Chapter 10
Polyanhydrides
Muntimadugu Eameema*, Lakshmi Sailaja Duvvuri*, Wahid Khan*,†, Abraham J. Domb†
⁎
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad, India
†
School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
Chapter Outline
10.1 History of Polyanhydrides 181
10.2 Properties of Polyanhydrides 182
10.2.1 Distinctive Features and Limitations 182
10.2.2 Thermal Properties  182
10.2.3 Solubility 182
10.2.4 Mechanical Properties  183
10.2.5 Stability 183
10.3 Synthesis of Polyanhydrides 183
10.3.1 Melt Condensation 183
10.3.2 Solution Polymerization 183
10.3.3 Dehydrative Coupling 184
10.3.4 Ring-Opening Polymerization 184
10.4 Classes of Polyanhydrides 184
10.4.1 Conventional Polyanhydrides 186
10.4.1.1 Aliphatic Polyanhydrides 186
10.4.1.2 Unsaturated Polyanhydrides 186
10.4.1.3 Aromatic Polyanhydrides 186
10.4.1.4 Aliphatic-Aromatic Polyanhydrides 186
10.4.1.5 Polymer Blends 186
ABBREVIATIONS
FA fumaric acid
CPH 1,3 bis(p-carboxyphenoxyhexane)
P(CPP) poly(carboxyphenoxypropane)
PAA poly(adipic acid)
PBSAM N,N´-bis(l-alanine)-sebacoylamide
PCL poly(caprolactone)
PHB poly(hydroxybutyrate)
PLA poly(lactic acid)
PTMC poly(trimethylene carbonate)
RA ricinoleic acid
Natural and Synthetic Biomedical Polymers
Copyright © 2014 Elsevier Inc. All rights reserved.
10.4.2 Advanced Polyanhydrides 186
10.4.2.1 Cross-Linked Polyanhydrides 186
10.4.2.2 Poly(Ester Anhydride) Polymers 186
10.4.2.3 Fatty Acid-Based Polyanhydrides 186
10.4.2.4 Amino Acid-Based Polyanhydrides 187
10.4.2.5 Poly(Anhydride-co-Imide)s 187
10.4.2.6 Polyanhydrides with Polyethylene
Glycol Functionality 187
10.5 Biodegradability 187
10.6 Biocompatibility 188
10.7 Applications 189
10.7.1 Drug Delivery 189
10.7.2 Programmable Drug Release 189
10.7.3 Immunomodulation 189
10.7.4 Protein Delivery 190
10.7.5 Tissue Engineering 190
10.1  HISTORY OF POLYANHYDRIDES
The class of polyanhydrides is one of the most widely
investigated biodegradable polymers, which have been
­
­investigated for more than three decades [1–3]. The histori-
cal development of polyanhydrides dates back to the 1900s
when Bucher and Slade documented first synthesis of poly-
anhydrides upon heating isophthalic acid and terephthalic
acid with acetic anhydride in 1909 [4]. This led to the inves-
tigation of polyanhydrides as textiles by Hill and Carothers
in the 1930s [5]. However, due to high hydrolytic instability
of anhydride linkages, they were not found to be suitable for
textile applications.
Systematic development of polyanhydrides, as substi-
tutes for polyesters in textile applications, was undertaken
181
182
initially by Conix et al. [6]. They prepared and studied a
number of aromatic and heterocyclic polyanhydrides that
were found to be quite stable towards hydrolysis and pos-
sessed excellent film- and fiber-forming properties. A new
class of heterocyclic crystalline polyanhydrides was in-
troduced by Yoda [7,8] who synthesized a variety of five-
membered heterocyclic dibasic acids and polymerized
these compounds with acetic anhydride at 200-300 °C un-
der vacuum and nitrogen atmosphere. These heterocyclic
polymers have melting point in the range of 70-190°C and
good film- and fiber-forming properties. Aliphatic polyan-
hydrides were considered immaterial due to their hydrolytic
instability. It was not until the 1980s that a connection was
made between polyanhydride degradation properties and
biomedical applications. In 1980, Langer was the first to
identify and accomplish the hydrolytic instability of these
polymers for controlled drug delivery applications and used
them as biodegradable carriers in various medical devices
[9]. Since then, extensive research has been going on to
explore the use of polyanhydrides for controlled delivery
and has also landed up in two devices for clinical use, i.e.,
Glaidel® [10] and Septacin™ [11].
10.2  PROPERTIES OF POLYANHYDRIDES
Polyanhydrides have been considered to be useful bioma-
terials as carriers of drugs to various organs of the human
body such as the brain, bone, blood vessels, and eyes. They
can be prepared easily from available, low-cost resources
and can be manipulated to meet desirable characteristics.
Since last 25 years, intensive research has been conducted,
which yielded hundreds of publications and patents de-
scribing new polymer with excellent film- and fiber-forming
properties, structures, studies on chemical and physical
characterization of these polymers, degradation and stabil-
ity properties, toxicity studies, and applications of polymers
for mainly controlled bioactive agents. However, due to
their rapid degradation and limited mechanical properties,
their main use has been limited to short-term controlled de-
livery of bioactive agents [1].
10.2.1  Distinctive Features and Limitations
The hydrolytic instability of polyanhydrides presents them
with both advantages and disadvantages [12,13].
● Resources are easily available with low cost and are
generally considered as safe dicarboxylic acid building
blocks.
● One-step synthesis with no need for purification steps.
● A well-defined polymer structure with controlled mo-
lecular weight and that degrades hydrolytically at a pre-
dictable rate.
● Manipulation of polymer to release bioactive agents at a
predictable rate for periods of weeks.
  Natural and Synthetic Biomedical Polymers
● They are processable by low-temperature injection
molding or extrusion for mass product and have versa-
tile properties, which can be varied by monomer selec-
tion, composition, surface area, and additives.
● They degrade to their respective diacids and completely
eliminate from the body within a period of weeks to months.
● They can be sterilized by terminal gamma irradiation
with minimal effect on polymer properties.
● They are highly instable to hydrolysis.
● They have poor mechanical strength.
● They possess poor fiber- and film-forming capacities.
● They are highly sensitive to heat and moisture (require a
storage temperature of −20 °C or below).
10.2.2  Thermal Properties
The melting point, as determined by differential scanning
calorimeter, of these aromatic polyanhydrides is much
higher than aliphatic polyanhydrides. The melting point
of aliphatic-aromatic copolyanhydrides is proportional
to aromatic content. For this type of copolymers, there is
characteristically a minimum Tm between 5 and 20 mol% of
lower-melting component. The introduction of fatty acids in
the copolymer chain lowers the melting point as compared
to that of bulk polymer [14].
Properties of polymer matrix other than melting point are
very important to obtain a proper drug release. Crystallinity
is an important factor that controls a polymer's erosion rate
and influences its solubility along with its melting point.
Almost all polyanhydrides show some degree of crystal-
linity as manifested by its melting point. Homopolymers
of aliphatic and aromatic diacids like sebacic acid (SA),
bis(carboxyphenoxy)propane (CPP), bis(carboxyphenoxy)
hexane (CPH), and fumaric acid (FA) are more crystalline
(>50% crystallinity), whereas their copolymers were found
to be less crystalline and degree of crystallinity increased
with increasing mole ratio of either aliphatic or aromatic di-
acid content [15]. The decrease in crystallinity was because
of random presence of other units in the polymer chain.
A detailed analysis of copolymers of SA with aromatic and
unsaturated monomers, CPP, CPH, and FA showed that co-
polymers with high ratios of SA and CPP or CPH were crys-
talline, while copolymers with equal ratios of SA and CPP
or CPH were amorphous [16]. In contrast, P(FA: SA) series
displayed high crystallinity despite comonomer ratio [15].
10.2.3 Solubility
The majority of polyanhydrides dissolve in solvents such
as dichloromethane and chloroform. However, the aromatic
polyanhydrides exhibit much lower solubility than aliphatic
polyanhydrides. But the copolymers of two different aro-
matic monomers showed increased solubility with a de-
crease in Tm [15].
Chapter | 10  Polyanhydrides 183

10.2.4  Mechanical Properties

Polyanhydrides show poor mechanical properties in compar-
ison with other polymers such as polyesters. It was observed
that increasing the CPP content in copolymer composition
increases the tensile strength and elongation of various poly-
anhydrides tested [14]. Despite the low molecular weight
(MW = 6400) of poly(CPP-SA) (60:40), it has a higher
tensile strength of 981 MPa (100 kgf/cm2) than it has in the
20:80 composition (MW = 18,900), 441 MPa (45 kgf/cm2).
Transparent and flexible films of fatty acid polyanhy-
drides were reported with a tensile strength of 4-19 MPa and
elongation at break in the range of 77-115%. Thus, intro-
duction of nonlinear fatty acid structures in polyanhydrides
provides hydrophobicity and flexibility to the polymers.

10.2.5 Stability
Polymers used in drug delivery applications should have not
only good solubility required for film casting or microen-
capsulation but also stability in both solid and solution state. SCHEME 10.1  Synthesis of polyanhydrides through melt condensation.
Polyanhydrides are considered as air-sensitive materials and
are stored at a temperature of −20 °C under argon atmo-
anhydride with acetic anhydride before subjecting the pre-
sphere [13]. A detailed analysis on stability of aromatic and
polymer to melt polycondensation and the schematic pro-
aliphatic polymers in solid state and dry chloroform solu-
cess is given in Scheme 10.1 [14].
tion showed that poly(1,1-bis(p-carboxyphenoxy)methane)
The polyanhydride thus obtained was of low molecu-
maintained their original molecular weight for at least 1 year
lar weight. For most of the practical applications, high-
in the solid state, whereas, aliphatic polyanhydrides, such as
molecular-weight polyanhydrides are desirable. Hence,
poly sebacic acid, showed decreased molecular weight over
a systematic study was undertaken to determine the fac-
time. The decrease in molecular weight was explained by an
tors that affected the polymer molecular weight. It was
internal anhydride interchange mechanism, as revealed from
found that the critical factors were monomer purity, re-
elemental and spectral analyses supported by the fact that
action time, and temperature, and an efficient system to
this decrease in molecular weight was reversible and heating
remove the by-product, acetic anhydride is required. The
the depolymerized polymer at 180 °C for 20 min yielded the
highest-molecular-weight polymers were obtained using
original high-molecular-weight polymers. However, under
pure isolated prepolymers and heating them at 180 °C for
similar conditions, the hydrolyzed polymer did not increase
90 min with a vacuum of 10−4 mmHg, using a dry ice/­
in molecular weight [17]. In many cases, it was observed
acetone trap. Significantly higher molecular weights
that the stability of polymers in the solid state or in organic
were obtained in shorter times by using coordination cat-
solution did not correlate with its hydrolytic stability [17].
alysts such as, cadmium acetate, earth metal oxides, and
A similar decrease in molecular weight as function of time
ZnEt2⋅H2O [20].
was also observed among the aliphatic-aromatic copolyan-
hydrides and imide-containing polyanhydrides [18,19].
10.3.2  Solution Polymerization
10.3  SYNTHESIS OF POLYANHYDRIDES The solution polymerization is carried out by Schotten-
Synthesis of polyanhydrides is carried out through gener- Baumann technique. In this method, the solution of diacid
alized methods such as melt polycondensation, solution chloride is added dropwise into an ice-cooled solution of
polymerization, use of coupling agents, and ring-opening a dicarboxylic acid. The reaction is facilitated by using an
polymerization. acid acceptor such as triethylamine. Polymerization takes
place instantly on contact of the monomers and is essen-
tially complete within 1 h. The solvents employed can be a
10.3.1  Melt Condensation single solvent or a mixture of solvents like dichlorometh-
Carothers and Hill first reported the synthesis of polyanhy- ane, chloroform, benzene, and ethyl ether. It was found that
drides through condensation. In this method, a prepolymer the order of addition is very important in obtaining rela-
is formed by converting the carboxylic group to a mixed tively high-molecular-weight polyanhydrides. Addition of
184   Natural and Synthetic Biomedical Polymers

a diacid s­olution dropwise to the diacid chloride solution
­consistently produced high-molecular-weight polymers [21].
HOOC − R − COOH + ClOC − R ′ − COCl Base
 → base K2CO3 [23].
(
− R − C (O) − O − C (O) − R ′ − C (O) − O − C (O)
− + Base − HCl
10.3.3  Dehydrative Coupling
Dicarboxylic acid monomer could be converted into the
polyanhydride using a dehydrative coupling agent under
ambient conditions. The dehydrative coupling agent, N´,N-
bis[2-oxo-3-oxazolidinyl]phosphonic chloride, was the
most effective in forming polyanhydrides with the degree
of polymerization around 20 [22]. It is essential that the
catalyst be ground into fine particles before use and should
be freshly prepared. A disadvantage of this method is that
the final product contains polymerization by-products that
have to be removed by washing with protic solvents such as
methanol or cold dilute hydrochloric acid. The washing by
protic solvents may evoke some hydrolysis of the polymer.
Coupling agents such as phosgene and diphosgene
could also be used for the polyanhydride formation.
Polymerization of SA using either phosgene or diphosgene
as coupling agents with the amine-based heterogeneous
acid acceptor, poly(4-vinyl pyridine), produced higher mo-
lecular weights in comparison to nonamine heterogeneous
)
10.3.4  Ring-Opening Polymerization
ROP offers an alternate approach to the synthesis of poly-
anhydrides used for medical applications. Albertsson and
coworkers prepared adipic acid polyanhydride from cyclic
adipic anhydride (oxepane-2,7-dione) using cationic (e.g.,
AlCl3 and BF3⋅(C2H5)2O), anionic (e.g., CH3COO−K+ and
NaH), and coordination-type inhibitors such as stannous-
2-ethylhexanoate and dibutyltin oxide [24,25]. ROP takes
place in two steps: (1) preparation of the cyclic monomer
and (2) polymerization of the cyclic monomers [26].
10.4  CLASSES OF POLYANHYDRIDES
Since the introduction of polyanhydrides to the regime of
polymers, hundreds of polyanhydride structures have been
reported. These polymers are divided into conventional and
advanced polyanhydrides, with various subclasses under
each category. Different classes of polyanhydrides with
their structures and examples are given in Table 10.1.

TABLE 10.1  Different Classes of Polyanhydrides [12,27]

Drug Delivery
S. No. Class Backbone Examples Systems References
 1 Aliphatic PSA (x = 8) PSA-co-Pluronic [28]
polyanhydrides microspheres for
the controlled
release of
nifedipine

PAA (x = 4) PAA microsphere [29]

gel for ocular
delivery of timolol
maleate

 2 Unsaturated PFA Fumaric [30]

polyanhydrides acid-based
polyanhydrides
as bioadhesive
excipient for oral
drug delivery

 3 Aromatic P(CPH) Discs of [31]

polyanhydrides zinc insulin-
impregnated
P(CPH) for
controlled delivery
Chapter | 10  Polyanhydrides 185

TABLE 10.1  Different Classes of Polyanhydrides—Cont’d

Drug Delivery
S. No. Class Backbone Examples Systems References
 4 Aliphatic- P(CPP-SA) copolymer Human serum [32]
aromatic albumin-loaded
polyanhydrides P(CPP-SA)
microspheres

 5 Polyanhydride Blends with polyanhydrides or other PSA blend PLA Delivery of [33]
blends polyesters or polycarbonates ofloxacin using
PLA-PSA blend for
the treatment of
bone infection

 6 Fatty acid-based P(RA-SA) P(RA-SA) [34]

polyanhydrides biodegradable
carrier for
paclitaxel

 7 Amino PSBAM Nerve [35]

acid-based regeneration
polyanhydrides

 8 Poly(anhydride- Poly(TMA-Tyr:SA:CPP) Bovine serum [36]

co-imide) albumin-loaded
poly(TMA-
Tyr:SA:CPP)
microspheres

 9 PEG containing SA-CPP-PEG polyanhydride Pulsatile delivery [37]

polyanhydride of parathyroid
hormone

10 Photo- MSA [R = (CH2)8] DNA delivery [38]

cross-linked MCPH from photo-cross-
polyanhydrides R =  linked MSA,
MCPH, and their
copolymers

n = number of monomer units.

Abbreviations—PSA, poly(sebacic acid); PAA, poly(adipic acid); P(CPH), 1,3 bis(p-carboxyphenoxyhexane); P(CPP-SA), poly(1,3 bis(p-
carboxyphenoxypropane-sebacic acid) copolymer; PLA, poly(d,l-lactide); Poly(TMA-Tyr:SA:CPP), tyrosine-containing poly(anhydride-co-imide); P(RA-SA),
poly(ricinoleic acid-sebacic acid) copolymer; PBSAM, N,N′-bis(l-alanine)-sebacoylamide; MSA, methacrylated sebacic acid; MCPH, methacrylated 1,3
bis(p-carboxyphenoxyhexane).
186
10.4.1  Conventional Polyanhydrides
10.4.1.1  Aliphatic Polyanhydrides
Aliphatic polyanhydrides synthesized from saturated diacid
monomers are crystalline, melt at temperatures below 100 °C,
and are soluble in chlorinated hydrocarbons. They are de-
graded and eliminated from the body within weeks [39].
10.4.1.2  Unsaturated Polyanhydrides
The unsaturated homopolymers are crystalline and in-
soluble in common organic solvents, whereas copolymers
with aliphatic diacids are less crystalline and soluble in
chlorinated hydrocarbons. They also provide a means for
cross-linking through the double bonds that remain intact
during polymerization process and thus their mechanical
­properties can be improved [40].
10.4.1.3  Aromatic Polyanhydrides
Aromatic homopolyanhydrides are insoluble in common or-
ganic solvents and melt at temperatures above 200 °C [15].
These properties limit the use of dictated polymers for films
and microspheres using solvent or melt technique. Fully aro-
matic polymers that are soluble in chlorinated hydrocarbons
and melt at temperatures below 100 °C were obtained co-
polymerization of aromatic diacids such as isophthalic acid
(IPA), terephthalic acid (TA), CPP, or CPH. But due to their
aromatic nature, they possess a slow degradation profile.
10.4.1.4  Aliphatic-Aromatic Polyanhydrides
These are the copolymers of aromatic and aliphatic diacid
monomers. Polyanhydrides of diacid monomers containing
poly(lactic acid) (PLA) and poly(hydroxybutyrate) (PHB)
are synthesized by either melt or solution with molecular
weights of up to 44,600 [17,18]. They were found to be less
crystalline in nature and possessed slow degradation due to
their aromatic content.
10.4.1.5  Polymer Blends
The physical and mechanical properties of polyanhydrides
can be altered by minor modifications. Biodegradable poly-
mer blends of polyanhydrides and polyesters have been
investigated as drug carriers [41]. A polymeric blend of
poly(trimethylene carbonate) (PTMC) with poly(adipic an-
hydride) and the matrix of PTMC-poly(adipic anhydride)
blend was found to be biocompatible in in vitro and in vivo
experiments and a promising candidate for controlled drug
delivery erosion with tunable erosion rate achieved by vary-
ing the proportion of PTMC and poly(adipic anhydride)
[42]. In general, polyanhydrides of different structures form
uniform blends with a single melting temperature. Low-
molecular-weight PLA, PHB, and poly(caprolactone) (PCL)
  Natural and Synthetic Biomedical Polymers
are miscible with polyanhydrides, while high-molecular-
weight polyesters (MW > 10,000) are not compatible with
polyanhydrides.
10.4.2  Advanced Polyanhydrides
10.4.2.1  Cross-Linked Polyanhydrides
Cross-linked polyanhydrides are in the form of a three-
dimensional network and have been developed for high
mechanical strength and slow degradation. The photo-
cross-linked polyanhydrides are prepared from the mono-
mers having anhydride bonds and unsaturated endcaps,
e.g., vinyl or 2-propenyl groups. These polyanhydrides are
­useful as degradable orthopedic fixation devices, for ex-
ample, pins and screws, for bone augmentation and regen-
eration, bone cement, etc. [40,43,44]. Anhydride monomers
like SA, CPH, and CPP endcapped with methacrylate func-
tionalities with degradation rate varying from 2 days for SA
to 1 year for CPH by varying network composition have
been reported [42].
10.4.2.2  Poly(Ester Anhydride) Polymers
These polymers are one of the modifications of polyan-
hydrides whereby the polymer contains both ester and an-
hydride groups as suggested by the name itself. These are
designed to display two-stage degradation profile wherein
the fast degradation of anhydride linkages allows a rapid
degradation of molecular weight of the polymer followed by
the slower degradation of remaining oligomers, the rate of
which is governed by the composition of polyester prepoly-
mers [45]. Di- and triblock copolymers of PCL, PLA, and
PHB have been prepared from carboxylic acid-­terminated
low-molecular-weight polymers copolymerized with SA
prepolymers by melt condensation. Salicylic acid-based
poly(ester anhydride)s have been reported to stimulate new
bone formation [12].
10.4.2.3  Fatty Acid-Based Polyanhydrides
Fatty acid incorporation in biodegradable polymers pro-
vides flexibility, low melting temperature, hydrophobicity,
and pliability. It degrades into naturally occurring com-
pounds and thus is environment-friendly. Fatty acids have
been incorporated in polymers as monomers using carbox-
ylic acid functionality. Most fatty acids that are monofunc-
tional in nature act as chain terminator in polymerization.
Dimerization of unsaturated fatty acids via the unsaturation
or creating a functional group on the fatty acid provides a
bifunctional monomer suitable for polymerization. These
copolymers are generally hydrophobic, soluble in com-
mon chlorinated organic solvents, and non- or semicrystal-
line; have low melting point (20-90 °C); and possess low
mechanical strength. Ricinoleic acid (RA)-based polymers
Chapter | 10  Polyanhydrides
SCHEME 10.2  Synthesis of trimellitylimidoglycine.
are the newest addition to polyanhydride series. RA (cis-12-
hydroxyoctadeca-9-eonoic acid) was found to be the most
appropriate alternative for the synthesis of the fatty acid-
based polyanhydrides. It is one of the few commercially
available fatty acids that have the additional 12-hydroxy
group. The advantage of RA is that it is a bifunctional fatty
acid containing a hydroxyl group along the acid group
and, therefore, can be incorporated into the polyanhydride
­backbone by the formation of an ester bond [46].
10.4.2.4  Amino Acid-Based Polyanhydrides
Linear amino acid-containing polyanhydrides were first
developed in 1990 with improved physical and chemical
properties [19]. They are synthesized by amidation of the
amino group of an amino acid with a cyclic anhydride or by
the amide coupling of two acids with a diacid chloride [47].
Introduction of amino acid in the polymer composition can
elicit various functions such as functioning as carriers for
controlled release of active agents or may provide a poly-
mer whereby the polymer itself or the degradation products
are the active agents. Various amino acids suitable for poly-
meric drug approach are natural α-amino acids like glycine,
γ-amino butyric acid (brain transmitters), oligopeptides as
peptide hormones, etc. [48].
10.4.2.5 Poly(Anhydride-co-Imide)s
These are also known as copolyimides synthesized via
melt condensation polymerization and were found to ex-
hibit good thermal resistance [47]. The imide segments
in polymer backbone imparted high mechanical strength.
Their insolubility in polar solvents was improved by us-
ing an imide diacid containing aliphatic-aromatic charac-
teristic whereby the starting monomers were composed of
aromatic acid anhydride and α-amino acid. Such polymers
were found to undergo degradation via anhydride bond
first followed by hydrolysis of imide bonds [49]. One such
example of aliphatic-aromatic monomer is that obtained
by trimellitic anhydride and glycine [50]. Polymers based
on succinic acid, trimellitylimidoglycine, and trimellity-
limidoalanine with compressive strengths in order of
­50-60 MPa suitable for orthopedic applications have been
reported [51]. An example of aliphatic-aromatic monomer
187
obtained by reaction of trimellitic anhydride with glycine
is given in Scheme 10.2 [50].
10.4.2.6  Polyanhydrides with Polyethylene
Glycol Functionality
Polyanhydrides because of their surface erosion ­properties
can be ideal materials for a constant rate release profile
(a zero order). Furthermore, these polyanhydrides are very
hydrophobic and their hydrolytic degradation may take
relatively a long time, which is not suitable for pulsatile
release. Hence, in order to achieve a tunable erosion kinet-
ics, a two-component polyanhydride made of SA precursor
and CPP precursor when copolymerized with polyethylene
glycol (PEG) was found to retain the surface erosion of
two-component polyanhydride while increasing the erosion
rate due to increased hydrophilicity by PEG functionality.
Relatively faster erosion rates can be achieved by adjusting
PEG precursor content [37].
10.5 BIODEGRADABILITY
Biodegradation actually involves two complementary pro-
cesses such as degradation and erosion. The process of deg-
radation refers to the chain scission process during which
polymer chains are cleaved to form oligomers and finally
to form monomers. Degradation of polymers can take place
passively by hydrolysis or actively by enzymatic reaction.
Erosion designates the loss of material owing to monomers
and oligomers leaving the polymer [52]. In ideal bulk ero-
sion, material is lost from the entire polymer volume at the
same time due to water penetrating the bulk. In this case,
the erosion rate depends on the total amount of the material.
In surface erosion, material is lost from the polymer matrix
surface only. These are generally hydrophobic polymers
wherein water cannot penetrate easily into the bulk. In ideal
surface erosion, the erosion rate will be proportional to the
surface area [53]. As polyanhydrides belong to the class of
water-insoluble hydrophobic polymers, it is mandatory for
these materials to degrade prior to erosion. These highly
hydrophobic polyanhydrides exhibit ideal surface erosion
because the rate of hydrolytic degradation at the surface
will be much faster than the rate of water penetration into
the bulk of the matrix [54].
188
Hydrolysis of the anhydride bond is base-catalyzed,
and, thus, the rate of degradation of the polymer and the
diffusion of oligomers and monomers formed by polymer
degradation depends on the pH of the surrounding me-
dium and solubility of these compounds in the medium.
Since polyanhydrides degrade into carboxylic acids, solu-
bility of these degradation products is more at higher pH
[55]. Polyanhydrides in general degrade more rapidly in
basic media than in acidic media [56]. At pH 7.4, pure
poly(carboxyphenoxypropane) (P(CPP)) degrades in about
3 years and the rate of degradation increases with increase
in pH, with the polymer degrading in just over 100 days at
pH 10.0 [57].
Erosion of the polymer matrices depends on processes
such as the rate of degradation, swelling, porosity, and ease
of diffusion of oligomers and monomers from the matri-
ces. Such erosion maintains constant surface area and hence
leads to zero-order drug release [52]. Degradation of the
polyanhydride, being a hydrolytically triggered process,
depends on the rate of water uptake into the polymer ma-
trix and pH of the surrounding medium. The rate of water
­uptake depends mainly on parameters like hydrophobicity
and the crystallinity of the matrix, the porosity of the ma-
trix, and the surface area/volume of the matrix. The higher
the hydrophobicity, the lower is the water permeability of
the matrix.
Type of monomers and their composition affect the
mechanism and rate of degradation of polyanhydrides.
All aliphatic polyanhydrides are rigid, crystalline material
and their melting point increases with the monomer chain
length. They usually erode fast and therefore are not much
useful alone for pharmaceutical applications except some
aliphatic polyanhydride such as P(FA:SA) having bioadhe-
sive properties. Aromatic polyanhydrides are high-melting
polymers and degrade slowly [15,58]. Combined properties
of aliphatic and aromatic polyanhydride have been used to
get the copolymer with improved mechanical characteris-
tics and adjustable erosion times. It has been found that the
initial molecular weight of polyanhydrides does not have a
significant effect on the rate of degradation of the polymeric
matrices [59]. Since there are no specific enzymes for anhy-
dride bond cleavage, the degradation rate of polyanhydrides
is unaffected by enzymes. Elevated temperatures can accel-
erate the erosion of polyanhydrides [54]. The rate of deg-
radation of polyanhydrides can be modulated by carefully
tuning one or more of the previously mentioned parameters.
10.6 BIOCOMPATIBILITY
Various biocompatibility studies reported on several poly-
anhydrides have shown them to be nonmutagenic and non-
toxic. In vitro tests measuring teratogenic potential were
also negative. Growth of two types of mammalian cells in
tissue culture was also not affected by the polyanhydride
  Natural and Synthetic Biomedical Polymers
polymers [60]; both the cellular doubling time and cellular
morphology were unchanged when either bovine aorta en-
dothelial cells or smooth muscle cells were grown directly
on the polymeric substrate.
Subcutaneous implantation in rats of high doses of the
20:80 copolymer of CPP and SA for up to 8 weeks indi-
cated relatively minimal tissue irritation with no evidence
of local or systemic toxicity [61]. Since this polymer was
designed to be used clinically to deliver an anticancer agent
directly into the brain for the treatment of brain neoplasms,
its biocompatibility in rat brain was also studied [62].
The tissue reaction of the polymer was compared to the
reaction observed with two control materials used in sur-
gery, oxidized cellulose absorbable hemostat (Surgicel®,
Johnson and Johnson), and with absorbable gelatin sponge
(Gelfoam®). The inflammatory reaction of the polymer was
intermediate between the controls [62]. A closely related
polyanhydride copolymer poly(CPP-SA) 50:50 was also
implanted in rabbit brains and was found to be essentially
equivalent to Gelfoam® in terms of biocompatibility evalu-
ations [63]. In a similar study conducted in monkey brains,
no abnormalities were noted in the CT scans and magnetic
resonance image nor in the blood chemistry or hematology
evaluations [64]. No systemic effects of the implants were
observed on histological examinations of any of the tissues
tested [65].
In the rabbit cornea bioassay, no evidence of inflamma-
tory response was observed with any of the implants at any
time. On an average, the bulk of the polymers disappeared
completely between 7 and 14 days after the implantation
[66]. In similar animal experiments in which polyanhy-
dride matrices containing tumor angiogenic factor (TAF)
were implanted in rabbit cornea, a significant vasculariza-
tion response was observed without edema or white cells.
Moreover, and most importantly from the biocompatibility
standpoint, polymer matrices without incorporated TAF
showed no adverse vascular response [67,68].
Based on the biocompatibility and safety preclinical
studies carried out in rats [61,62], rabbits [63], and mon-
keys [64,65] reviewed here showing quite acceptability
of the polyanhydrides for human use, a phase I/II clini-
cal protocol was instituted [69]. In these clinical trials, a
polyanhydride dosage form (Gliadel®) consisting of wafer
polymer implants of poly(CPP-SA) 20:80 and containing
the chemotherapeutic agent carmustine (BCNU) was used
for the treatment of glioblastoma multiforme, a universally
fatal form of brain cancer. In these studies, up to eight of
these wafer implants were placed to line the surgical cav-
ity ­created during the surgical debulking of the brain tumor
in patients undergoing a second operation for surgical de-
bulking of either a grade III or IV anaplastic astrocytoma.
In keeping with the results of the earlier preclinical studies
suggesting a lack of toxicity, no central or systemic toxicity
of the treatment was observed during the course of ­treating
Chapter | 10  Polyanhydrides
21 patients under this protocol. Phase III human clinical
­trials have demonstrated that site-specific delivery of BCNU
from a P(CPP:SA) 20:80 wafer (Gliadel®) in patients with
recurring brain cancer (glioblastoma multiforme) signifi-
cantly prolongs patient survival [70]. Gliadel® finally got
the approval from FDA as an adjunct therapy for the treat-
ment of brain tumors.
10.7 APPLICATIONS
10.7.1  Drug Delivery
Polyanhydrides have been investigated as a candidate for
controlled release devices for drugs treating eye disorders,
chemotherapeutic agents, local anesthetics, anticoagulants,
neuroactive drugs, and anticancer agents [12]. BCNU
loaded in poly(CPP-SA) 20:80 wafer (Gliadel®) for treating
brain tumors is approved for clinical use worldwide [70].
Septacin™ is a polyanhydride implant of a copolymer of
EAD and sebacic acid in a 1:1 weight ratio that is being
­developed for osteomyelitis. It is a controlled release im-
plant that contains gentamicin sulfate dispersed into a poly-
anhydride polymer matrix [11]. Both the marketed products
are listed in Table 10.2.
10.7.2  Programmable Drug Release
Surface-eroding polymers have been used in the develop-
ment of erodible polymer matrix that can release drugs
or antigens in two phases with a first drug release period
of 1-2 weeks and a second period lasting another week.
TABLE 10.2  Marketed Products of Polyanhydrides
Gliadel®
Drug Carmustine
Polymer composition P(CPP:SA, 20:80)
Therapeutic application Glioblastoma multiforme
Fabrication Wafer
189
Such systems could be beneficial for the local treatment
of cancer because they allow switching from one drug to
another or for vaccination to release antigens twice dur-
ing a month. Loading different layers of laminated ma-
trices with drugs, surface erosion releases the drug out
of these layers one after another. Gopferich reported pro-
grammable drug release from polymeric implants that
were manufactured using a combination of fast-eroding
poly(1,3 bis[p-carboxyphenoxypropane]-co-sebacic acid)
(p(CPP-SA) 20:80), a polyanhydride, and slow-eroding
poly(d,l-lactic acid) [71].
10.7.3 Immunomodulation
Use of hydrophobic synthetic biodegradable polymeric
biomaterials as immune modulators can eliminate the use
of microbial-derived adjuvant that suffers from toxicity
­issues and other drawbacks. Moreover, these polymers can
simultaneously serve as delivery devices for the antigens
in the form of microspheres or nanospheres for enabling
­alternate routes of delivery and provide sustained release
to facilitate single-dose vaccines and eliminate the need for
booster shots [72]. Polyanhydride-based systems for anti-
gen delivery have exhibited improved adjuvanticity, anti-
gen stabilization, and enhanced immune responses [73,74].
A desirable feature of polyanhydrides as antigen carri-
ers is the enhanced protein stability conferred by them
[75,76]. Polyanhydrides are capable of stabilizing poly-
peptides and sustaining their release without the inclu-
sion of potentially reactive excipients or stabilizers
[37,72,77,78].
Septacin™
Gentamicin
P(EAD:SA, 50:50)
Osteomyelitis
Beads
190
10.7.4  Protein Delivery
Biodegradable polymeric materials have been used suc-
cessfully in protein delivery. Some of the characteristics of
biodegradable carriers that can be manipulated to maintain
protein stability include water swelling, hydrophobicity,
and chemical nature of degradation products [79].
Since polyanhydrides are surface-eroding polymers,
they have a distinct advantage for protein stabilization be-
cause they prohibit water penetration, thereby preventing
proteins from denaturing due to physiological conditions.
Unfortunately, increasing the aromatic content increases the
hydrophobicity of the polymer, which may lead to protein
aggregation along the hydrophobic domains inside the poly-
mer matrix. One method of preventing protein destabiliza-
tion is to increase the hydrophilicity of the polyanhydride.
But aliphatic diacids do not reduce the hydrophobic interac-
tions enough for stabilization or do not degrade in a useful
time period [80]. A novel amphiphilic polyanhydride system
has been developed based on copolymers of the anhydride
monomers, CPH and 1,8-bis(p-carboxyphenoxy)-3,6-diox-
aoctane (CPTEG), which contains oligomeric ethylene gly-
col. The incorporation of oligomeric ethylene glycol into
the backbone of an aromatic polyanhydride creates the nec-
essary hydrophilicity to create the amphiphilic environment
needed for protein stabilization [81].
10.7.5  Tissue Engineering
Polyanhydrides have been developed into various sys-
tems with mainly bone tissue engineering applications in
mind. These polymers have mechanical strength much
lower than that of bone but have been combined with other
polymers, such as poly(imide)s, to resolve this problem.
Polyanhydrides have been developed into photo-cross-­
linkable systems, based on dimethacrylated anhydrides, and
also injectable systems, but little interest into these poly-
mers with regard to tissue engineering has been taken in the
recent past [82].
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