Note: Descriptions are shown in the official language in which they were submitted.
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Polymer Blends Containing Absorbable Polyoxaesters
Field of the Invention
The present invention relates to a bioabsorbable
polymeric material and blends thereof and more particularly
to absorbable surgical products made from such polymers
and blends thereof.
Background of the Invention
Since Carothers early work in the 1920s and 1930s,
aromatic polyesters particularly polyethylene
terephthalate) have become the most commercial important
polyesters. The usefulness of these polymers is
intimately linked to the stiffening action of the p-
phenylene group in the polymer chain. The presence of the p-
phenylene group in the backbone of the polymer chain leads
to high melting points and good mechanical properties
especially for fibers, films and some molded products. In
fact polyethylene terephthalate) has become the polymer of
choice for many common consumer products, such as one and
two liter soft drink containers.
Several related polyester resins have been described
in U.S. Patents 4,440,922, 4,552,948 and 4,963,641 which
seek to improve upon the properties of polyethylene
terephthalate) by replacing terephthalic acid with other
related dicarboxylic acids which contain phenylene groups.
These polymers are generally designed to reduce the gas
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permeability of aromatic polyesters.
Other aromatic polyesters have also been developed
for specialty applications such as radiation stable
bioabsorbable materials. U.S. Patents 4,510,295,
4,546,152 and 4,689,424 describe radiation sterilizable
aromatic polyesters which can be used to make sutures and
the like. These polymers like, polyethylene
terephthalate), have phenylene groups in the backbone of
the polymers.
However, less research has been reported on aliphatic
polyesters. After Carothers initial work on polyesters,
aliphatic polyesters were generally ignored because it was
believed that these materials had low melting points and
high solubilities. The only aliphatic polyesters that
have been extensively studied are polylactones such as
polylactide, polyglycolide, polyp-dioxanone) and
polycaprolactone. These aliphatic polylactones have been
used primarily for bioabsorbable surgical sutures and
surgical devices such as staples. Although polylactones
have proven to be useful in many applications they do not
meet all the needs of the medical community. For example
films of polylactones do not readily transmit water vapor,
therefore, are not ideally suited for use as bandages
where the transmission of water vapor would be desired.
Only recently has there been renewed interest in non-
lactone aliphatic polyesters. U.S. Patent 5,349,028
describes the formation of very simple aliphatic
polyesters based on the reaction of a diol with a
dicarboxylic acid to fona prepolymer chains that are then
coupled together. These polyesters are being promoted for
use in fibers and molded articles because these polyesters
are biodegradable after they are buried such as in a
landfill. However, these materials are not disclosed as
being suitable for use in surgical devices.
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Thus it is an object of the present invention to
provide a new class of aliphatic polyesters and blends
thereof that are bioabsorbable and may be used in surgical
devices such as sutures, molded devices, drug delivery
matrices, coatings, lubricants and the like.
Summarv of the Invention
We have discovered a new class of synthetic polymeric
materials and blends thereof that may be used to produce
surgical devices such as sutures, sutures with attached
needles, molded devices, drug delivery matrices, coatings,
lubricants and the like. The invention also contemplates
a process for producing the bioabsorbable polymers and
copolymers. The polymer blends of the present invention
comprise an aliphatic polyoxaesters having a first
divalent repeating unit of formula I:
[O-C(O)-C(R~) (RZ)-O-(R3)-O-C(R~) (RZ)-C(O)-] I
and a second repeating unit selected from the group of
formulas consisting of:
[ -O-Ra- ] ,, ~ I I
[-O-Rs-C(O)-]H. III
( [ -O-Rs-C ( 0 ) l e-~- ) ~G XI
and combinations thereof, wherein R1 and R2 are
independently hydrogen or an alkyl group containing 1 to
8 carbon atoms; R3 is an alkylene unit containing from 2 to
12 carbon atoms or is an oxyalkylene group of the
following formula:
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- C ( CHz ) c-O- ~ n- ( CHz ) e- I V
wherein C is an integer in the range of from 2 to about 5,
D is an integer in the range of from about 0 to about
2,000, and E is an integer in the range of from about 2 to
about 5, except when D is zero, in which case E will be an
integer from 2 to 12; R4 is an alkylene unit containing
from 2 to 8 carbon atoms ; A is an integer in the range of
from 1 to 2,000; RS is selected from the group consisting
of -C (R6) (R~) -, -(CHz) 3-0-, -CHz-CHz-O-CHz-, -CRBH-CHz-, -
(CHz) 4-, - (CHz) F-0-C (O) - and - (CHz) F-C (O) -CHz-; R6 and R~ are
independently hydrogen or an alkyl containing from 1 to 8
carbon atoms; Re is hydrogen or methyl; F is an integer in
the range of from 2 to 6; B is an integer in the range of
from 1 to n such that the number average molecular weight
of fonaula III is less than about 200,000, preferably less
than about 100,000 and most preferably less than 40,000;
P is an integer in the range of from 1 to m such that the
number average molecular weight of formula XI is less than
about 1,000,000, preferably less than about 200,000 and
most preferably less than 40,000; G represents the residue
minus from 1 to L hydrogen atoms from the hydroxyl group
of an alcohol previously containing from 1 to about 200
hydroxyl groups; and L is an integer from about 1 to about
200; and 'a second polymer selected from the group
consisting of homopolymer and copolymer of lactone type
polymers with the repeating units described by formulas
III and XI, aliphatic polyurethanes, polyether
polyurethanes, polyester polyurethanes, polyethylene
copolymers, polyamides, polyvinyl alcohols, polyethylene
oxide), polypropylene oxide, polyethylene glycol,
polypropylene glycol, polytetramethylene oxide, polyvinyl
pyrrolidone, polyacrylamide, poly(hydroxy ethyl acrylate),
poly(hydroxyethyl methacrylate) and combinations thereof.
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Detailed Description of the Invention
The aliphatic polyoxaesters of the present invention
are the reaction product of an aliphatic polyoxycarboxylic
acid and at least one of the following compounds: a diol
(or polydiol), a lactone (or lactone oligomer), a coupling
agent or combination thereof.
Suitable aliphatic alpha-oxycarboxylic acids for use
in the present invention generally have the following
formula:
HO-C ( O ) -C ( Rl ) ( RZ ) -O- ( R3 ) -O-C ( R~ ) ( RZ ) -C ( O ) -OH V
wherein Rl and RZ are independently selected from the group
consisting of hydrogen or an alkyl group containing from
1 to 8 carbon atoms and R3 is an alkylene containing from
2 to 12 carbon atoms or is an oxyalkylene group of the
following formula:
- C ( CH2 ) C-~- J D- ( CH2 ) E- IV
wherein C is an integer in the range of from about 2 to
about 5, D is an integer in the range of from about 0 to
about 2,000 and preferably from 0 to 12, and E is an
integer in the range of from about 2 to about 5. These
aliphatic alpha-hydroxycarboxylic acids may be formed by
reacting a diol or polydiol with an alpha-halocarboxylic
acid such bromoacetic acid or chloroacetic acid under
suitable conditions.
Suitable diols or polydiols for use in the present
invention are diol or diol repeating units with up to 8
carbon atoms having the formulas:
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H[-(O-R4-)A]OH, or
wherein R4 is an alkylene unit containing from 2 to 8
methylene units; A is an integer in the range of from 1 to
about 2,000 and preferably from 1 to about 1000. Examples
of suitable diols include diols selected from the group
consisting of 1,2-ethanediol (ethylene glycol), 1,2-
propanediol (propylene glycol), 1,3-propanediol, 1,4-
butanediol, 1,5-pentanediol, 1,3-cyclopentanediol, 1,6-
hexanediol, 1,4-cyclohexanediol, 1,8-octanediol and
combinations thereof. Examples of preferred polydiols
include polydiols selected from the group consisting of
polyethylene glycol (H[-O-CHZ-CHZ-]OOH) and polypropylene
glyco 1 ( H [ -O-CHZ-CH ( CH3 ) - ] AOH ) .
The polymer produced by reacting the aliphatic
dioxycarboxylic acid with the diols discussed above should
provide a polymer generally having the formula:
[-O-C(O)-C(Ri) (Rz)-O-(Ra)-O-C(Rt) (Rz)-C(O)-(O-Ra)n-]H
wherein R,, RZ, R3, R4 and A are as described above; and N
is an integer in the range of from about 1 to about 10,000
and preferably is in the range of from about 10 to about
1,000 and most preferably in the range of from about 50 to
about 200:
Suitable lactone monomers that may be used in the
present invention generally have the formula:
~o-R5-~ ( o )-~, v~
These lactone monomers may be polymerized to provide
polymers of the following general structures:
H [ -O-RS-C ( O ) - ] BOH IX
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( H WO-Rs-C ( o ) ~ r-o- ) ~G X
wherein Rs is selected from the group consisting of -
C (~) (R~) -~ - (CHz) 3-0-. -CHz-CHz-O-CHz-, -CRBH-CHz-, -
( CHz ) d-, - ( cH2 ) F-o-c ( o ) - and - ( cHz ) P-c ( o ) -cH2-; R6 and R,
are
independently hydrogen or an alkyl containing from 1 to 8
carbon atoms; Re is hydrogen or methyl; F is an integer of
from about 2 to 6; B is an integer in the range of from 1
to n such that the number average molecular weight of
formula IX is less than about 200,000, preferably less
than 100,000, and most preferably less than 40,000; P is
an integer in the range of from 1 to m such that the
number average molecular weight of formula X is less than
1,000,000 about, preferably less than about 200,000 and
most preferably less than 40, 000; G represents the residue
minus from 1 to L hydrogen atoms from the hydroxyl groups
of an alcohol previously containing from 1 to about 200
hydroxyl groups; and L is an integer from about 1 to about
200. In one embodiment G will be the residue of a
dihydroxy alcohol minus both hydroxyl groups. In another
embodiment of the present invention G may be a polymer
containing pendent hydroxyl groups (including
polysaccharides). Suitable lactone-derived repeating units
may be generated from the following monomers include but
are not limited to lactone monomers selected from the
group consisting of glycolide, d-lactide, 1-lactide, meso-
lactide, e-caprolactone, p-dioxanone, trimethylene
carbonate, 1,4-dioxepan-2-one, 1,5-dioxepan-2-one and
combinations thereof.
The polymer formed by reacting the above described
diol (or polydiol) VI and the aliphatic polyoxycarboxylic
acid V may also be copolymerized in a condensation
polymerization with the lactone polymers IX described
above to form a polymer generally of the formula:
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f ('~(o)'~(Rt) (Rz)w'R3'o'~(R~) (Rz)'~(o) Wo'~)~'o)s
W~)'Rs'~)s~w XII
or
C (w(o)'~(R~) (Rz)'wR3'ow(R~) (Rz)w(o)'(o'~)Aw)s
~~'~'Rs'C~~) ~P'~')~G~w XIII
wherein S is an integer in the range of from about 1 to
about 10,000 and preferably from about 1 to about 1,000
and W is an integer in the range of from about 1 to about
1,000. These polymers may be made in the form of random
copolymers or block copolymers. To the diols, aliphatic
polyoxycarboxylic acids and lactone monomers described
above there may be added a coupling agent selected from
the group consisting of trifunctional or tetrafunctional
polyols, oxycarboxylic acids, and polybasic carboxylic
acids (or acid anhydrides thereof). The addition of the
coupling agents causes the branching of long chains, which
can impart desirable properties in the molten state to the
polyester prepolymer. Examples of suitable polyfunctional
coupling agents include trimethylol propane, glycerin,
pentaerythritol, malic acid, citric acid, tartaric acid,
trimesic acid, propane tricarboxylic acid, cyclopentane
tetracarboxylic anhydride and combinations thereof.
The amount of coupling agent to be added before
gelation occurs is a function of the type of coupling
agent used and the polymerization conditions of the
polyoxaester or molecular weight of the prepolymer to
which it is added. Generally in the range of from about
0.1 to about 10 mole percent of a trifunctional or a
tetrafunctional coupling agent may be added based on the
moles of aliphatic polyoxaester polymers present or
anticipated from the synthesis.
The polymerization of the aliphatic polyoxaester is
preferably performed under melt polycondensation
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conditions in the presence of an organometallic catalyst
at elevated temperatures. The organometallic catalyst is
preferably a tin-based catalyst e.g. stannous octoate.
The catalyst will preferably be present in the mixture at
a mole ratio of diol, aliphatic polyoxycarboxylic acid and
optionally lactone monomer to catalyst will be in the
range of from about 15, 000 to 80, 000/ 1. The reaction is
preferably performed at a temperature no less than about
120°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 .
Generally, the reaction mixture will be maintained at
about 220°C. The polymerization reaction can be allowed to
proceed at this temperature until the desired molecular
weight and percent conversion is achieved for the
copolymer, which will typically take about 15 minutes to
24 hours. Increasing the reaction temperature generally
decreases the reaction time needed to achieve a particular
molecular weight.
In another embodiment, copolymers of aliphatic
polyoxaester can be prepared by forming an aliphatic
polyoxaester prepolymer polymerized under melt
polycondensation conditions, then adding at least one
lactone monomer or lactone prepolymer. The mixture would
then be subjected to the desired conditions of temperature
and time to copolymerize the prepolymer with the lactone
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monomers.
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
polyoxaester 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 at 25°C. Those skilled in the art
will recognize that the aliphatic polyoxaester prepolymers
described herein can also be made from mixtures of more
than one diol or dioxycarboxylic acid.
One of the beneficial properties of the aliphatic
polyoxaester 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 aliphatic dioxycarboxylic acid and the diol
for the formation of the aliphatic polyoxaester
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.
These aliphatic polyoxaesters described herein and
those described in Serial No. 08/399,308, filed March 6,
1995 and assigned to Ethicon, now U.S. Patent No.
5,464,929 may be blended together with other homopolymers,
copolymers and graft copolymers to impart new properties
to the material formed by the blend. The other polymers
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which the aliphatic polyoxaesters may be blended with
include but are not limited to homopolymer and copolymer
of lactone type polymers with the repeating units
described by Formula VIII, aliphatic polyurethanes,
polyether polyurethanes, polyester polyurethanes
polyethylene copolymers (such as ethylene-vinyl acetate
copolymers and ethylene ethyl acrylate copolymers),
polyamides, polyvinyl alcohols, polyethylene oxide),
polypropylene oxide, polyethylene glycol, polypropylene
glycol, polytetramethylene oxide, polyvinyl pyrrolidone,
polyacrylamide, poly(hydroxy ethyl acrylate),
poly(hydroxyethyl methacrylate). The copolymers (i.e.
containing two or more repeating units) including random,
block and segmented copolymers. Suitable lactone-derived
repeating units may be generated from the following
monomers include but are not limited to lactone monomers
selected from the group consisting of glycolide, d-
lactide, 1-lactide, meso-lactide, e-caprolactone, p-
dioxanone, trimethylene carbonate, 1,4-dioxepan-2-one,
1,5-dioxepan-2-one and combinations thereof. The blends
may contain about 1 weight percent to about 99 weight
percent of the aliphatic polyoxaesters.
For some applications it may be desirable to add
additional ingredients such as stabilizers, antioxidants
radiopacifiers, fillers or the like.
The polymer blends of this invention can be melt
processed by numerous methods to prepare a vast array of
useful devices. These polymer blends 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 polymer blends can be extruded to
prepare fibers. The filaments thus produced may be
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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 polymer blends can be molded to
form films which, when sterilized, are useful as adhesion
prevention barriers. Another alternative processing
technique for the polymer blends 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
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h. bandages for skin surfaces
i. suture knot clip
j. orthopedic pins, clamps, screws, and plates
k. clips (e.g.,for vena cava)
1, staples
m. hooks, buttons, and snaps
n. bone substitutes (e. g., mandible prosthesis)
o. intrauterine devices (e.g.,spermicidal devices)
p. dra~.xii.ng or testing tubes or capillaries
q. surgical instruments
r. vascular implants or supports
s, vertebral discs
t. extraeorporeal tubing for kidney and heart-lung
machinas
u. artificial skin
v. catheters (including, but not limited to, the
cathet8rs described in U.S. Patent N'O. 4,883,699).
w, Scaffoldings for tissue engineering applications.
In another embodiment, the aliphatic polyoxaester is
used to coat a surface of a surgical article to enhance
the lubri~iry of the coated surface. The polymer may be
applied as a coating using conventional techniques. For
example, tlxe polymer may be solubilized in a dilute
solution of: a volatile organic solvent, e.g, acetone,
methanol, ethyl acetate or toluene, and then the article can
be immersed in the solution to coat its surface. Once the
surface is coated, the surgical article can be removed from
the solution where it can be dried at an elevated
temperature until the solvent and any residual reactants are
removed.
For use in coating applications the polymer blends
should exhibit an inherent viscosity, as measured in a O.I gram
per decilits;r (g/d1) of hexafluoroisopropanol (HFIp),
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between about 0.05 to about 2.0 dl/g, preferably about
0.10 to about 0.80 dl/g. If the inherent viscosity were
less than about 0.05 dl/g, then the polymer blend may not
have the integrity necessary for the preparation of films
or coatings for the surfaces of various surgical and
medical articles. On the other hand, although it is
possible to use polymer blends with an inherent viscosity
greater than about 2.0 dl/g, it may be exceedingly
difficult to do so.
Although it is contemplated that numerous surgical
articles (including but not limited to endoscopic
instruments) can be coated with the polymer blends of this
invention to improve the surface properties of the
article, the preferred surgical articles are surgical
sutures and needles. The most preferred surgical article
is a suture, most preferably attached to a needle.
Preferably, the suture is a synthetic absorbable suture.
These sutures are derived, for example, from homopolymers
and copolymers of lactone monomers such as glycolide,
lactide, e-caprolactone, 1,4-dioxanone, and trimethylene
carbonate. The preferred suture is a braided
multifilament suture composed of polyglycolide or
poly(glycolide-co-lactide).
The amount of coating to be applied on the surface of
a braided suture can be readily determined empirically,
and will depend on the particular polymer blend and suture
chosen. Ideally, the amount of coating applied to the
surface of the suture may range from about 0.5 to about 30
percent of the weight of the coated suture, more
preferably from about 1.0 to about 20 weight percent, most
preferably from 1 to about 5 weight percent. If the
amount of coating on the suture were greater than about 30
weight percent, then it may increase the risk that the
coating may f lake of f when the suture is passed through
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tissue.
Sutures coated with the polymer blends of this
invention are desirable because they have a more slippery
feel, thus making it easier for the surgeon to slide a
knot down the suture to the site of surgical trauma. In
addition, the suture is more pliable, and therefore is
easier for the surgeon to manipulate during use. These
advantages are exhibited in comparison to sutures which do
not have their surfaces coated with the polymer of this
invention.
In another embodiment of the present invention when
the article is a surgical needle, the amount of coating
applied to the surface of the article is an amount which
creates a layer with a thickness ranging preferably
between about 2 to about 20 microns on the needle, more
preferably about 4 to about 8 microns. If the amount of
coating on the needle were such that the thickness of the
coating layer was greater than about 20 microns, or if the
thickness was less than about 2 microns, then the desired
performance of the needle as it is passed through tissue
may not be achieved:
In yet another embodiment of the present invention,
the polymer blends can be used as a pharmaceutical carrier
in a drug delivery matrix. To form this matrix the
polymer blends would be mixed with a therapeutic agent to
form the matrix. The variety of different therapeutic
agents which can be used in conjunction with the aliphatic
polyoxaesters of the invention is vast. In general,
therapeutic agents which may be administered via the
pharmaceutical compositions of the invention include,
without limitation: antiinfectives such as antibiotics and
antiviral agents; analgesics and analgesic combinations;
anorexics; antihelmintics; antiarthritics; antiasthmatic
agents; anticonvulsants; antidepressants; antidiuretic
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agents; antidiarrheals; antihistamines; antiinflammatory
agents; antimigraine preparations; antinauseants;
antineoplastics; antiparkinsonism drugs; antipruritics;
antipsychotics; antipyretics, antispasmodics;
anticholinergics; sympathomimetics; xanthine derivatives;
cardiovascular preparations including calcium channel
blockers and beta-blockers such as pindolol and
antiarrhythmics; antihypertensives; diuretics;
vasodilators including general coronary, peripheral and
cerebral; central nervous system stimulants; cough and
cold preparations, including decongestants; hormones such
as estradiol and other steroids, including
corticosteroids; hypnotics; immunosuppressives; muscle
relaxants; parasympatholytics; psychostimulants;
sedatives; and tranquilizers; and naturally derived or
genetically engineered proteins, polysaccharides,
glycoproteins, or lipoproteins.
The drug delivery matrix may be administered in any
suitable dosage form such as oral, parenteral, a
subcutaneously as an implant, vaginally or as a
suppository. Matrix formulations containing the aliphatic
polyoxaester may be formulated by mixing one or more
therapeutic agents with the polyoxaester. The therapeutic
agent, may be present as a liquid, a finely divided solid,
or any other appropriate physical form. Typically, but
optionally, the matrix will include one or more
additives, e.g., nontoxic auxiliary substances such as
diluents, carriers, excipients, stabilizers or the like.
Other suitable additives may be formulated with the
polyoxaester and pharmaceutically active agent or
compound, however, if water is to be used it should be
added immediately before administration.
The amount of therapeutic agent will be dependent
upon the particular drug employed and medical condition
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being treated. Typically, the amount of drug represents
about 0.001% to about 70%, more typically about 0.001% to
about 50%, most typically about 0.001% to about 20% by
weight of the matrix.
The quantity and type of polymer blends incorporated
into the parenteral will vary depending on the release
profile desired and the amount of drug employed. The
product may contain blends of polymers having different
molecular weights to provide the desired release profile
or consistency to a given formulation.
The polyoxaester contained in the blends, upon
contact with body fluids including blood or the like,
undergoes gradual degradation (mainly through hydrolysis)
with concomitant release of the dispersed drug for a
sustained or extended period (as compared to the release
from an isotonic saline solution). This can result in
prolonged delivery (over, say 1 to 2,000 hours, preferably
2 to 800 hours) of effective amounts (say, 0.0001
mg/kg/hour to 10 mg/kg/hour) of the drug. This dosage
form can be administered as is necessary depending on the
subject being treated, the severity of the affliction, the
judgment of the prescribing physician, and the like.
Individual formulations of drugs and polymer blends
may be tested in appropriate in vitro and in vivo models
to achieve the desired drug release profiles. For
example, a drug could be formulated with a polymer blends
and orally administered to an animal. The drug release
profile could then be monitored by appropriate means such
as, by taking blood samples at specif is times and assaying
the samples for drug concentration. Following this or
similar procedures, those skilled in the art will be able
to formulate a variety of formulations.
In a further embodiment of the present invention the
polyoxaesters and polymer blends of the present invention
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can be used in tissue engineering applications as supports for
cells. Appropriate tissue scaffolding structures are known
in the art such as the prosthetic articular cartilage
described in U.S. Patent 5,306,311, the porous biodegradable
scaffolding described in WO 94/25079, and the
prevascularized implants described in WO 93/08850. Methods of
seeding and/or culturing cells in tissue scaffoldings are
also known in the art such as those methods disclosed in EPO
422 209 B1, WO 88/03785, WO 90/12604 and WO 95/33821.
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.
Example 1
Preparation of 3,6-Dioxaoctanedioic acid dimethylester
The diacid, 3,6-dioxaoctanedioic acid, was
synthesized by oxidation of triethylene glycol. The
oxidation was carried out in a 500 milliliter, three-neck
round bottom flask equipped with a thermometer, an
additional funnel, a gas absorption tube and a magnetic
spinbar. The reaction flask was lowered into an oil bath
resting upon a magnetic stirrer. To the reaction flask was
added 157.3 ml of a 60% nitric acid solution; 37.0 g of
triethylene glycol was added to the additional funnel. The
contents of the flask were heated to 78-80~C. A test tube
containing 0.5 g of glycol and one milliliter of
concentrated nitric acid was warmed in a water bath until
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0
HO~O~O~OH HN~ H O~O~O~OH
O
Triettrylene glycol
3,&Dioxaoctanedioic acid
CH30H
H+
0
~~~~~0~~3
0
Dimethyl ester of 3,6-dioxaoctanedioic aci
3~s 9(~
brown fumes started appearing. The contents wer~ then
added to the reaction flask. The mixture was stirred for
a few minutes; the glycol was then carefully added. The
rate of addition had to be monitored extremely carefully
to keep the reaction under control. The addition rate was
slow enough so that the temperature of the exothermic
reaction mixture was maintained at 78-82'C. After the
addition was completed (80 minutes), the temperature of
the reaction mixture was maintained at 78-80'C for an
additional hour. While continuing to maintain this
temperature range, the excess nitric acid and water was
then distilled off under reduced pressure (water
suction). The syrupy residue was cooled; some solids
appeared. The reaction product had the IR and NI~t spectra
expected for the dicarboxylic acid; the crude product was
used as such for esterification.
Esterification of the crude 3,6-dioxaoctanedioic acid
was accomplished as follows: To the reaction flask
containing 36 g of the crude diacid, was added 110 ml of
methanol. This was stirred for 3 days at room temperature
after which 15 g of sodium bicarbonate was added and
ETH-1122
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stirred overnight. The mixture was filtered to remove
solids. To the liquor was added an additional 10 g of
sodium bicarbonate; this mixture was stirred overnight.
The mixture was again filtered; the liquor was
fractionally distilled.
NMR analysis of the esterified product showed a
mixture of dimethyl triglycolate (78.4 mole%) and
monomethyltriglycolate (21.6 mole%). No significant
condensation of diacid was observed.
Example 2
Preparation of polyoxaester from the methyl esters of
3,6-dioxaoctanedioic acid and ethylene glycol
O
H3C0 ~ O
+ HO-CH2-C'-''' ~"
O O CH3
O
Methyl esters of 3,&dioxaoctanedioic acid
O
~O~ ~O~7
\~O v 'O
O
POLY "OXA" ESTERS
A flame dried, mechanically stirred, 50-milliliter
glass reactor suitable for polycondensation reaction,.was
charged with 20.62 g (approximately 0.1 mole) of the
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- 2189521
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methyl esters of 3,6-dioxaoctanedioic acid from Example 1,
18.62 g (0.3 mole) of distilled ethylene glycol, and
0.0606 ml of a solution of 0.33M stannous octoate in
toluene. After purging the reactor and venting with
nitrogen, the temperature was gradually raised over the
course of 26 hours to 180'C. A temperature of 180'C was
then maintained for another 20 hours; all during these
heating periods under nitrogen at one atmosphere, the
methanol formed was collected. The reaction flask was
allowed to cool to room temperature; it was then slowly
heated under reduced pressure (0.015-1.0 mm) over the
course of about 32 hours to 160'C, during which time
additional distillates were collected. A temperature of
160'C was maintained for 4 hours after which a sample, a
few grams in size, of the polymer formed was taken. The
sample was found to have an inherent viscosity (I.V.) of
0.28 dl/g, as determined in hexaflouroisopropanol (HFIP)
at 25'C at a concentration of 0.1 g/dl. The polymerization
was continued under reduced pressure while raising the
temperature, in the course of about 16 hours, from 160'C
to 180'C; a temperature of 180'C was maintained at for an
additional 8 hours, at which time a polymer sample was
taken and found to have an I.V. of 0.34 dl/g. The reaction
was continued under reduced pressure for another 8 hours
at 180'C. The resulting polymer has an inherent viscosity
of 0.40 dl/g, as determined in HFIP at 25'C and at a
concentration of 0.1 g/dl.
Example 3
Preparation of polyoxaester with 3,6,9
trioxaundecanedioic
acid and ethylene glycol
ETH-1122
2189521
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A flame dried, mechanically stirred, 250-milliliter
glass reactor, suitable for polycondensation reaction, was
charged with 44.44 g (0.2 mole) of 3,6,9-
trioxaundecanedioic acid, 62.07 g (1.0 mole) of distilled
ethylene glycol, and 9.96 milligrams of dibutyltin oxide.
After purging the reactor and venting with nitrogen, the
contents of the reaction flask were gradually heated under
nitrogen at one atmosphere, in the course of about 32
HO~O~p~O~OH ,~ HO-CH2-CH2-OH
O~ - ~O
3,6,9-Trioxaundecanedioic acid
~O~O~O~O~O~n
O O
POLY "OXA" ESTERS
hours, to 180'C, during which time the water formed was
collected. The reaction mass was allowed to cool to room
temperature. The reaction mass was then heated under
reduced pressure (0.015-1.0 mm), gradually increasing the
temperature to 180'C in about 40 hours; during this time
additional distillates were collected. The polymerization
was continued under reduced pressure while maintaining
180'C for an additional 16 hours. The resulting polymer
has an inherent viscosity of 0.63 dl/g as determined in
HFIP at 25'C and at a concentration of 0.1 g/dl.
ETH-1122
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Example 4
Preparation of polyoxaester with polyglycol diacid
and ethylene glycol
O
HO O Ov 'OH + HO-CH2-CH2 ~''
,n
O
Polyglycol diacid (n=10-12)
O
O~O~O
n
0
POLY"OXA"ESTERS
A flame dried, mechanically stirred, 500-milliliter
glass reactor (suitable for polycondensation reaction) was
charged with 123.8 g (0.2 mole) polyglycol diacid
(molecular weight about 619), 62.07 g (1.0 mole) of
distilled ethylene glycol, and 9.96 milligrams of
dibutyltin oxide. After purging the reactor and venting
with nitrogen, the contents of the reaction flask was
heated under nitrogen at one atmosphere, gradually
increasing the temperature to 200'C in about 32 hours;
during this time the water formed was collected. The
reaction flask was heated gradually under reduced pressure
(0.015-1.0 mm) from room temperature to 140'C in about 24
hours, during which time additional distillates were
collected. A polymer sample of about ten grams was taken
at this stage, and found to have an I.V. of 0.14 dl/g in
HFIP at 25'C, 0.1 g/dl. The polymerization was continued
ETH-1122
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- 24 -
under reduced pressure while heating from 140°C to 180'C
in about 8 hours, and then maintained at 180'C for an
additional 8 hours. A polymer sample was again taken and
found to have an I.V. of 0.17 dl/g. The reaction
temperature was then increased to 19o'C and maintained
there under reduced pressure for an additional 8 hours.
The resulting polymer has an inherent viscosity of 0.70
dl/g as determined in HFIP at 25'C and at a concentration
of 0.1 g/dl.
Example 5
Copolymer of polyoxaester/caprolactone/trimethylene
carbonate at 5/5/5 by weight
A flame dried, 50-milliliter, round bottom single-
neck flask was charged with 5 grams of the aliquot of
the polyoxaester of Example 4 having an I.V. of 0.14
dl/g, 5.0 grams (0.0438 mole) of e-caprolactone, 5.0
grams (0.0490 mole) of trimethylene carbonate, and
0.0094 milliliters of a 0.33 molar solution of stannous
octoate in toluene.
The flask was fitted with a magnetic stirrer bar.
The reactor was purged with nitrogen three times before
venting with nitrogen. The reaction mixture was heated
to 160°C and maintained at this temperature for about 6
hours. The copolymer was dried under vacuum (0.1 mm Hg)
at 80'C for about 16 hours to remove any unreacted
monomer. The copolymer has an inherent viscosity of 0.34
dl/g, as determined in HFIP at 25'C and at a
concentration of 0.1 g/dl. The copolymer is a viscous
liquid at room temperature. The mole ratio of
polyoxaester/PCL/PTMC was found by NMR analysis to be
ETH-1122
-25-
47.83/23.73/28.45.
-26-
Example s
2~1895~ 1
Copolymer of polyoxaester/caprolactone/glycolide
at x/8.1/0.9 by weight
A flame dried, 25-milliliter, round bottom, single-
neck flask was charged with 6 grams of the polyoxaester
of Example 4 having an I.V. of 0.17 dl/g., 8.1 grams
(0.0731 mole) of e-caprolactone, 0.9 grams (0.008) mole
of glycolide and 0.0080 milliliters of a 0.33 molar
stannous octoate solution in toluene. The flask was
fitted with a magnetic stirrer bar. The reactor was
purged with nitrogen three times before venting with
nitrogen. The reaction mixture was heated to 160'C and
maintained at this temperature for about 18 hours. The
copolymer has an inherent viscosity of 0.26 dl/g in HFIP
at 25'C and at a concentration of 0.1 g/dl. The
copolymer is solid at room temperature. The mole ratio
of polyoxaester/PCL/PGA/caprolactone was found by NMR
analysis to be 56.54/37.73/3.79/1.94.
Example 7
In Vitro Hydrolysis
The polyoxaester of Example 3 was tested for in
vitro hydrolysis at both 50'C and at reflux temperature.
A 100 mg sample of the polyoxaester, placed in 100 ml of
a phosphate buffer solution (0.2 M in phosphate, pH
7.27), was completely hydrolyzed in about 7 days at
50'C, whereas at reflux it was completely hydrolyzed in
about 16 hours.
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Example 8
In Vitro Hydrolysis
Polyoxaester of Example 2 was tested for in vitro
hydrolysis at 50'C and at reflux temperature. A 100 mg
sample of the polyoxaester, placed in a 100 ml buffer
solution (pH 7.27), was completely hydrolyzed in about
25 days at 50'C, whereas at reflux it was completely
hydrolyzed in about 16 hours.
ETH-1122
