Copolymers of an aromatic anhydride and aliphatic ester

A copolymer of an aromatic anhydride and an aliphatic ester suitable for use in surgical devices and a process for making said copolymer.

BACKGROUND OF THE INVENTION 
This invention relates to copolymers of aromatic anhydrides and aliphatic 
esters. More specifically, it relates to copolymers of aromatic anhydrides 
and aliphatic esters particularly well suited for melt processing to 
prepare biomedical devices, especially wound closure devices. 
Polymers of aliphatic and aromatic anhydrides have been extensively studied 
for many years. As long ago as the 1930's, Carothers had prepared a series 
of aliphatic polyanhydrides for use as fibers in the textile industry (see 
J. Am. Chem. Soc., 54, 1569 (1932)). Later, in the mid 1950's, Conix was 
able to synthesize aromatic polyanhydrides with improved film and fiber 
forming properties (see J. Polym. Sci., 29 343 (1958)). However, these 
early attempts to make polyanhydrides with outstanding properties were 
unsuccessful because these polyanhydrides exhibited poor thermal and 
hydrolytic stability. Therefore, during this time, no commercial 
applications of polyanhydrides were found. 
More recently polyanhydrides with sustained drug release properties have 
been made. U.S. Pat. No. 4,757,128, and Domb et al., J. of Polymer Sci., 
25, 3373 (1987), disclose the preparation of polyanhydrides from pure, 
isolated prepolymers of diacids and acetic acid under well defined 
polymerization reaction conditions of temperature and time, optionally in 
the presence of a coordination catalyst. The molecular weight of the 
polyanhydrides prepared from the isolated prepolymers is reported to be 
higher than that achieved when an unisolated prepolymer mixture is used. 
However, as stated by Domb et al., the polyanhydrides depolymerize to form 
a rubbery gel if the polymerization temperature is maintained at elevated 
temperatures for an extended period of time. 
The synthesis techniques described by Domb have lead to the use of 
polyanhydrides as biodegradable matrices for the controlled release of 
biologically active substances. See, for example, U.S. Pat. No. 4,857,311, 
and U.S. Pat. No. 4,888,176. One of the factors which make a polyanhydride 
particularly well suited as a biodegradable matrix is that it breaks down 
into biocompatible degradation products based on the monomeric diacids 
when exposed to moist bodily tissue for extended periods of time. These 
biocompatible degradation products can be readily passed through the 
tissue without any significant tissue response or harm to the digestive or 
vascular systems. 
Recent attempts have been made to optimize the synthesis of anhydride 
copolymers. Specifically, anhydride copolymers which will exhibit longer 
release and degradation times when used as a matrix for drug release have 
been studied. U.S. Pat. No. 4,789,724 describes preparing copolymers from 
individually prepared, isolated prepolymers. Domb, Macromolecules, 25, 12 
(1992), describes preparing relatively low molecular weight (I.V.&lt;0.45 
dl/g) aromatic copolymers of anhydrides which are highly soluble in 
conventional solvents, and therefore suitable for the preparation of 
solvent cast drug release devices. 
Although the extensive studies performed by Domb and his colleagues, as 
described above, have shown the feasibility of preparing cert in 
polyanhydrides which are suitable as matrices for drug release, this 
significant class of polyanhydrides are unsuitable for numerous biomedical 
applications, especially for the preparation of implantable devices for 
wound closure. Upon a careful review of Domb's work, it becomes apparent 
that Domb was able to prepare aliphatic polyanhydrides of high molecular 
weight, but the reported values for the molecular weight of polyanhydrides 
which are predominately aromatic are too low for conventional melt 
processing techniques required to make biomedical devices. Although it is 
possible to prepare drug delivery devices from aliphatic polyanhydrides, 
it is most likely that it would not be possible to make biomedical devices 
from the aliphatic polyanhydrides described in Domb due to their poor 
thermal stability. However, it would be highly desirable to fabricate 
devices from polymers which can withstand the effects of melt processing 
and sterilization using conventional melt processing and irradiation 
techniques. In this regard, the incorporation of aromatic functionality in 
the polymer chains of the polyanhydride is critical for the application of 
melt processing to fabricate biomedical devices or the application of 
irradiation to achieve sterilization. See, for example, U.S. Pat. Nos. 
4,435,590, 4,510,295, and 4,546,152, which describe the preparation of 
polymers for biomedical applications with a high degree of aromatic 
functionality capable of withstanding the effects of irradiation for 
sterilization. 
Other polymer compositions containing anhydride functionality have been 
described in the literature. For example, U.S. Pat. No. 4,414,381 
describes the preparation of aromatic poly(ester-anhydride) copolymers. 
These copolymers are described as being melt processable, and useful for 
preparing fibers, films and molding powders. Unfortunately, these 
copolymers are not bioabsorbable, and therefore are unsuitable for 
numerous implantable, medical device applications. 
The failure of Domb and others to synthesize bioabsorbable, aromatic 
polyanhydride polymers with high molecular weights limits the suitability 
of such polyanhydrides to their use as biomedical devices. Additionally, 
it would be highly desirable to develop aromatic polyanhydride containing 
polymers, such as aliphatic polyesters, which were quickly absorbable in 
vivo. In view of these deficiencies, it would be most desirable if an 
aromatic polyanhydride copolymer could be developed which was 
bioabsorbable. Accordingly, it would be desirable to prepare copolymers 
that contain an aromatic polyanhydride which exhibits the requisite 
bioabsorbability for the preparation of biomedical devices, especially 
using melt processing techniques such as injection or extrusion molding. 
Likewise, it would be desirable to prepare copolymers that contain 
aromatic polyanhydrides which have outstanding thermal and dimensional 
stability at elevated temperatures for prolonged periods, and the ability 
to maintain physical and biological properties upon sterilization using 
conventional irradiation techniques. All of these properties would be most 
beneficial in a bioabsorbable polymer which contains an aromatic 
polyanhydride for the preparation of biomedical devices, especially 
implantable wound closure devices and adhesion prevention barriers which 
are absorbable in bodily tissue without causing adverse tissue response or 
other adverse reactions. 
SUMMARY OF THE INVENTION 
In one aspect, the invention provides a novel copolymer of an aromatic 
polyanhydride and aliphatic ester. 
In another aspect, the invention provides a process for preparing a 
copolymer of an aromatic anhydride and an aliphatic ester. 
Unlike the aromatic polyanhydrides of the prior art, the copolymers 
prepared from an aromatic anhydride and an aliphatic ester exhibit 
suitable bioabsorbability profiles and the necessary physical properties 
for incorporation into sutures and other bioabsorbable devices. Moreover, 
their outstanding thermal stability has made it possible to melt process 
the copolymers of this invention. In combination with the mechanical 
properties of articles so produced, numerous applications of these 
copolymers can be utilized. 
Furthermore, the aromatic anhydride/aliphatic ester copolymers described 
herein are relatively stable to the effects of conventional radiation 
treatments. 
Therefore, the outstanding mechanical properties of these copolymers are 
not sacrificed when the copolymers are exposed to radiation required for 
sterilization of medical grade parts. 
The aromatic anhydride/aliphatic ester copolymers exhibit desirable 
bioabsorbability when exposed to bodily tissue. The overall spectrum of 
properties for this new class of polymers is particularly well-suited for 
the preparation of biomedical devices, especially implantable wound 
closure devices such as surgical staples, clips and sutures. Furthermore, 
their application as drug delivery vehicles as well as adhesion prevention 
barriers should also be apparent.

DETAILED DESCRIPTION OF THE INVENTION 
The aromatic anhydride/aliphatic ester copolymer of the present invention 
possess physical properties which render the copolymers suitable for drug 
delivery systems, extrusion into fibers or films, injection molding into 
surgical devices such as staples, clips and the like. 
Generally these polymers contain a mole ratio of aromatic anhydride 
repeating unit to aliphatic ester repeating unit of from 95:5 to 5:95 and 
most preferably have a mole ratio of from 10:90 to 90:10. The lower limit 
of the aliphatic ester repeating unit is desirable because the addition of 
5 mole percent of ester provides faster bioabsorbability to the copolymer. 
The lower limit of aromatic anhydride repeating unit is desirable because 
the addition of 5 mole percent of an aromatic anhydride allows the 
copolymer to be radiation sterilized using conventional irradiation 
techniques. 
The aromatic anhydride repeating unit incorporated in the copolymer are 
provided by polymerizing an aromatic anhydride with an aliphatic ester. 
Suitable aromatic anhydride repeating units may be selected from the group 
consisting of aromatic repeating units having the formula: 
##STR1## 
where Y is preferably a direct link but may be a divalent 
--(CH.sub.2).sub.n --or --(CH.sub.2).sub.n O--radical in which n may be 
from 1 to 4 and the ether oxygen, if present, is directly linked to X, and 
the: 
##STR2## 
groups are symmetrically disposed on the divalent aromatic radical X, 
wherein X is selected from the group consisting of 
##STR3## 
wherein R is selected from the group consisting of a --(CH.sub.2).sub.q 
--where q is an integer from 1 to 20, --0--, --C(CH.sub.3).sub.2)--, 
(--(O--(CH.sub.2).sub.m).sub.n --where m is an integer form 1 to 20 and p 
is an integer form 0 to 20, 
##STR4## 
wherein R.sup.1 is selected from the group consisting of --0--, 
--C(CH.sub.3).sub.2 --; and n is an integer from 1 to 4 and combination of 
two or more thereof. Preferred are aromatic anhydride repeating units 
selected from the group of aromatic repeating units having the formula: 
##STR5## 
wherein r is an integer from 1-20; and 
##STR6## 
wherein s is an integer from 1-20 and t is an integer from 0-20. 
Most preferred are aromatic repeating units wherein r is an integer from 2 
to 6. Suitable monomers to provide these repeating units are aromatic 
anhydride monomers selected from the group consisting of 
1,2-bis(p-carboxyphenoxy)ethane anhydride, 
1,3-bis(p-carboxyphenoxy)propane anhydride, 
1,4-bis(p-carboxyphenoxy)butane anhydride and 
1,6-bis(p-carboxyphenoxy)hexane anhydride and combinations of two or more 
thereof. 
Suitable aromatic anhydrides for use in the present invention may be 
prepared by known processes, such as by heating an appropriate aromatic 
dicarboxylic acid in the presence of an excess of an anhydride of a 
monofunctional carboxylic acid, such as acetic anhydride. Alternatively 
free acids or their alkali metal salts may be reacted with acyl chlorides 
to provide the desired aromatic anhydride. The conventional steps of 
reacting an aromatic dicarboxylic acid with an anhydride to form an 
aromatic anhydride monomer, isolating and purifying the monomer, are 
described in U.S. Pat. No. 4,757,128 (the "'128 patent") and Domb et al., 
J. of Polymer Sci., 25, 3373 (1987), each of which is incorporated by 
reference herein. 
It is preferred for the practice of this invention that, a purified 
dicarboxylic acid essentially free of impurities be used to form the 
aromatic anhydride monomer. The purified dicarboxylic acid is "essentially 
free" of impurities if the amount of non-dicarboxylic or inert impurities 
contained in the acid is no greater than about 0.5 percent of the weight 
of the acid, preferably no greater than about 0.3 percent, and most 
preferably no greater than about 0.1 percent. If the concentration of 
impurities is greater than about 0.5 percent, then it may not be possible 
to carry out the melt polycondensation of the anhydride monomer under 
conditions sufficient to achieve an increased molecular weight which is 
necessary to obtain a molded article which, after melt processing, 
maintains excellent mechanical properties. One suitable method for forming 
an aromatic anhydride monomer from a purified dicarboxylic acid is 
disclosed in U.S. patent application Ser. No. 07/916,919, filed Jul. 20, 
1992, titled Aromatic Polyanhydrides, the text of which is hereby 
incorporated by reference. 
In a preferred embodiment of this invention, the aromatic anhydride monomer 
is prepared from an aromatic dicarboxylic acid by reacting an excess of 
the an anhydride at reflux for at least 60 minutes to form the anhydride 
monomer. This relatively longer reaction period, in comparison to the 
reaction time period of 15 minutes described in the previous literature, 
is advantageously sufficient to react substantially all of the acid with 
the anhydride. Therefore, in this embodiment, it becomes unnecessary to 
attempt removing unreacted anhydride from the reaction mixture. This may 
be significant because the unreacted anhydride may act as an impurity when 
the monomer is polymerized with the aliphatic ester under melt 
polycondensation conditions, causing a destabilizing effect on the 
molecular weight, chemical structure, and thermal stability of the 
aromatic anhydride/aliphatic ester copolymer prepared from this 
polymerization. 
Suitable aliphatic ester comonomers may be selected form the group 
consisting of glycolide, lactide (l, d, dl or meso), trimethylene 
carbonate, p-dioxanone, dioxepanone, delta-valerolactone, 
beta-butyrolactone, epsilondecalactone, 2,5-diketomorpholine, 
pivalolactone, alpha, alpha-diethylpropiolactone, ethylene carbonate, 
ethylene oxalate, 3-methyl-1,4-dioxane-2,5-dione, 3,3-dimethyl 
1,4-dioxane-2, 5-dione, 3-methyl-1,4-dioxane-2,5-dione, 3,3-diethyl-1,4- 
dioxan-2,5-dione, pivalolactone, gammabutyrolactone, 1,4-dioxepan-2-one, 
1,5-dioxepan-2-one, 1,4-dioxan-2-one, 6-8-dioxabicyclooctane-7-one and 
combination of two or more thereof. Preferred aliphatic ester comonomers 
are selected from the group consisting of glycolide, lactide, p-dioxanone, 
trimethylene carbonate and combination of two or more thereof. 
The aromatic anhydride/aliphatic ester copolymers are preferably prepared 
in a two-step polymerization process. The first step is the preparation of 
a aliphatic ester prepolymer via a melt ring-opening polymerization. The 
second step of the polymerization is a melt polycondensation. 
Suitable methods for preparing the aliphatic prepolymers described above 
are well known in the art. The molecular weight of the prepolymer as well 
as its composition can be varied depending on the desired characteristic 
which the prepolymer is to impart to the copolymer. However, it is 
preferred that the aliphatic ester prepolymers from which the copolymer is 
prepared have a molecular weight that provides an inherent viscosity 
between about 0.2 to about 2.0 deciliters per gram (dl/g) as measured in a 
0.1 g/dl solution of hexafluoroisopropanol (HFIP) at 25.degree. C. Those 
skilled in the art will recognize that the aliphatic prepolymers described 
herein can also be made from one or more aliphatic esters. If two or more 
aliphatic esters are use to form the prepolymer then one of the aliphatic 
esters may be caprolactone. 
The prepolymer of the aliphatic ester can be prepared by polymerizing the 
desired proportions of one or more aliphatic esters in the presence of an 
organometallic catalyst and an initiator at elevated temperatures. The 
organometallic catalyst is preferably a tin-based catalyst, e.g. stannous 
octoate, and is present in the monomer mixture at a mole ratio of monomer 
to catalyst ranging from about 15,000 to 80,000/l. The initiator is 
typically an alkanol, a glycol, a hydroxyacid, or an amine, and is present 
in the monomer mixture at a mole ratio of monomer to initiator ranging 
from about 100 to 5000/l. The polymerization is typically carried out at a 
temperature range from 80.degree. to 220.degree. C., preferably 
160.degree.-190.degree. C., until the desired molecular weight and visco 
are achieved. 
After the aliphatic ester prepolymer is prepared, the polymerization of the 
aromatic anhydride and aliphatic ester is preferably performed under melt 
polycondensation conditions at a temperature no less than about 
200.degree. C. under reduced pressure. Higher polymerization temperatures 
may lead to further increases in the molecular weight of the copolymer, 
which may be desirable for numerous applications. The exact reaction 
conditions chosen will depend on numerous factors, including the 
properties of the polymer desired, the viscosity of the reaction mixture, 
and the glass transition temperature and softening temperature of the 
polymer. The preferred reaction conditions of temperature, time and 
pressure can be readily determined by assessing these and other factors. 
For example if the temperature is increased during the melt 
polymerization, transesterification will be favored in the 
polycondensation which will result in the copolymer having a random 
polymeric structure. Similarly the polycondensation conditions can be 
controlled to favor the formation of block copolymers by, for example, 
lowering the temperature and/or shortening the reaction time. 
Generally, after the aliphatic ester prepolymer is formed the temperature 
of the reaction mixture will be increased to about 220.degree. C. and then 
one or more aromatic anhydride monomers or a prepolymer of an aromatic 
anhydride will be added with vigorous stirring to the aliphatic ester 
prepolymer. The polymerization reaction will be allowed to proceed for 
about 15 to 360 minutes at an elevated temperature. The temperature is 
then lowered to about 200.degree. C. The polymerization may continue at 
this temperature until the desired molecular weight and percent conversion 
is achieved for the copolymer, which will typically take about 1 to 24 
hours. 
In another embodiment, copolymers of aromatic anhydride/aliphatic ester can 
be prepared by using a aromatic anhydride prepolymer polymerized under 
melt polycondensation conditions prior to being added to the aliphatic 
ester prepolymer. Once each individual prepolymer is isolated and 
purified, the aromatic anhydride prepolymers will be mixed with the 
aliphatic ester prepolymer and subjected to the desired conditions of 
temperature and time to copolymerize the prepolymers in a melt 
polycondensation polymerization and subsequently prepare the aromatic 
anhydride/aliphatic ester copolymer. 
Suitable methods for preparing the aromatic anhydride prepolymers described 
above are well known in the art. The molecular weight of the prepolymer as 
well as its composition can be varied depending on the desired 
characteristic which the prepolymer is to impart to the copolymer. 
However, it is preferred that the aromatic anhydride prepolymers from 
which the copolymer is prepared have a molecular weight that provides an 
inherent viscosity between about 0.2 to about 2.0 deciliters per gram 
(dl/g) as measured in a 0.1 g/dl solution of chloroform (CHCl.sub.3) at 
25.degree. C. Those skilled in the art will recognize that the aromatic 
anhydride prepolymers described herein can also be made from one or more 
aromatic anhydrides. 
One of the beneficial properties of the aromatic polyanhydride/aliphatic 
ester copolymers made by the process of this invention is that the ester 
linkages are hydrolytically unstable, and therefore the polymer is 
bioabsorbable because it readily breaks down into small segments when 
exposed to moist bodily tissue. In this regard, while it is envisioned 
that co-reactants could be incorporated into the reaction mixture of the 
aromatic dicarboxylic acid and the anhydride for the formation of the 
anhydride prepolymer, it is preferable that the reaction mixture does not 
contain a concentration of any co-reactant which would render the 
subsequently prepared polymer nonabsorbable. Preferably, the reaction 
mixture is substantially free of any such co-reactants if the resulting 
polymer is rendered nonabsorbable, especially any reactants which possess 
aromatic polyester functionalities, which are well known to be 
nonabsorbable. 
The copolymers of this invention desirably can exhibit a yield stress, e.g. 
tensile strength, greater than about 3000 psi, preferably greater than 
about 4500 psi. These tensile strengths can be achieved while varying the 
modulus and elongation of the polymer for desired applications, depending 
particularly on the chemical structure of the prepolymers chosen. 
The copolymers of this invention can be melt processed by numerous methods 
to prepare a vast array of useful devices. These copolymers can be 
injection or compression molded to make implantable medical and surgical 
devices, especially wound closure devices. The preferred wound closure 
devices are surgical clips, staples and sutures. 
Alternatively, the copolymers can be extruded to prepare fibers. The 
filaments thus produced may be fabricated into sutures or ligatures, 
attached to surgical needles, packaged, and sterilized by known 
techniques. The polymers of the present invention may be spun as 
multifilament yarn and woven or knitted to form sponges or gauze, (or 
non-woven sheets may be prepared) or used in conjunction with other molded 
compressive structures as prosthetic devices within the body of a human or 
animal where it is desirable that the structure have high tensile strength 
and desirable levels of compliance and/or ductility. Useful embodiments 
include tubes, including branched tubes, for artery, vein or intestinal 
repair, nerve splicing, tendon splicing, sheets for typing up and 
supporting damaged surface abrasions, particularly major abrasions, or 
areas where the skin and underlying tissues are damaged or surgically 
removed. 
Additionally, the copolymers can be molded to form films which, when 
sterilized, are useful as adhesion prevention barriers. Another 
alternative processing technique for the copolymers of this invention 
includes solvent casting, particularly for those applications where a drug 
delivery matrix is desired. 
In more detail, the surgical and medical uses of the filaments, films, and 
molded articles of the present invention include, but are not necessarily 
limited to: 
Knitted products, woven or non-woven, and molded products including: 
a. burn dressings 
b. hernia patches 
c. medicated dressings 
d. fascial substitutes 
e. gauze, fabric, sheet, felt or sponge for liver hemostasis 
f. gauze bandages 
g. arterial graft or substitutes 
h. bandages for skin surfaces 
i. suture knot clip 
j. orthopedic pins, clamps, screws, and plates 
k. clips (e.g.,for vena cava) 
l. staples 
m. hooks, buttons, and snaps 
n. bone substitutes (e.g., mandible prosthesis) 
o. needles 
p. intrauterine devices (e.g.,spermicidal devices) 
q. draining or testing tubes or capillaries 
r. surgical instruments 
s. vascular implants or supports 
t. vertebral discs 
u. extracorporeal tubing for kidney and heart-lung machines 
v. artificial skin and others. 
As an additional aid to understanding the overall process for making the 
aromatic anhydrides/aliphatic ester copolymers described herein, FIG. 1 
outlines a process scheme for the preparation of the copolymers. 
The Examples set forth below are for illustration purposes only, and are 
not intended to limit the scope of the claimed invention in any way. 
Numerous additional embodiments within the scope and spirit of the 
invention will become readily apparent to those skilled in the art. 
EXAMPLES 
The following Examples describes a new copolymer of an aromatic anhydride 
and an aliphatic ester, potentially useful as biomedical devices, with 
high molecular weights. 
In this synthetic process, the high molecular weight 
copoly(anhydride-ester) is prepared by a method consisting of reacting a 
prepolymerized aliphatic poly(ester) via a melt ring-opening 
polymerization at temperatures of 110.degree. to 230.degree. C. for 3 to 
24 hours under an inert nitrogen atmosphere, followed by melt 
polycondensation with a highly pure aromatic mixed anhydride at 
temperatures of 110.degree. to 230.degree. C. under a high vacuum (&lt;20 
microns). 
The various times and temperatures of the polymerization collaborate to 
yield aromatic poly(anhydride)-aliphatic poly(ester)s with high molecular 
weights. 
In the examples, high molecular weight aromatic 
copoly(anhydride)-aliphatic(ester) polymers prepared from highly pure 
aromatic mixed anhydride monomers such as 1,6-bis(p-carboxyphenoxy)hexane, 
1,4-bis(p-carboxyphenoxy) butane, and 1,2-bis(p-carboxyphenoxy)ethane, 
with aliphatic poly(ester)s based on lactone monomers such as glycolide, 
lactide, PDO, and others. 
The polymers and monomers were characterized for chemical composition and 
purity (NMR, FT-IR, elemental analysis), thermal analysis (DSC), melt 
rheology (melt stability and viscosity), and molecular weight (inherent 
viscosity). Baseline and in-vitro mechanical properties (Instron 
stress/strain) were determined on molded cylindrical dumbbell test 
articles. 
FT-IR was performed on a Nicolet FT-IR. Polymer samples were melt pressed 
into thin films. Monomers were pressed into KBr pellets. 1H NMR was 
performed on a 200 MHz NMR using CDCl3 as a reference. Elemental analysis 
was performed at Schwarzkopf Microanlytical Laboratories. 
Thermal analysis of polymers and monomers was performed on a DuPont 912 
Differential Scanning Calorimeter (DSC) at a heating rate of 10.degree. 
C./min. A Fisher-Johns melting point apparatus was also utilized to 
determine melting points of monomers. Thermal gravimetric analysis was 
performed on a Dupont 951 TGA at a rate of 10.degree. C./min. under a 
nitrogen atmosphere. Isothermal melt stability of the polymers was also 
determined by a Rheometrics Dynamic Analyzer RDA II for a period of 1 hour 
at temperatures ranging from 220.degree. C. to 260.degree. C. under a 
nitrogen atmosphere. 
Inherent viscosities (I.V.) of the polymers were measured using a 50 bore 
Cannon-Ubbelhode dilution viscometer immersed in a thermostatically 
controlled water bath at 25.degree. C. at a concentration of 0.025 gm/25 
ml using an appropriate solvent. Molecular weight (melt viscosity) was 
also determined utilizing a Rheometrics Dynamic Analyzer RDA II at 
temperatures ranging from 160.degree. C. to 290.degree. C. at rate of 
1.degree. C./min. to 10.degree. C./min. at frequencies of 1 cm.sup.-1 to 
100 cm.sup.-1 under a nitrogen atmosphere. 
The cylindrical dumbbells were prepared by utilizing a CSI Mini-max 
injection molder equipped with a dry nitrogen atmospheric chamber at 
temperatures ranging from 120.degree. C. to 260.degree. C. with a 
residence time of 2-3 minutes. 
Baseline and in-vitro mechanical properties copolymers of the cylindrical 
dumbbells of the copolymers so produced were performed on an Instron model 
1122 at a crosshead rate of 0.35 in/min. Specimen gauge length was 0.35 
in., with a width of 0.06 in. Results are an average of 8 to 12 dumbbell 
specimens. 
In-vitro studies were determined in a buffer solution (pH=7.27) at a 
temperature of 37.degree. C. for periods of 1, 3, 6, and 9 weeks. Eight to 
10 cylindrical dumbbells (2.4 to 3.0 grams) were placed in 100 ml of 
buffer solution. The buffer solution was replaced on a weekly basis. 
Sterilization of the dumbbells was conducted by Cobalt-60 irradiation at a 
dosage of 2.5 Mrad. 
Several copolymer synthesis examples will be described in the following few 
pages: 
EXAMPLE 1 
Poly[1, 6-bis(p-carboxyphenoxy)hexane anhydride-glycolide] 
Polymerization of 1,6-bis(p-carboxyphenoxy)hexane anhydride/glycolide 50/50 
weight percent in the feed 
To a flamed-out, dry 250 ml 2-neck round bottom flask equipped with an 
overhead mechanical stirrer, vacuum adapter, 75.degree. adapter, 
distillate bend with a vacuum take-off and a 50 ml collection flask, 15 
grams of pure glycolide and 4.8 microliters of stannous octoate in a 0.33 
molar toluene solution were added via a nitrogen purged glove box. 
The assembly was then secured to a high vacuum (&lt;10 microns) diffusion pump 
and placed in a high temperature oil bath at 180.degree. C. under a flow 
of nitrogen. The stirred glycolide monomer immediately began to melt. 
After 30 minutes the viscosity began to increase. The low viscosity melt 
was then heated to 230.degree. C. and 15 grams of freshly prepared 
1,6-bis(p-carboxyphenoxy)hexane anhydride was added via a powder addition 
funnel. After 15 minutes the melt became uniform. It was then cooled to 
200.degree. C. and a strong vacuum was placed on the system and a high 
volume of distillate (acetic anhydride, acetic acid, and glycolide 
monomer) began to evolve, and was collected. After 30 minutes, the melt 
became viscous. The polymerization was then heated to 230.degree. C. and 
allowed to continue under high vacuum (10 to 30 microns) with occasional 
stirring for 3 hours. 
The high molecular weight polymer, poly-1,6-bis (p-carboxyphenoxy)hexane 
anhydride-poly(glycolide) copolymer (also referred to as 1,6-PA-PGA), was 
removed from the bath, cooled to room temperature under a stream of 
nitrogen, isolated and ground to a fine powder. The polymer was then 
placed under vacuum at 50.degree. C. for 24 hours. The final yield was 70 
to 75 percent. 
Several other compositions were prepared under the same conditions. They 
are 90/10, 75/25, 25/75, and 10/90 wt. % 1,6-bis(p-carboxyphenoxy)hexane 
anhydride/glycolide. Table 1 describes the properties, including weight 
loss, of this series of poly(anhydride-ester) copolymers. 
TABLE 1 
__________________________________________________________________________ 
PROPERTIES OF POLY[1,6-BIS(CARBOXYPHENOXY)HEXANE ANHYDRIDE]-PGA 
COPOLYMERS 
CYLINDRICAL DUMBBELLS 
TENSILE % STRAIN 
TENSILE ACTUAL 
1,6 PA-PGA STRENGTH (PSI) 
AT YIELD 
MODULUS (PSI) 
COMPOSIITON (WT 
WT. 
__________________________________________________________________________ 
LOSS* 
10-90 12500 6.2 192000 16-84 3% 
25-75 8300 6 149000 32-68 5% 
50-50 6900 6.7 108000 55-45 10% 
75-25 6100 7 88000 80-20 50% 
90-10 6100 7 87000 93-07 100% 
__________________________________________________________________________ 
PGA = POLY(GLYCOLIDE) 
STANDARD DEVIATION OF 5 TO 10% 
DATA IS AN AVERAGE OF 5 TO 10 CYLINDRICAL DUMBBELLS 
*WEIGHT LOSS IN REFLUXING CHLOROFORM EXTRACTION (1 GM/200 ML, 24 HRS.) 
Since 1,6-polyanhydride is soluble in chloroform, the amount of unreacted 
or low molecular weight polyanhydride can be determined by the weight loss 
incurred in an extraction study of the copolymer. The data in Table 1 for 
the weight loss for the copolymer series is quite low for copolymers 
containing less than 50% polyanhydride. For example, a copolymer 
containing 32 wt. % polyanhydride lost less than 5 weight percent, well 
within experimental error. This indicates that the polymers are true 
copolymers and not blends of a homo-polyanhydride and homo-polyglycolide, 
since it would be expected that all of the polyanhydride would be 
extracted by refluxing chloroform if the polyanhydride had not reacted 
with the polyglycolide, a polymer that is quite insoluble in chloroform. 
Properties of these copolymers such as physical strength and modulus lie 
between that of the homo-polyanhydride and polyglycolide. The copolymers 
physical properties ranged from yield strengths of 6,000 to 13,000 psi 
with moduli of 80,000 to 190,000 psi. 
It was also believed that incorporation of aromatic poly(anhydride)s into 
the backbone of aliphatic lactone polymers would lead to cobalt 
sterilizable materials since previous work at Ethicon (U.S Pat. Nos. 
4,510,295 and 4,532,928) and on aromatic homo-polyanhydrides has 
established that incorporation of aromatic substituents in the polymer 
backbone yields irradiation stability. 
Consequently, test coupons of the 1,6-poly(anhydride-glycolide) were 
subjected to cobalt irradiation. The results of these tests are reported 
in Table 2. 
TABLE 2 
__________________________________________________________________________ 
PROPERTIES OF POLY[1,6-BIS(CARBOXYPHENOXY)HEXANE ANHYDRIDE]- 
PGA COPOLYMERS 50/50 
TENSILE % STRAIN 
TENSILE 
CYLINDRICAL DUMBBELLS 
STRENGTH (PSI) 
AT YIELD 
MODULUS (PSI) 
YIELD* 
__________________________________________________________________________ 
UNIRRADIATED 6600 6.6 125000 YES 
1 WEEK IN-VITRO 4200 4.1 100000 NO 
3 WEEK IN-VITRO 3200 4.6 64000 NO 
4 WEEK IN-VITRO 2000 3.8 56000 NO 
IRRADIATED (2.5 Mrad) 
6500 7 112000 YES 
1 WEEK IN-VITRO 4100 3.4 102000 NO 
2 WEEK IN-VITRO 3100 3.9 80000 NO 
3 WEEK IN-VITRO 2900 4.1 71000 NO 
4 WEEK IN-VITRO 2100 5 42000 NO 
__________________________________________________________________________ 
STANDARD DEVIATION OF 5 TO 10% 
DATA IS AN AVERAGE OF 10 CYLINDRICAL DUMBBELLS 
*YIELD = DID POLYMERS YIELD 
No loss in the strength or modulus was observed at baseline. However, it is 
also important to establish the polymers physical characteristics as a 
function of exposure time in-vitro. This is a necessary requirement, since 
past work has shown that polymers subjected to cobalt may exhibit little 
change in physical/mechanical baseline properties, but when tested 
in-vitro rapidly lose all physical strength. As can be seen in FIG. 2, no 
difference is observed in in-vitro properties between coupons subjected to 
cobalt versus unirradiated coupons. 
Therefore, Table 2 establishes that the copolymers of an aromatic 
poly(anhydride)-aliphatic poly(glycolide)s can be cobalt irradiated 
without loss in physical properties. Since it is less likely that a blend 
would improve cobalt stability, this additional evidence suggests that the 
1,6 PA is truly incorporated into the backbone of PGA. 
EXAMPLE 2 
Poly[1,6-bis(p-carboxyphenoxy)hexane anhydride-glycolide-lactide] 
Polymerization of 1,6-bis(p-carboxyphenoxy) hexane 
anhydride/glycolide-lactide 90-10 50/50 weight percent in the feed 
To a flamed-out, dry 250 ml 2-neck round bottom flask equipped with an 
overhead mechanical stirrer, vacuum adapter, 75.degree. adapter, 
distillate bend with a vacuum take-off and a 50 ml collection flask, 15 
grams of pure glycolide, 1.86 grams of lactide, 135 microliters of 
ethylene glycol (DEG), and 3.33 microliters of a 0.333 molar solution of 
stannous octoate in toluene were added via a nitrogen purged glove box. 
The assembly was then secured to a high vacuum (&lt;10 microns) diffusion pump 
and placed in a high temperature oil bath at 185.degree. C. under a flow 
of nitrogen. The stirred glycolide monomer immediately began to melt. 
After 30 minutes the viscosity began to increase. The low viscosity melt 
was then heated to 220.degree. C. and allowed to stand for an additional 
180 minutes. 
Then, 15 grams of freshly prepared 1,6-bis(p-carboxyphenoxy)hexane 
anhydride was added via a powder addition funnel. After 15 minutes the 
melt became uniform. The uniform melt was then placed under a strong 
vacuum and a high volume of distillate (acetic anhydride, acetic acid) 
began to evolve, and was collected. After 30 minutes, the melt became 
viscous. The polymerization was allowed to continue under high vacuum (10 
to 30 microns) with occasional stirring for 3 hours. 
The high molecular weight polymer, poly-1,6-bis(p-carboxyphenoxy)hexane 
anhydride-poly(glycolide-lactide) terpolymer, was removed from the bath, 
cooled to room temperature under a stream of nitrogen, isolated and ground 
to a fine powder. The polymer was then placed under vacuum at 50.degree. 
C. for 24 hours. The final yield was 70 to 75 percent. 
Several other compositions were prepared under the same conditions. They 
are 75/25 and 25/75 wt. % 1,6-bis(p-carboxyphenoxy)hexane 
anhydride/glycolide-lactide (Table 3). Since this polymer is soluble in 
HFIP, NMR has been utilized to investigate the true nature, terpolymer or 
blend, of this material. NMR indicates that the anhydride and glycolide 
have transesterified (FIG. 3). 
This evidence, along with the extraction studies and cobalt sterilization 
results, establishes that these polymers are true co- and terpolymers and 
not blends of a homo-polyanhydride and homo-polyglycolide or 
copolyglycolide-lactide. 
Several compositions of 1,4-bis(p-carboxyphenoxy) butane 
anhydride/glycolide-lactide (90-10) as well as 
1,2-bis(p-carboxyphenoxy)ethane anhydride/glycolide-lactide (90-10) have 
been prepared by the above method (Tables 3, 4, 5, 6, 7, 8, and 9). 
TABLE 3 
__________________________________________________________________________ 
PROPERTIES OF 1,6 POLY(ANHYDRIDE)-(PGA--PLA 90-10) POLYMERS 
PA--PGA--PLA 
BREAKING % STRAIN 
TENSILE 
WT % (FEED) 
STRENGTH (PSI) 
AT BREAK 
MODULUS (PSI) 
YIELD* 
__________________________________________________________________________ 
75/25 6500 127 133000 YES 
50/50 9300 6 176000 YES 
25/75 5000 2.4 196000 SOME 
1,6 PA 5000 150 50000 YES 
__________________________________________________________________________ 
STANDARD DEVIATION OF 5 TO 10%, PLA = POLY(LACTIDE) 
DATA IS AN AVERAGE OF 5 TO 10 CYLINDRICAL DUMBBELLS 
*YIELD = DID POLYMERS YIELD 
TABLE 4 
__________________________________________________________________________ 
PROPERTIES OF 1,4 POLY(ANHYDRIDE)-(PGA--PLA 90-10) POLYMERS 
PA--PGA--PLA 
BREAKING % STRAIN 
TENSILE 
WT % (FEED) 
STRENGTH (PSI) 
AT BREAK 
MODULUS (PSI) 
YIELD* 
__________________________________________________________________________ 
75/25 8400 55 137000 YES 
50/50 8800 34 171000 YES 
25/75 9800 7 191000 YES 
1,4 PA 7500 120 80000 YES 
__________________________________________________________________________ 
STANDARD DEVIATION OF 5 TO 10% 
DATA IS AN AVERAGE OF 5 TO 10 CYLINDRICAL DUMBBELLS 
*YIELD = DID POLYMERS YIELD 
TABLE 5 
__________________________________________________________________________ 
PROPERTIES OF 1,4-POLYANHYDRIDE-(PGA--PLA 90-10) COPOLYMERS 50/50 
TENSILE % STRAIN 
TENSILE 
CYLINDRICAL DUMBBELLS 
STRENGTH (PSI) 
AT BREAK 
MODULUS (PSI) 
YIELD* 
__________________________________________________________________________ 
UNIRRADIATED 8800 34 171000 YES 
1 WEEK IN-VITRO 7200 5.7 143000 SOME 
2 WEEK IN-VITRO 1900 1.6 108000 NO 
3 WEEK IN-VITRO 400 1.0 43000 NO 
__________________________________________________________________________ 
STANDARD DEVIATION OF 5 TO 10% 
DATA IS AN AVERAGE OF 10 CYLINDRICAL DUMBBELLS 
*YIELD = DID POLYMERS YIELD 
TABLE 6 
__________________________________________________________________________ 
PROPERTIES OF 1,4-POLYANHYDRIDE-(PGA--PLA 90-10) COPOLYMERS 75/25 
TENSILE % STRAIN 
TENSILE 
CYLINDRICAL DUMBBELLS 
STRENGTH (PSI) 
AT BREAK 
MODULUS (PSI) 
YIELD* 
__________________________________________________________________________ 
UNIRRADIATED 8400 55 137000 YES 
1 WEEK IN-VITRO 7500 16 106000 YES 
2 WEEK IN-VITRO 6000 7 102000 SOME 
3 WEEK IN-VITRO 4500 6 78000 NO 
4 WEEK IN-VITRO 3200 5 68000 NO 
__________________________________________________________________________ 
STANDARD DEVIATION OF 5 TO 10% 
DATA IS AN AVERAGE OF 10 CYLINDRICAL DUMBBELLS 
TABLE 7 
__________________________________________________________________________ 
PROPERTIES OF 1,2 POLY(ANHYDRIDE)-(PGA--PLA 90-10) POLYMERS 
PA--PGA--PLA 
BREAKING % STRAIN 
TENSILE 
WT % (FEED) 
STRENGTH (PSI) 
AT BREAK 
MODULUS (PSI) 
YIELD* 
__________________________________________________________________________ 
75/25 11800 46 175000 YES 
50/50 13000 13 235000 YES 
25/75 12800 6 242000 YES 
1,2 PA 11300 80 115000 YES 
__________________________________________________________________________ 
STANDARD DEVIATION OF 5 TO 10% 
DATA IS AN AVERAGE OF 5 TO 10 CYLINDRICAL DUMBBELLS 
*YIELD = DID POLYMERS YIELD 
TABLE 8 
__________________________________________________________________________ 
PROPERTIES OF 1,2-POLYANHYDRIDE-(PGA--PLA 90-10) COPOLYMERS 50/50 
TENSILE % STRAIN 
TENSILE 
CYLINDRICAL DUMBBELLS 
STRENGTH (PSI) 
AT BREAK 
MODULUS (PSI) 
YIELD* 
__________________________________________________________________________ 
UNIRRADIATED 13000 13 235000 YES 
1 WEEK IN-VITRO 11300 7.4 202000 YES 
2 WEEK IN-VITRO 3900 2.1 167000 NO 
3 WEEK IN-VITRO 1500 2.0 87000 NO 
__________________________________________________________________________ 
STANDARD DEVIATION OF 5 TO 10% 
DATA IS AN AVERAGE OF 10 CYLINDRICAL DUMBBELLS 
*YIELD = DID POLYMERS YIELD 
TABLE 9 
__________________________________________________________________________ 
PROPERTIES OF 1,2-POLYANHYDRIDE-(PG--PLA 90-10) COPOLYMERS 75/25 
TENSILE % STRAIN 
TENSILE 
CYLINDRICAL DUMBBELLS 
STRENGTH (PSI) 
AT BREAK 
MODULUS (PSI) 
YIELD* 
__________________________________________________________________________ 
UNIRRADIATED 11800 46 175000 YES 
1 WEEK IN-VITRO 10300 10 163000 SOME 
2 WEEK IN-VITRO 6700 5 136000 SOME 
3 WEEK IN-VITRO 4300 11 88000 SOME 
4 WEEK IN-VITRO 2500 3 76000 SOME 
__________________________________________________________________________ 
STANDARD DEVIATION OF 5 TO 10% 
DATA IS AN AVERAGE OF 10 CYLINDRICAL DUMBBELLS 
*YIELD = DID POLYMERS YIELD 
Tables 4 through 9 describe the properties of several 1,4 and 1,2 
polyanhydride/glycolide-lactide terpolymers. Like the 1,6 PA-PGA 50-50, 
the 1,4 PA and 1,2 PA-PGA-PLA terpolymers were also molded into 
cylindrical dumbbells, and baseline as well as in-vitro physical 
properties were determined. 
As can be seen from these tables and FIGS. 4 through 7, the yield strength 
and moduli are greater than that of 1,6 PA-PGA 50-50. This is as expected, 
since the 1,4 PA and 1,2 PA contain less methylene groups per repeat unit. 
This leads to a polymeric chain which is slightly stiffer and, therefore, 
causes a corresponding increase in yield strength and modulus. 
It should also be apparent that the 1,4 and 1,2 PA-PGA-PLA 75-25 wt. % 
terpolymers have greater BSR at longer in-vitro time periods than the 
50-50 wt. % terpolymers. This is as expected since these terpolymers have 
a larger percentage of polyanhydride than the 50-50 wt. % polymers. 
The polyanhydrides have been shown to have a very broad range of BSR 
profiles, from an induction period where little loss of strength occurs in 
the first 3 to 6 weeks followed by a linear decrease in strength (i.e., 
1,4 and 1,6 PA), to a linear decrease in strength without an induction 
period (i.e., 1,2 PA). With the incorporation of bulk degradation polymers 
such as PGA and PLA, an even broader range of BSR profiles is possible. 
This type of behavior is displayed in FIGS. 4 through 7. 
EXAMPLE 3 
Poly[1,2-bis(p-carboxyphenoxy)hexane anhydride]-poly(dioxanone) 
To a flamed-out, dry 250 ml 2-neck round bottom flask equipped with an 
overhead mechanical stirrer, vacuum adapter, 75.degree. adapter, 
distillate bend with a vacuum take-off and a 50 ml collection flask, 20 
grams of pure PDO, 37 microliters of ethylene glycol (DEG), and 11.8 
microliters of stannous octoate in a 0.333 molar solution in toluene were 
added via a nitrogen purged glove box. 
The assembly was then secured to a high vacuum (&lt;10 microns) diffusion pump 
and placed in a high temperature oil bath at 110.degree. C. under a flow 
of nitrogen. The stirred PDO monomer immediately began to melt. After 30 
minutes the viscosity began to increase. The low viscosity melt was 
allowed to stand at 110.degree. C. for 6 hours. The polymerization was 
then continue for an additional 18 hours at 90.degree. C. 
Then, the temperature of the polymerization was raised to 110.degree. C. 
and 15 grams of freshly prepared 1,2-bis(p-carboxyphenoxy)ethane anhydride 
was added via a powder addition funnel in the molten state. After 15 
minutes the melt became uniform. The uniform melt was then placed under a 
strong vacuum and a high volume of distillate (acetic anhydride, acetic 
acid) began to evolve, and was collected. After 30 minutes, the melt 
became viscous. The polymerization was allowed to continue under high 
vacuum (10 to 30 microns) with occasional stirring for 3 hours. 
The high molecular weight polymer was removed from the bath, cooled to room 
temperature under a stream of nitrogen, isolated and ground to a fine 
powder. The polymer was then placed under vacuum at 50.degree. C. for 24 
hours. The final yield was 70 to 75 percent. 
A 75/25 wt. % 1,2-bis(p-carboxyphenoxy)ethane anhydride-PDO composition was 
also prepared under the same conditions. 
EXAMPLE 4 
Polymerization of 1,6-bis(p-carboxyphenoxy) hexane anhydride/acetoxybenzoic 
acid 75/25 weight percent in the feed 
The method descried below is similar to U.S. Pat. No. 4,414,381. 
To a flamed-out, dry 250 ml 1-neck round bottom flask equipped with an 
overhead mechanical stirrer, vacuum adapter, 75.degree. C. adapter, 
distillate bend with a vacuum take-off and a 50 ml collection flask, 33 
grams of freshly prepared 1,6-bis(p-carboxyphenoxy)hexane anhydride and 11 
grams of pure acetoxybenzoic acid were added via a nitrogen purged glove 
box. 
The assembly was then secured to a high vacuum (&lt;10 microns) diffusion pump 
and placed in a high temperature oil bath at 220.degree. C. under a flow 
of nitrogen. The stirred anhydride monomer immediately began to melt. 
Shortly thereafter, acetoxybenzoic acid began to melt. Once the monomers 
had melted, a strong vacuum was placed on the system and a high volume of 
distillate (acetic anhydride, acetic acid) began to evolve, and was 
collected. After 15 to 20 minutes, the melt became viscous. The 
polymerization was allowed to continue under high vacuum (10 to 30 
microns) with occasional stirring. The total reaction time was 200 
minutes. 
The high molecular weight polymer, poly-1,6-bis(p-carboxyphenoxy)hexane 
anhydride-poly(oxybenzoate) copolymer, was removed from the bath, cooled 
to room temperature under a stream of nitrogen, isolated and ground to a 
fine powder. The polymer was then placed under vacuum at 50.degree. C. for 
24 hours. The final yield was 70 to 75 percent. 
Several other compositions were prepared under the same conditions. They 
are 95/5, 90/10, and 85/15 wt. % 1,6-bis(p-carboxyphenoxy)hexane 
anhydride/acetoxybenzoic acid. 
Table 10 below compares the physical characteristics of several aromatic 
anhydride/aliphatic ester copolymers to aromatic anhydride/aromatic ester 
copolymers, an aromatic anhydride homopolymer and an aliphatic ester 
homopolymer. 
TABLE 10 
__________________________________________________________________________ 
PHYSICAL PROPERTIES OF POLY[1,6-(CARBOXYPHENOXY)HEXANE 
ANHYDRIDE] COPOLYMERS 
WT-WT % TENSILE ELONGATION 
TENSILE 
1,6-PA--PE* 
STRENGTH (PSI) 
TO BREAK (%) 
MODULUS (PSI) 
HYDROLYSIS** 
__________________________________________________________________________ 
90-10 5700 170 51000 40 
1,6 PA--POB 
75-25 7100 149 63000 51 
1,6 PA--POB 
50-50 8200 26 66000 65 
1,6 PA--POB 
90-10 6400 120 87000 5 
1,6 PA--PGA--PLA 
75-25 7000 100 133000 0 
1,6 PA--PGA--PLA 
50-50 8500 25 149000 0 
1,6 PA--PGA--PLA 
1,6 PA 5000 150 50000 10 
PGA--PLA 17000 20 200000 0 
__________________________________________________________________________ 
*1,6 PA = POLYANHYDRIDE 
*PE = POLYESTER, POB = POLYOXYBENZOATE, PGA--PLA = 
POLY(GLYCOLIDE--LACTIDE) 9010 
**PERCENT POLYMER REMAINING AFTER 2 DAYS INVITRO AT 100 C. (pH = 7.27) 
The data in Table 10 demonstrates that the aromatic anhydrides/aliphatic 
ester copolymers show improved tensile strength and tensile modulus as 
compared to the aromatic anhydride/aromatic ester copolymers. 
Additionally, the hydrolysis rate of the aromatic anhydride/aliphatic 
ester copolymer is significantly faster than the hydrolysis rate of the 
aromatic anhydride homopolymer and the aromatic anhydride/aromatic ester 
copolymer. 
This is a strong indication that incorporation of small proportions 
aliphatic polyesters into aromatic polyanhydrides increases the breakdown 
characteristics of aromatic polyanhydrides. While incorporation of small 
proportions of aromatic polyesters into aromatic polyanhydrides does not 
lead to increased hydrolysis, but actually slows hydrolysis rates for the 
polyanhydride, leading to nonabsorbable materials.