Page 225 - 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

802 Pharmaceuticals, Controlled Release of

products. The mean diameter of liposomes is less than A second type of device uses implants made from bio-
0.1 µm. This allows them selectively to extravasate into degradable polymers. Because the device is biodegrad-
tissues characterized by leaky vasculature, such as solid able, device retrieval once drug delivery is complete is
tumors, achieving targeted delivery to the diseased organ no longer necessary. This makes the device much more
with low adverse effects on normal tissues. acceptable to patients. Unfortunately, it is technically dif-
The first liposome product on the market was Ambi- ficult to create implantable, biodegradable devices that de-
some, containing amphotericin B, an antifungal encapsu- liver drug reliably for more than 1 or 2 months. Therefore,
lated in liposomes to reduce its toxicity. Since then, liposo- these devices are generally restricted to delivering drugs
mal preparations of other drugs have been developed, most for 4–6 weeks. Examples include Abbot’s Lupron Depot
importantly Daunoxome, an anticancer product contain- formulation, a single monthly injection of leuprolide for
ing the antitumoral drug daunorubicin for the treatment endometriosis, and Zoladex, Zenaca’s 4-week implantable
of Kaposi’s sarcoma. Liposomes are also being investi- formulations of goserelin for endometriosis in women and
gated as vehicles for gene therapy. Their main advantages prostrate cancer in men.
over viral carriers is a higher loading capacity and a lower A final category of implantable devices, in late-stage
risk of evoking an immune response. Surface-coating li- development, is miniature pumps driven by osmosis or
posomes with antibodies to allow active targeting to a par- fluorocarbon propellants. These pumps are designed to
ticular disease site is also being studied in clinical trials. If deliver essentially any drug at a predetermined rate for
these products are successful, targeted drug delivery will weeks or even months. The problem to be solved in this
be a breakthrough in the treatment of a number of major caseistomakethepumpsmallenoughandreliableenough
diseases. that the trauma of device removal is outweighted by its
A second approach to targeted drug delivery uses drug delivery benefits.
polyethylene glycol (PEG), a water-soluble polymer cova-
lently linked to proteins, which alters their properties and
extendstheirpotentialuse.Themainproductusingthisap- IV. FUTURE DIRECTIONS
proach is for α-interferon for the treatment of hepatitis C.
This technique has been applied to several proteins in- Theeraofmoderncontrolleddrugdeliverystartedwiththe
cluding adenosine deaminase, cytokines, and granulocyte- launching of the first product registered at the U.S. Food
macrophage colony-stimulating factor. Generally the re- and Drug Agency in terms of both the total amount of drug
sults obtained by the modification with PEG are increased delivered and the rate of drug delivery. This first product,
circulating life, reduced immunogenicity and antigenicity, Alza’s Ocusert, was launched in 1974. By 1990 the total
and increased stability and solubility with a minimal loss controlled release market was approximately $1 billion.
of biological activity. Since then the market has grown 20-fold, and the number
of such products is expected to continue to grow rapidly
in the next few years.
E. Implants
The largest growth area will be the extension of al-
Three types of implantable drug delivery devices are cur- ready developed controlled release technologies to a wider
rently in use or being developed. The first type is an im- number of drugs. A long list of oral and some transder-
plantable polymeric capsule most commonly made from mal controlled release products are in late-stage clinical
silicone rubber, which when placed under the skin delivers trials and should appear on the market in the next few
the drug load at a constant rate for as long as 2–5 years. years.
Upjohn’s Depo-Provera and American Homes’ Norplant, A second area of significant future growth will be
used to deliver contraceptive steroids for long-term con- the use of controlled release systems to deliver the new
traception, are examples of this approach. Implantable de- generation of peptide and protein drugs. As a conse-
vices achieve long-term, controlled delivery of the drug quence of the sequencing of the human genome, the in-
and patient compliance is no longer an issue, both signif- formation required to design protein and peptide drugs
icant advantages. The key disadvantage is the size of the to treat important diseases is at hand. However, many of
device, which means minor surgery is required to insert these new drugs are essentially ineffective if administered
the implant and later to remove the device once its drug as conventional pharmaceutical formulations. New, well-
delivery role has been completed. There is also a potential designed controlled release systems that can deliver the
to release all of the drug in a few days if the capsule be- drugs intact at a prolonged steady rate close to the site
gins to leak. For these reasons this type of nondegradable of action are required; such systems are being actively
device has not become a major product. developed.