Biomedical Engineering Reference
In-Depth Information
treatment of glioblastoma multiformae, a universally
fatal brain cancer (
Madrid
et al.
, 1991
). For this appli-
cation, BCNU-loaded implants made of the poly-
anhydride derived from bis-
p
-carboxyphenoxypropane
and sebacic acid received FDA regulatory approval in the
fall of 1996 and are currently being marketed under the
name Gliadel.
Poly(ortho esters) are a family of synthetic, degrad-
able polymers that have been under development for
a number of years (
Heller
et al.
, 1990
). Devices made of
poly(ortho esters) can erode by ''surface erosion'' if ap-
propriate excipients are incorporated into the polymeric
matrix. Since surface eroding, slab-like devices tend to
release drugs embedded within the polymer at a constant
rate, poly(ortho esters) appear to be particularly useful
for controlled-release drug delivery applications. For
example, poly(ortho esters) have been used for the
controlled delivery of cyclobenzaprine and steroids and
a significant number of publications describe the use of
poly(ortho esters) for various drug delivery applications
(
Heller, 1993
). Poly(ortho esters) have also been in-
vestigated for the treatment of postsurgical pain,
ostearthritis, and ophthalmic diseases (
Heller
et al.
,
2002
). Since the ortho ester linkage is far more stable in
base than in acid, Heller and his co-workers controlled
the rate of polymer degradation by incorporating acidic
or basic excipients into the polymer matrix. One concern
about the ''surface erodability'' of poly(ortho esters) is
that the incorporation of highly water-soluble drugs into
the polymeric matrix can result in swelling of the poly-
mer matrix. The increased amount of water imbibed into
the matrix can then cause the polymeric device to exhibit
''bulk erosion'' instead of ''surface erosion'' (see below for
a more detailed explanation of these erosion mecha-
nisms) (
Okada and Toguchi, 1995
).
By now, there are three major types of poly(ortho
esters). First, Choi and Heller prepared the polymers by
the trans-esterification of 2,2
0
-dimethoxyfuran with
a diol. The next generation of poly (ortho esters) was
based on an acid-catalyzed addition reaction of diols with
diketeneacetals (
Heller
et al.
, 1980
). The properties of
the polymers can be controlled to a large extent by the
choice of the diols used in the synthesis. Recently, a third
generation of poly(ortho esters) have been prepared.
These materials are very soft and can even be viscous
liquids at room temperature. Third-generation poly
(ortho esters) can be used in the formulation of drug
delivery
attachment of drugs, cross-linking agents, or pendent
groups that can be used to modify the physicomechanical
properties of the polymer. In addition, poly(amino acids)
usually show a low level of systemic toxicity, due to their
degradation to naturally occurring amino acids.
Early investigations of poly (amino acids) focused on
their use as suture materials (
Miyamae
et al.
, 1968
), as
artificial skin substitutes (
Spira
et al.
, 1969
), and as drug
delivery systems (
McCormick-Thomson and Duncan,
1989
). Various drugs have been attached to the side
chains of poly(amino acids), usually via a spacer unit that
distances the drug from the backbone. Poly(amino acid)-
drug combinations investigated include poly(
L
-lysine)
with methotrexate and pepstatin (
Campbell
et al.
,
1980
), and poly(glutamic acid) with adriamycin,
a widely used chemotherapeutic agent (van Heeswijk
et al.
, 1985).
Despite their apparent potential as biomaterials,
poly(amino acids) have actually found few practical ap-
plications. Most poly(amino acids) are highly insoluble
and nonprocessible materials. Since poly(amino acids)
have a pronounced tendency to swell in aqueous media, it
can be difficult to predict drug release rates. Further-
more, the antigenicity of polymers containing three or
more amino acids limits their use in biomedical appli-
cations (
Anderson
et al.
, 1985
). Because of these diffi-
culties, only a few poly(amino acids), usually derivatives
of poly(glutamic acid) carrying various pendent chains at
the g-carboxylic acid group, have been investigated as
implant materials (
Lescure
et al.
, 1989
). So far, no im-
plantable devices made of a poly(amino acid) have been
approved for clinical use in the United States.
In an attempt to circumvent the problems associated
with conventional poly(amino acids), backbone-modified
''pseudo''-poly(amino acids) were introduced in 1984
(
Kohn and Langer, 1984, 1987
). The first ''pseudo''-
poly(amino acids) investigated were a polyester from
N-protected
trans-
4-hydroxy-
L
-proline, and a poly-
iminocarbonate derived from tyrosine dipeptide. The
tyrosine-derived ''pseudo''-poly(amino acids) are easily
processed by solvent or heat methods and exhibit a high
degree of biocompatibility. Recent studies indicate that
the backbone modification of poly(amino acids) may be
a generally applicable approach for the improvement of
the physicomechanical properties of conventional
poly(amino acids). For example, tyrosine-derived poly-
carbonates (
Nathan and Kohn, 1996
) are high-strength
materials that may be useful in the formulation of de-
gradable orthopedic implants. One of the tyrosine-
derived pseudo-poly(amino acids), poly(DTE carbonate)
exhibits a high degree of bone conductivity (e.g., bone
tissue will grow directly along the polymeric implant)
(
Choueka
et al.
, 1996; James and Kohn, 1997
).
The reason for the improved physicomechanical
properties of ''pseudo''-poly(amino acids) relative to
systems
that
can
be
injected
rather
than
implanted into the body.
Poly(amino acids) and ''Pseudo''-Poly(amino
acids) Since proteins are composed of amino acids, it is
an obvious idea to explore the possible use of poly(amino
acids) in biomedical applications (
Anderson
et al.
, 1985
).
Poly(amino acids) were regarded as promising candidates
since the amino acid side chains offer sites for the
