Synthesis and characterization of biodegradable copolyesters and copolyanhydrides prepared from fumaric and succinic acid trimers and oligomers

Article abstract of DOI:10.1560/EDR4-8FC1-CQ8M-J6RL

A series of new biodegradable copolymers and copolyanhydrides built of trimers of fumaric and succinic acid and propylene glycol, covering a wide range of compositions, were prepared and characterized for use as drug carriers. The polymers were found to degrade within a period of weeks. Polyanhydrides loaded with ibuprofen as a model drug released the drug for a period of one week, while the polyesters released the drug for more then 30 days. The biocompatibility and the rate of evacuation of trimer-based polymers of fumaric and succinic acids were investigated in rats. All polymers were found compatible when implanted in mice.

Full text of DOI:10.1560/EDR4-8FC1-CQ8M-J6RL

Synthesis and Characterization of Biodegradable Copolyesters and
Copolyanhydrides Prepared from Fumaric and Succinic Acid Trimers
and Oligomers
b
SHIMON BEN-SHABAT,a,* OMAR ELMALAK,b ABRAHAM NYSKA,c ABRAHAM J. DOMB
aDepartment of Pharmacology and School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev,
Be’er Sheva 84105, Israel
bDepartment of Medicinal Chemistry and Natural Products, School of Pharmacy, Faculty of Medicine,
The Hebrew University of Jerusalem, Jerusalem 91120, Israel
cLaboratory of Experimental Pathology, National Institute of Environmental Health and Sciences,
National Institutes of Health, Research Triangle Park, North Carolina 27709, USA
(Received 20 May 2005)
Abstract. A series of new biodegradable copolymers and copolyanhydrides built
of trimers of fumaric and succinic acid and propylene glycol, covering a wide range
of compositions, were prepared and characterized for use as drug carriers. The
polymers were found to degrade within a period of weeks. Polyanhydrides loaded
with ibuprofen as a model drug released the drug for a period of one week, while the
polyesters released the drug for more then 30 days. The biocompatibility and the rate
of evacuation of trimer-based polymers of fumaric and succinic acids were
investigated in rats. All polymers were found compatible when implanted in mice.
INTRODUCTION
carriers for therapeutic substances since the 1980s.4–7
Degradable polymers are of considerable interest for a Studies on copolymers of several polyanhydride
variety of applications and have attracted significant families have shown that varying co-monomer ratios
attention for use in numerous medical and biomedical produces erosion profiles ranging from days to years.8
applications.1,2 These polymers can help significantly to Syntheses of polyesters and polyanhydrides have been
overcome many problems since they are biodegradable published for the controlled delivery of drugs providing
(being sensitive to hydrolysis), nontoxic, and bio- a sustained release rate over a long period of time.9–12 It
compatible. Examples of their importance can be found has also been demonstrated by tissue-response and toxi-
in the field of drug delivery, releasing a dose of drug cology studies that polyanhydrides are not only degrad-
over an extended period of time.3 Biodegradable poly- able but also highly biocompatible.13
mers can stabilize the drug reservoir from premature
Oligomers are thought to accelerate the hydrolytic
inactivation; concurrently, the polymer can control the degradation of devices prepared from poly(lactide-co-
release of drug out of the reservoir, and finally the glycolide), PLGA, due to their increased number of
degradability of the material helps to overcome the need carboxylic end groups.14,15 The oligomers increase the
for any post-application removal. There have been only concentration of carboxyl groups, which results in an
a few cases in recent years in which new degradable increased degradation rate and autocatalysis of ester
polymers were custom-made for application in humans. hydrolysis. The formation of propylene fumarate oligo-
Polyanhydrides, a versatile family of biodegradable and mers was reported for use in bioerodible bone cement
biocompatible polymers, are one of these.
Biodegradable polyanhydrides based on aromatic
and aliphatic dicarboxylic acids have been studied as
composites.2,6 The effects of the oligomer molecular
*Authortowhomcorrespondenceshouldbeaddressed. E-mail:
sbs@bgu.ac.il
Israel Journal of Chemistry
Vol. 45
2005 pp. 411–420

412
pyridine (3 mL) and heated to reflux with constant stirring.
Propylene oxide (200 mL) was added dropwise over 14 h until
a clear solution was obtained. The solvent was evaporated to
dryness to yield the PFP trimer as a slightly yellow viscous oil.
weight and end groups on the chemical and mechanical
properties have been investigated.2 Although oligomers
and trimers play an important role in the complex bulk
degradation mechanism, only a few works have studied
their influence on degradation and their combination
in copolymers and copolyanhydrides for use as drug
carriers.
In this paper, we describe the preparation of new
biodegradable copolyesters and copolyanhydrides using
trimers and oligomers of fumaric and succinic acids.
The copolymers were prepared by condensation without
solvent in the requested molar or weight ratios. Their
importance lies in their unique structure, which can be
degraded by hydrolysis into nontoxic products that are
easily eliminated from the body. The polymers were
evaluated for their degradation properties and their po-
tential use as controlled delivery carriers of drugs.
1
δ H NMR (CDCl3): 1.15 (d, 3, J = 6.3 Hz); 1.26 (d, 3, J =
6.6 Hz); 3.67 (m, 1); 4.07 (m, 2); 4.19 (m, 2); 5.03 (m, 1); 6.89
(d, 2, J = 8.1 Hz). IR data: 1630, 1720, 3380, cm–1. Elemental
analysis: (C10H16O6) C, 51.67, H, 7.02 (Calcd. C, 51.72, H,
6.89). Titration with NaOH of PFP in acetone solution to the
end point of phenolphthalein revealed the absence of acids.
Preparation of propylene-bis(hydrogen maleate) (MPM)
MPM trimer was synthesized by the reaction of propylene
glycol (0.5 mol, 39 g) and maleic anhydride (1 mol, 98 g) in
toluene (100 mL) at 100 ºC. Propylene glycol was added
dropwise over 15 min into the solution of maleic anhydride in
toluene. After 24 h at 100 ºC, the mixture was left to cool to
room temperature, and a liquid oil was separated. Toluene was
decanted, and the oily residue was evaporated to dryness to
1
produce a viscous liquid. δ H NMR (acetone d6): 1.31 (m, 3);
4.26 (m, 2); 5.14 (m, 1); 6.38 (d, 1, J = 6.0 Hz); 6.78 (d, 1, J =
6.0 Hz); 9.69 (s(br), 2). IR data: 1630, 1720, cm–1. Elemental
analysis: (C11H12O8) C, 48.32, H, 4.61 (Calcd. C, 48.53, H,
4.41). Titration with NaOH confirmed the calculated acid
content.
EXPERIMENTAL
Materials
Succinic anhydride, propane-1,2-diol, fumaric acid, maleic
anhydride, and propylene oxide were obtained from Aldrich
(Milwaukee, WI). Pyridine, toluene, dichloromethane, ether,
and petroleum ether were purchased from Frutarom, Israel.
Preparation of propylene bis-(hydrogen succinate)trimer
(SPS)
Succinic anhydride (1 mol, 100 g) was mixed with toluene
(100 mL) in a bath at 110 ºC. Propane-1,2-diol (0.5 mol,
37.5 mL) was added dropwise during 30 min and the reaction
was left overnight at 110 °C. The mixture was moved to a
separatory funnel. The solvent was removed and the product
was dissolved in ether (200 mL) and precipitated with petro-
Instrumentation
Infrared (IR) spectroscopy was performed on an Anelect
Instruments FT-IR model fx-6160 on samples cast on NaCl
plates from solutions in CH2Cl2. Ultraviolet (UV) spectros-
copy was performed on a Kontron Instruments Uvikon model
930. Thermal analysis was carried out on a Perkin Elmer DSC
7 differential scanning calorimeter, calibrated with Zn and In
standards, at a heating rate of 20 ºC/min. Melting points were
obtained on an electrothermal melting point apparatus (BDH,
Poole, UK). Molecular weights of polymers were estimated on
a gel permeation chromatography (GPC) system consisting of
a Spectra Physics (Darmstadt, Germany) P1000 pump with
UV detection (Applied Bioscience 759A Absorbance UV de-
tector) at 254 nm, a Rheodyne (Coatati, CA) injection valve
with a 20 µL loop, and a Spectra Physics Data Jet integrator.
Samples were eluted with CHCl3 through a linear Styrogel
column (10-Å pore size) at a flow rate of 1 mL/min. Molecular
weights were determined relative to polystyrene standards
(Polyscience, Warrington, PA) with a molecular weight range
of 400 to 1,500,000 with the aid of a WINner/286 computer
program. 1H NMR spectra (CDCl3/TMS/d/ppm) were ob-
tained on a Varian 300 MHz spectrometer.
1
leum ether (500 mL). δ H NMR (CDCl3): 1.225 (d, J = 6.9 Hz,
CHCH3); 2.642 (m, CH2CH2); 4.058 (dd, Jaa = 12.0 Hz,
J″ab = 6.3 Hz, CHCH″H′); 4.197 (dd, CHCH′H″, Jaa =
12.0 Hz, J′ab = 3.0 Hz); 5.156 (ddq, J′ab = 3.0 Hz, J″ab =
6.3 Hz, Jac = 6.9 Hz, CH3CHCH′H″). δ 13C NMR (CDCl3):
178.2, 178.1, 171.9, 171.7, 68.6, 66.2, 28.9, 28.7, and 16.2 ppm.
IR data: 2938, 1736, 1719, 1407, and 1165 cm–1. Elemental
analysis: C, 47.79; H, 5.88 (Calcd. C, 47.83; H5.60).
Preparation of poly(propylene succinate)-diol (PPS)
Succinic anhydride (0.5 mol, 50.0 g) and propane-1,2-diol
(0.6 mol, 45 mL) were mixed together and remained overnight
at 140 ºC. Afterward, 100 mL of toluene and 150 mL of
concentrated H2SO4 were added. The reaction was connected
to a system of Dean–Stark and was heated in a bath at 155 ºC
for 12 h. The solvents were evaporated to give the crude
product. The transparent yellow oligomer was dissolved in
dichloromethane (150 mL) and precipitated with 600 mL of
ether/petroleum ether (70:30), the upper layer was removed,
and the solvent was evaporated to get PPS-diol with a molecu-
Synthesis of Polyesters and Polyanhydrides based on
Propylene Fumarate and Succinate
1
Preparation of bis(2-hydroxypropyl fumarate) trimer
(PFP trimer)
lar weight of Mw = 3100, Mn = 2030. δ H NMR (CDCl3):
1.232 (m, CHCH3); 2.620 (m, CH2CH2); 4.039–4.188 (m,
PFP trimer was synthesized as previously described.16 In CH2CH); 5.133 (m, CHCH3). IR data: 3464, 2984, 1736, 1411,
brief, PFP trimer was prepared as follows: fumaric acid 1379, and 1161 cm–1. Elemental analysis: (C136H179O78) C,
(1 mol, 116 g) was mixed with acetone (200 mL) and dry 53.79; H, 6.18 (Calcd. C, 53.75; H, 5.85).
Israel Journal of Chemistry
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413
Preparation of poly(propylene fumarate) di-succinate
under a pressure of 0.1–0.5 mmHg for 30 to 180 min. Charac-
A solution of PFP trimer (0.1 mol, 23.2 g) and succinic terization of the copolyesters was carried out by GPC,
anhydride (0.2 mol, 20.0 g) in toluene (100 mL) was melt 1H NMR, IR, and DSC.
1
mixed at 100 ºC for 10 h. Afterward, the reaction mixture was
P(MPM-SA): δ H NMR (CDCl3): 1.243 (m, CHCH3);
dissolved in dichloromethane (200 mL) and filtered. The sol- 1.311 (m, (CH2)4CH2CH2COOCO); 1.643 (m, CH2CH2COO-
vent was evaporated to dryness to get bis-(hydroxypropylene CO); 2.435 (t, Jab = 7.2 Hz, CH2COOCO); 4.187–4.381 (m,
fumarate)-di-succinate with a molecular weight of Mw = 554, CHCH2); 5.214–5.330 (m, CHCH2); 6.329 (m, CH = CH-
1
Mn = 482. δ H NMR (CDCl3): 1.231–1.346 (m, CHCH3); anhydride); 6.873 (m, CH = CH, ester). IR data: 2930, 2851,
2.617–2.798 (m, CH2CH2); 4.100–4.408 (m, CHCH2); 5.161– 1812, 1741, 1473, 1412, and 1043 cm–1.
1
5.371 (m, CHCH3); 6.211–6.388 and 6.807–6.910 (m, CH =
P(MPM): δ H NMR (CDCl3): 1.242–1.398 (m, CHCH3);
CH). IR data: 3455, 2985, 1725, 1645, 1456, 1296, 1161, and 4.218–4.371 (m, CHCH2); 5.277 (m, CHCH3); 6.384 (m,
1079 cm–1. Elemental analysis: (C10H16O6) C, 51.67; H, 7.02 CH = CHCOOCO anhydride); 6.818–7.004 (m, CH =
(Calcd. C, 51.72, H, 6.89).
CHCOO ester). IR data: 2990, 1803, 1732, 1639, 1454, 1386,
1230, and 1074 cm–1.
Preparation of propylene bis(hydrogen maleate)di-
acetate (MPMpp)
P(SPS): δ 1H NMR (CDCl3): 1.241 (d, Ja = 6.6 Hz,
CHCH3); 2.726 (m, CH2CH2); 4.085 (dd, Jaa = 11.7 Hz,
J″ab = 6.6 Hz, CHCH″H′); 4.196 (dd, Jaa = 11.7 Hz, J′ab =
3.3 Hz, CHCH′H″); 5.156 (ssq, J′ab = 3.3 Hz, J′ab 6.6 Hz, Jac
= 6.6 Hz, CH3CHCH′H″). IR data: 2942, 1822, 1737, 1411,
1358, 1181, and 1051 cm–1.
Pre-polymers of diacids were prepared as previously de-
scribed.17 In brief, MPM trimer (0.1 mol, 27.2 g) was added to
boiling acetic anhydride (350 mL) for 30 min. The solvent was
evaporated at 60 ºC, and the viscous liquid was dissolved in
dichloromethane (100 mL) and washed in ether (500 mL). The
lower layer was separated and the residue of solvent was
1
P(SPS-SA): δ H NMR (CDCl3): 1.245 (d, J = 6.6 Hz,
CHCH3); 1.307 (m, (CH2)4CH2CH2COOCO); 1.640 (m,
CH2CH2COOCO); 2.423 (t, J = 7.5 Hz, CH2COOCO); 2.644
(m, CH2CH2); 2.746 (m, CH2CH2); 4.090 (dd, Jaa = 12.3 Hz,
J″ab = 6.6 Hz CHCH″H′); 4.202 (dd, Jaa = 12.3 Hz, J′ab =
3.3 Hz, CHCH′H″); 5.132–5.192 (ddq, J′ab = 3.3 Hz, J″ab =
6.6 Hz, Jac = 6.6 Hz, CH3CHCH′H″). IR data: 2931, 2852,
1815, 1741, 1472, 1413, and 1045 cm–1.
1
evaporated. δ H NMR (CDCl3): 1.255–1.377 (m, CHCH3);
2.217 (s, CH3COOCO); 4.131–4.391 (m, CHCH2OCO);
5.210–5.369 (m, OCH(CH3)CH2); 6.208–6.399 (m, CH =
CHCOOCO); 6.751–6.920 (m, CH = CHCOOCH2). IR data:
2992, 1817, 1732, 1641, and 1096 cm–1.
Bis-(2-hydroxypropyl fumarate)di-succinate (PFP-
disuccinate)
P(PPF-SUCC-SA): δ 1H NMR (CDCl3): 1.315 (m,
(CH2)4CH2CH2COOCO); 1.647 (m, CH2CH2COOCO); 2.437
(t, J = 7.2 Hz, CH2COOCO); 2.714 (m, CH2CH2); 4.061–
4.390 (m, CHCH2); 5.179–5.388 (m, CHCH3); 6.844 (m, CH
= CH). IR data: 2930, 2851, 1810, 1739, 1472, 14212, 1360,
1286, and 1044 cm–1.
1
δ H NMR (CDCl3): 1.211–1.335 (m, CHCH3); 2.625 (sbr,
CH2CH2); 4.011–4.391 (m, CHCH2); 5.177–5.383 (m,
CHCH3); 6.814–6.868 (m, CH = CH). IR data: 2985, 1723,
1646, 1357, 1297, and 1159 cm–1.
Poly(propylene fumarate)di-succinate (PPF-succinate)
1
Preparation of triblock copolymer of poly(propylene
fumarate) or succinate-ester with lactones (PLA, PCL,
PTMC, and PLGA
δ H NMR (CDCl3): 1.231–1.346 (m, CHCH3); 2.617–
2.798 (m, CH2CH2); 4.100–4.408 (m, CHCH2); 5.161–5.371
(m, CHCH3); 6.211–6.388 and 6.807–6.910 (m, CH = CH). IR
data: 3455, 2985, 1725, 1645, 1456, 1296, 1161, and 1079 cm–1.
Poly(propylene fumarate) diol (2.0 g) was dissolved in
60 mL dry toluene. The solution was heated to 135 ºC, and
8.0 g of cyclic monomer was added. The system was boiled for
60 min and afterward a stannous octoate (1% in toluene, 0.2%
in ratio with the cyclic monomer) was added. The reaction
mixture was heated and stirred for > 5 h. The solvent was
evaporated with argon for 2 h following vacuum of
1–0.5 mmHg for 15 min. The yellow viscous polymer was
stored in dry conditions. The copolyesters in Table 2 were
prepared using the same procedure.
Propylene bis-(hydrogen succinate)pre-polymer (SPSpp)
1
δ H NMR (CDCl3): 1.220–1.241 (m, CHCH3); 2.200 (s,
CH3COCO); 2.592–2.798 (m, CH2CH2COO); 4.014–4.205
(m, CH2CH); 5.145 (m, CHCH3). IR data: 2988, 2943, 1822,
1737, 1412, 1316, 1179, and 1081 cm–1.
Poly(propylene fumarate)di-succinate pre-polymer
1
δ H NMR (CDCl3): 1.260–1.348 (m, CHCH3); 2.221 (s,
CH3COOCO); 2.722–2.798 (m, CH2OCOOCCH2CH2);
2.8721–2.964 (m, CH = CHOCCH2CH2); 4.128–4.391 (m,
CHCH2); 5.169–5.370 (m, CHCH3); 6.244, 6.387 and 6.847
(m, CH = CH). IR data: 2988, 1823, 1787, 1725, 1646, 1297,
1260, and 1080 cm–1.
1
PPF-PCL: δ H NMR (CDCl3): 1.281 (m, CHCH3); 1.358
(m, CH2CH2(CH2)2CH2COO); 4.038 (t, J = 6.6 Hz,
CH2CH2COO); 4.208–4.365 (m, CHCH2); 5.163 (m,
CHCH3); 6.218 (m, CH = CH); 6.856 (m, CH = CH). IR data:
2946, 2867, 1727, 1367, 1295, 1244, and 1191 cm–1.
Preparation of copoly(anhydride-ester)
PPF-PTMC: δ 1H NMR (CDCl3): 1.314 (m, CHCH3);
All polymers were prepared by the same method. The pre- 2.041 (p, J = 6.3 Hz, CH2CH2CH2COOCO); 4.229 (t, J = 6.3
polymers were polymerized by condensation without solvent. Hz, CH2CH2OCOO); 4.266 (m, CHCH2); 5.216 (m, CHCH3);
The pre-polymer mixtures in the requested molar or weight 6.241 (m, CH = CH); 6.830 (s(br), CH = CH). IR data: 2972,
ratios were polymerized at a temperature of 160 ºC or 180 ºC 2909, 1798, 1747, 1460, 1407, 1331, 1248, and 1034 cm–1.
Ben-Shabat et al. / Biodegradable Copolyesters and Copolyanhydrides

414
1
PPF-PLA: δ H NMR (CDCl3): Multiplates at 1.339, 1.553,
The implantation areas and the residues of the polymers
4.277, 5.161, 6.227, and 6.817 ppm. IR data: 2994, 1753, were removed and examined by light microscopy following
1453, 1382, 1268, 1189, 1131, 1092, and 1052 cm–1.
routine tissue processing and hematoxylin and eosin slide
1
PPS-PLA: δ H NMR (CDCl3): Multiplates at 1.240, 1.561, preparation, as described elsewhere.17
2.628, 4.122, and 5.153 ppm. IR data: 2993, 2945, 1745, 1454,
1381, 1269, 1188, and 1091 cm–1.
RESULTS AND DISCUSSION
Preparation of copolymers of fumaric or muconic acid
with sebacic acid
Preparation and Characterization of Polymers
Trimers and oligomers of fumaric and succinic acids
were used for the preparation of new polyesters and
polyanhydrides. The polymers were prepared from tri-
mers and oligomers composed of propane-1,2-diol, suc-
cinic and maleic anhydride, and were polymerized to
give copolyanhydrides and copolyesters. Propylene bis-
(hydrogen succinate) trimer (SPS) was prepared by
condensation reaction between propane-1,2-diol with
succinic anhydride in a molar ratio of 2:1 (Fig. 1).
Changing the ratio to 1:1.1 led to the poly(propylene
succinate)-diol (PPS) with molecular weight of Mw =
3100, Mn = 2030 (Fig. 1).
Sebacic acid (5.0 g) and fumaric or muconic acid (5.0 g)
were stirred with 70 mL acetic anhydride at 180 ºC for 40 min.
The residue of the acetic anhydride was removed by evapora-
tor and the mixture was polymerized at 180 ºC for 30 min.
Copoly(fumaric acid-co-sebacic acid) P(PA-SA): δ
1H NMR (CDCl3): 1.305 (m, CH2CH2CH2CH2COO); 1.636
(m, CH2CH2COO); 2.625 (t, J = 7.2 Hz, CH2CO); 6.891 (s,
CH). IR data: 2918, 2879, 1812, 1778, and 1171 cm–1.
Copoly(muconic acid-co-sebacic acid) P(MA-SA)
δ
1H NMR (CDCl3): 1.311 (m, CH2CH2CH2CH2CO);
1.642 (m, CH2CH2CO); 2.434 (t, J = 7.4 Hz, CH2CO); 6.260
(d, J = 5.4 Hz, CHCHCO); 7.0404 (d, J = 5.4 Hz, CHO). IR
data: 2935, 2859, 1809, 1748, and 1125 cm–1.
For the preparation of polyanhydride acetate
anhydride derivatives of the carboxylic acid end were
prepared from the reaction with acetic anhydride.
Homo- and copolyanhydrides based on trimers of succi-
nate and fumarate, poly(propylene succinate) and
poly(propylene fumarate)anhydrides and their copoly-
mers with sebacic acid were synthesized by melt con-
densation (Table 1). Characterization of the copoly-
anhydride esters was carried out with GPC, NMR, IR,
and DSC. The polymers obtained from PPF-dicarboxy-
late and HPM were dark colored due to the presence of
double bonds in the polymeric chain and conjugation
between these bonds and the anhydride bonds. In order
to obtain light polymer, the PPF-disuccinate was pre-
pared in various molecular weights leading to an
unconjugated system. The units were prepared by reac-
tion between PPF-diol or propylene fumarate (PFP)
with an equivalent amount of succinic anhydride
(Fig. 2). These diacid derivatives were polymerized to
get light polyanhydrides.
The oligomers of PPS and PPF can also be used for
the synthesis of copolyesters. The oligomers contain
two terminal hydroxyl groups that can react with cyclic
monomer, such as lactide, glycolide, caprolactone, and
trimethylene carbonate in coordinative catalysis and
ring-opening polymerization, while the hydroxyl groups
are initiating the polymerization (Fig. 3). In that way we
obtained ABA triblock copolyesters from type in differ-
ent molecular weights (Table 2).
In Vitro Hydrolytic Degradation
Rectangular polymer specimens prepared by melt molding
were placed in 20 mL of 0.1 M phosphate buffer, pH 7.4, at
37 ºC with continuous shaking (100 rpm). At each time point,
as requested, a polymer sample was removed from the buffer
and dried at room temperature under high vaccum for 2 h. The
hydrolysis of the polymer was monitored in terms of weight
loss of the sample (GPC) and disappearance of the anhydride
bonds (IR spectroscopy).
In Vitro Drug Release
The drug, 5 wt% ibuprofen, was dispersed in the polymer
solution, and the solvent was removed under vacuum. Tablets
were prepared by melt casting of the polymer–drug mixture
into 3 × 5 × 8 mm slabs. In vitro drug release was determined
in 0.1 M phosphate buffer, pH 7.4, at 37 ºC. Ibuprofen concen-
trations in the solutions were determined by UV absorption at
287 nm.
In Vivo Biocompatibility and Polymer Elimination
The biocompatibility and the rate of evacuation of trimer-
based polymers of fumaric and succinic acids, P(MPM-SA)
50:50, P(SPS-SA) 50:50, and 1:1:1 PPS-PLGA, were investi-
gated in rats. Three representative polymers from the above
series were chosen for in vivo evaluation. Smooth disks of 2 ×
5 × 10 mm were prepared in clean conditions. The disks were
sterilized in γ irradiation (2.5 Mrad) and were examined in
GPC to confirm that there is no influence on their molecular
weight as well as on their mechanical and spectral properties.
The clean samples of the polymers and the synthetic sur-
gery wire Vicryl, used as control, were implanted subcutane-
ously in two different sites at the dorsal side of the rats. In
these studies 20 rats were used and 2 samples of polymers
were implanted in each rat simultaneously and in sterilized
conditions. Table 3 describes the different groups of rats and
their scarifying time in days.
In Vitro Degradation Properties and Drug Release of
the Polymers
The polymer degradation for several synthetic
polyanhydrides was evaluated following the decrease in
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415
Table 1. Polyanhydrides based on propylene fumarate or succinate and fumaric or muconic acids
Fig. 1. Schematic description for the preparation of bis-(hydrogen succinate) (SPS) and poly(propylene succinate)-diol (PPS)
trimers.
Fig. 2. Reaction between poly(propylene fumarate)-diol (PPF-diol) and succinic anhydride for the preparation of poly(propylene
fumarate)-di-succinate (PPF-succinate).
Ben-Shabat et al. / Biodegradable Copolyesters and Copolyanhydrides

416
molecular weight (GPC), weight loss, loss of anhydride P(MPM-SA), at the same conditions, present the typical
bonds (IR), and absorption of water. Penetration of profile reported in the literature for polyanhydride5 (Fig.
water into the polymer matrix leads to hydrolysis of 5a,b). As shown in Fig. 5, decrease in the molecular
anhydride and ester bonds and results in a decrease in weight from 110,000 to about 5,000 and weight loss of up
molecular weight.18–20 The rate of loss in the anhydride to 55% occurred during the first 48 hours of the polymer
bonds in copolymers that contain sebacic acid increased degradation. It is possible also to conclude that a higher
with the rise in sebacic acid content in the polymer. percentage of the trimers SPS and MPM in the polymer
Water absorption of copolyanhydride of P(SPS-SA) and leads to a faster weight loss of the respective polymer
P(MPM-SA) in phosphate buffer was found to act simi- resulting from the water solubility of these trimers. The
larly. With higher sebacic acid content in the copoly- release of ibuprofen from the polymers was examined
mer, water absorption increased (Fig. 4). Hydrolytic and showed complete correspondence between the water
degradation of the polyanhydrides, P(SPS-SA) and absorption and drug release (Fig. 6). Fast water absorption
Fig. 3. Preparation of triblock copoly(propylene fumarate or succinate) with cyclic monomers.
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417
Table 2. Structures of copolyesters based on PPS and PPF
Table 3. Groups of rats and their scarifying time in days. The experiment was conducted for 21 days, 6 animals were sacrificed
at 3, 7, and 21 days after the implantation. The final group was sacrificed at the 21st day
group
A
number of animals
test-article
sacrifice time, days (no. of animals)
3 (2), 7 (2), 21 (2)
6(3 × 2)
P(MPM-SA) 50:50
(Left and right sides)
P(SPS-SA) 50:50
(Left and right sides)
PPS-PLGA (1:1:1)
(Left and right sides)
Vicryl
B
C
D
6(3 × 2)
6(3 × 2)
2(1 × 2)
3 (2), 7 (2), 21 (2)
3 (2), 7 (2), 21 (2)
(Left and right sides)
21 (2)
Fig. 4. Water gain, described by weight change of copolyanhydride esters in different ratio mixtures during hydrolysis.
Molecular weight was determined by GPC. Hydrolysis was conducted in phosphate buffer, pH 7.4, at 37 ºC. SD 5%.
Ben-Shabat et al. / Biodegradable Copolyesters and Copolyanhydrides

418
leads to rapid hydrolytic degradation of the polymer ma-
trix and hence to solubility and secretion of the drug by
diffusion.
Similar in vitro experiments were performed for the
copolyesters and copolycarbonate esters under the same
conditions. The selected polymers were PPS-PLA, PPS-
PLGA, and PPS-PTMC in diverse ratios. The decrease in
the molecular weight for the copolyesters PPS-PLA and
Fig. 5. Degradation studies at different ratios. (A) Weight loss
of copolyanhydride esters. (B) Change in molecular weight
during hydrolytical degradation of copolyanhydride esters.
Molecular weight was determined by GPC. Hydrolysis was
conducted in phosphate buffer, pH 7.4, at 37 ºC. SD 5%.
Fig. 7. (a) Ibuprofen release from polymer tablets of PPS-PLA
in different ratios. (b) Ibuprofen release from polymer tablets
Fig. 6. In vitro ibuprofen release from mixtures of copoly- of PPS-PLGA in different ratios. (c) Ibuprofen release from
anhydride esters in different ratios. Release from 5 wt% polymer tablets of PPS-PTMC in different ratios. Release
loaded ibuprofen in polymer tablets was conducted in phos- from 5 wt% loaded ibuprofen in polymer tablets was con-
phate buffer, pH 7.4, at 37 ºC and determined by UV at ducted in phosphate buffer, pH 7.4, at 37 ºC and determined by
287 nm. SD 5%.
UV at 287 nm. SD 5%.
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419
PPS-PLGA was found to be the same, up to 4000 after 4 swelling or pathological signs during the experiment or
weeks in phosphate buffer (data not shown). Figure 7 a,b at time of sacrificing. The implantation sites were clean
describes the total release of the ibuprofen from the and normal, without inflammatory or swelling signs.
copolyesters (PPS-PLA and PPS-PLGA) for 4 weeks, and The residues of the polymers were removed easily with
Fig. 7c describes the release of the drug from the triblock almost complete elimination at day 21. Improvement in
copolycarbonate esters (PPS-PTMC) for the same period. the tissues over time was found in all the groups and in
The polymer PPS-PTMC in a ratio of 1:2 showed release biocompatibility at the implantation site.
of 80% of ibuprofen, while in a ratio of 1:4 it showed
In general, the degree of severity in the tissues 21
release of 50%, after 4 weeks of the experiment (Fig. 7c). days after implantation, for groups (A), P(MPM-SA),
In this way it is possible to accelerate the degradation rate and (B), P(SPS-SA), were essentially equal to those
of polycarbonates that are known for their high hydro- obtained for group D, the synthetic surgery wire Vicryl.
lytical stability. This stability was the major obstacle to The degree of inflammation severity for group C (PPS-
using the polycarbonates as degradable polymers.
PLGA) was clear and without any specific findings
relative to those observed for groups (A) and (B) at all
times (Table 4).
Biocompatibility and Elimination
All animals implanted with polymer were in good
Histopathology examinations of tissues at the implant
health and gained weight throughout the study. Macro- site, showed slight inflammation at a degree of 1–2, on a
scopic examination of the implant site indicated no scale of 1–5, where 5 is determined as severe damage.
Table 4. Degree of inflammation at the closest areas to the tissues that were in contact with the implanted polymers: (A) Shem
(control) and Vicryl after 21 days of implantation. (B) The polymers at all scarifying times
(A)
Shem
2
Vicryl
2
Implants (n)
Lesion
Hemorrhage
Edema
Necrosis
Vascular inflammation
Acute inflammation
Subcutaneous inflammation
Giant cells
0
0
0
0
0
0
0
0
0
0
0
0.5
0
1.5
0
2.0
2.0
2.0
2.0
0.1
Fibrosis
Foreign material
Thickness of inflammatory layer (mm)
(B)
P(SPS-SA)
P(MPM-SA)
PPS-PLGA
Implants (n)
Sacrifice day
Lesion
4
4
4
7
3
21
4
4
4
7
3
21
2
4
4
7
4
21
Hemorrhage
Edema
Necrosis
Vascular inflammation
Acute inflammation
Subcutane inflammation
Giant cells
Fibrosis
Foreign material
Thickness of inflammatory layer (mm) 0.38
0.75
1.0
0
0.25
1.5
2.6
0
0
1.0
0
1.75
0.75
2.0
0.75
1.5
1.25
0.6
0
1.0
0
1.0
0.6
2.0
1.6
2.0
1.6
0.32
0.5
1.0
0
0.25
1.5
2.0
0.25
0.75
3.0
0.4
0.5
1.25
0.5
0
0.6
0
1.3
1.0
2.0
2.0
1.6
2.0
0.3
0
0.5
0
1.0
1.0
1.0
0
1.0
2.0
0
1.0
0
0.5
1.0
1.0
1.0
1.0
2.0
0
0
0
0
0
1.25
1.5
2.0
1.5
1.75
2.25
1.0
1.5
2.25
0.65
1.0
2.0
1.75
0.2
0.08
0.21
Toxicity rating: 0—no remarkable change; 1—minimal change; 2—moderate change, and 3—marked change.
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420
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This level of inflammation is similar to that of the
clinically used PLA-based polymers (Vicryl). In all
cases no encapsulation of the polymer by the tissue was
found.
CONCLUSIONS
This work describes the formation of a range of poly-
anhydrides and polyesters made from trimers of fumaric
and succinic acid and propylene glycol. All polymers
were found to degrade within a period of weeks. Poly-
anhydrides loaded with ibuprofen as model drug re-
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