of the instructions
nitroglycerin (for angina), estradiol (for hormone replace- increases. In one study of patients given once-per-day es-
ment), and nicotine (for control of smoking addiction). trogen/progesterone contraceptive tablets in a controlled
Many others have followed Alza’s success, and more than fashion, the pregnancy rate was less than 1 per 1000
20 transdermal products, delivering a variety of drugs, are patient-years. The same tablets prescribed to a normal
now available. Alza also developed the first widely used population of women resulted in a pregnancy rate of 50
osmotic controlled release drug delivery systems under the per 1000 patient-years due to noncompliance. Delivery
trade name Oros. The first billion-dollar controlled release of the similar contraceptive steroid levonorgestrel from a
product was an osmotic product, Procardia XL, delivering sustained release implant resulted in a pregnancy rate of