Page 220 - Academic Press Encyclopedia of Physical Science and Technology 3rd BioTechnology

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

Pharmaceuticals, Controlled Release of 797

membranes, that is, membranes permeable to water but ter raises the hydrostatic pressure inside the tablet slightly.
completely impermeable to the osmotic agent. However, This pressure is relieved by a flow of saturated agent so-
this is a good approximation for most membranes. Sub- lution out of the device through the small orifice. Thus,
stituting Eq. (11) for the flux across the membrane gives the tablet acts as a small pump, in which water is drawn
osmotically into the tablet through the membrane wall and
A θ πc
dM t
= . (12) then leaves as a saturated drug solution through the ori-
dt l
fice. This process continues at a constant rate until all the
The osmotic pressure of the saturated salt solution is high, solid drug inside the tablet has been dissolved and only a
on the order of tens of atmospheres, and the small pres- solution-filled shell remains. This residual dissolved drug
sure required to pump the suspension of active agent is continues to be delivered, but at a declining rate, until the
insignificant in comparison. Therefore, the rate of water
osmotic pressures inside and outside the tablet are equal.
permeation across the semipermeable membrane remains
The driving force that draws water into the device is the
constant as long as sufficient solid salt is present in the
difference in osmotic pressure between the outside en-
salt chamber to maintain a saturated solution and hence a
vironment and a saturated drug solution. Therefore, the
constant-osmotic-pressure driving force.
osmotic pressure of the dissolved drug solution has to
Variations of the Rose–Nelson pump have been devel-
be relatively high to overcome the osmotic pressure of the
oped as tools for drug delivery tests in animals. How-
body. For drugs with solubilities greater than 5–10 wt%,
ever, the development that made osmotic delivery a major
this device functions very well. Later variations on the
method of achieving controlled drug release was the in-
simple osmotic tablet design use water-soluble excipients
vention of the elementary osmotic pump by Theeuwes in
to provide part of the osmotic pressure driving force; this
1974. The concept behind this invention is illustrated in
overcomes the solubility limitation.
Fig. 8. The device is a simplification of the Rose–Nelson
pump, and eliminates the separate salt chamber by using
the drug itself as the osmotic agent. The water required III. IMPORTANT CONTROLLED
to power the device is supplied by the body, so a sep- RELEASE PRODUCTS
arate water chamber is also eliminated. The Theeuwes
device is formed by compressing a drug having a suit- The controlled release sector is a rapidly expanding part
able osmotic pressure into a tablet using a tableting ma- of the pharmaceutical industry. Growth has occurred at the
chine. The tablet is then coated with a semipermeable remarkable annual rate of 15% over the past decade, fueled
membrane, usually cellulose acetate, and a small hole is by an explosion of new technologies. The value of the
drilled through the membrane coating. When the tablet is pharmaceuticals using controlled drug delivery reached
placed in an aqueous environment, the osmotic pressure of $20 billion in 1999, and while only modest growth in the
the soluble drug inside the tablet draws water through the
overall pharmaceutical market is projected for the next few
semipermeable coating, forming a saturated aqueous so-
years, the drug delivery share of the market is expected to
lution inside the device. The membrane does not expand,
continue to grow at least 15% per annum. As much as
so the increase in volume caused by the imbibition of wa-
20% of the U.S. pharmaceutical market is projected to be
controlled release products by 2005.
The majority of drug delivery products reach the market
as a result of a strategic alliance between a drug delivery
company, which supplies the technology, and a pharma-
ceutical company, which supplies the drug and the re-
sources needed for full development. A good example of
such a collaboration is provided by protein and peptide
drugs, an increasingly important area of pharmaceuticals
driven by recent advances in biotechnology. Currently, a
major factor limiting the use of these drugs is the need
for their administration by repeated injections. This is be-
cause peptides and proteins are poorly absorbed in the
GI tract, so cannot be delivered as oral tablets, and have
very short biological half-lives, so cannot be delivered as
FIGURE 8 The Theeuwes elementary osmotic pump. This sim-
ple device consists of a core of water-soluble drug surrounded by a single, long-acting injection. Several specialized drug
a coating of a water-permeable polymer. A hole is drilled through delivery companies are developing innovative techniques
the coating to allow the drug to escape. that will allow these drugs to be delivered orally, by nasal