CA2186553A1

CA2186553A1 - High strength, melt processable, lactide-rich poly (lactide-co-p-dioxanone) copolymers

Info

Publication number: CA2186553A1
Application number: CA002186553A
Authority: CA
Inventors: Rao S. Bezwada; Kevin Cooper
Original assignee: Ethicon Inc
Current assignee: Ethicon Inc
Priority date: 1995-10-02
Filing date: 1996-09-26
Publication date: 1997-04-03
Also published as: JP3739501B2; AU6581696A; ZA968255B; US5714551A; JPH09132639A; EP0768329A2; DE69628110T2; US5639851A; EP0768329A3; DE69628110D1; EP0768329B1; US5868788A

Abstract

Absorbable, segmented copolymers of aliphatic polyesters based on lactone monomers lactide, and p-dioxanone are described. The segmented copolymers exhibit a broad range of properties, especially high strength and long elongations. This unique elastomeric behavior makes the copolymers of the present invention useful in a varity of medical device applications, especially adhesion prevention barriers and hemostatic devices.

Description

2186~3 S HIGI~ D _~t.~ IIELT ~.~h~ ~, LACT~DlS--RIC}r, ~!OLY~LACTIDE--CO--P--DIO~ANOUE) COPOLY~IER8 FiQld The field of art to which this invention relates is polymers, more specifically, biocompatible, absorbable copolymers; in particular, segmented copolymers of aliphatic polyesters of lactide, and p-dioxanone.
r ' of thQ In~ontion Polymers, including homopolymers and copolymers, which are both biocompatible and absorbable in vivo are well known in the art. Such polylaers are typically used to r-nllfa~t~1re medical device~ which are i~nplanted in body tissue and absorb over time. Examples of such medical devices ~anufactured from these absorbable biocompatible polymer~ include suture anchor devices, sutures,' 2s staples, surgical tacks, clips, plates and screws, etc.
Absorbable, biocompatible polymers uqeful for manufacturing medical devices include both natural and synthetic polymers. Natural polymers include cat gut, cellulose derivatives, collagen, etc. Synthetic polymers may consist of various aliphatic polyesters, polyanhydrides, poly ~orthoester) s, and the like .
Natural polymers typically absorb by an enzymatic degradation process in the body, while synthetic ~rEl-1077 218~5~3 .

absorbable polymers generally degrade primarily by a hydrolytLc r--h~ni Sm .
Synthetic absorbable polymers which are ty~ically used s to manufacture medical devices include homopolymer~ such a3 po l y ( glycol ide ), po l y ( lacti de ~, po l y ~-capro lactone ), poly(trimethylene carbonate) and poly(p-rli.-,Y~n.-,~e) and copolymers such as poly(lactide-co-glycolide), poly(L-caprolactone-co-glycolide), and poly(glycolide 10 trimethylene carbonate). The polymers may be Ytatistically random copolymers, 3 ~ted copolymers;
block copolymers, or graft copolymers. It is also known that both homopolymer3 and copolymers can be used to prepare blend3.
U.S. Patents 4, 643,191, 5, 080, 665 describe several biocompatible, ~hyorh-hle, poly~p~ - r c~ lactide) copolymers useful as biomedical devices.
U.S. Patent 5,080,665 describe~ block or graft copolymer~ of poly(p~ o~ , lactLde) prepared ~y a process in which the p-dioxanone monomer is reacted initially for a certain periodl of time, typically one hour at about 180C, followed by reaction with lactide at about 200C. This process leads to block or graft copolymers which are useful due to their formation of a "hard" pha3e formed from the lactide repeating unit blocks, and a "soft" phase formed from the p-dioxanone repeating unit blocks (Figure~ 1, 2, 3 and 4).
Furthermore, U.S. Patent 4, 643,191 describes p-dioxanone-rich, poly (p-dioxanone-co-lactide) segmented copolymers comprising about 70 weight percent to about 98 weight percent polymerized p-dioxanone with the Er~-1077 ~18655~
~ -ininq small portion of the copolymer polymerized with lactide.
Although the above described copolymers yield materials 5 with excellent properties such as high strength and stiffness and long BSR profiles as found with the block copolymers, or good strength and shorter BSR profiles as found for the p-dioxanone-rich segmented copolymers, there is a need in this art for new copolymer lO compositions having characteristics not found for the block copolymer~ of U.S. Patent 5, 080, 665 and the segmented copolymers of U.S. Patent 4, 643,191.
Accordingly, what is needed in this art are novel 15 copolymer compositions which are elastomeric, useful as, for example, adhesion prevention film barriers and other rubber toJ~ r~ medical devices ~uch aq foams for tisque scaffolds and hemostatic barriers.

Di ~ of th~ In~ution Surprisingly, it has been discovered that by preparing copolymers of poly(lactide-co-p-~l;oY~none) rich in 25 lactide by a process in which the small proportion of p-dioxanone monomer is reacted at low temperatures from about 100C to about 130C followed by reaction with lactide at higher temperatures of about 160C to about 190C, segmented poly(lactide~-rich copolymers with 30 small proportions of poly(p-dioxanone) can be formed that have high strength, toughness, long elongations and are very elastomeric. These polymers are useful in a variety of biomedical devi6es such as suture anchor devices, staples, surgical tacks, clips, plates and 2186~53 screw9, and especially adhesion prevention films, hemostatic foams and tissue scaf folds .
Accordingly, novel, absorbable, biocompatible, 5 poly(lactide-co-p-dioxanone) segmented copalymers are di~closed. The copolymers have a major t comprising about 30 mole percent to about 95 mole percent of repeating units of lactide, and a minor ~ -ne~t comprising about 70 mole percent to about 5 10 mole percent repeating units of p-r~ n~me.
Yet another aspect of the present invention is a biomedical device made from the above described copolymers, ~pec;~l ly implantable devices such as 15 suture anchor devices, staples, surgical tacks, clips, plates and screws, and most especially for adhesion prevention films and foam~ for hemo~tatic barriers and tissue scaffolds.
20 An additional aspect of the present invention is a process for producinq a s~ ted copolymer. The initial step of the process is to polymerize p--li oy~non~ in the presence of a catalytically effective amount of cataly~t and an initiator at a sufficient temperature and for a 25 sufficient period of time effective to yield a first mixture of p-rlioY~non~ monomer and p-dioxanone homopolymer. Then, lactide is added to the first mixture to form a second mixture. Next, the second mixture is polymerized at a sufficient temperature and for a 30 sufficient amount of time effective to produce a segmented copolymer comprising a major ~-~ p~ ent comprising about 30 mole percent to about 95 mole percent of repeating units of lactide and a minor ~ 218~53 ; ent comprisinq about 70 mole percent to about 5 mole percent of repeating units of p-dioxanone.
Still yet a further aspect of the present invention is s the copolymer of the present invention which is a product of the process of the present invention.
The foregoing and other features and advantages of the inYention will become more apparent from the following description and accompanying examples.
Bri~f D~cription of th~ Dr~ring~
FIG. 1 illustrates a synthetic process for the preparation of poly (p-dioxanone-b-lactide) block copolymers as described in U.S. Patent 5,080,665.
FIG. 2 illustrates a schematic representation of poly(p-~lioY~n~ne-b-lactide) block copolymers as described in U.S. Patent 5, 080, 665.
FIG. 3 illustrate~ a synthetic process for the preparation of poly(p-~ r~ co-lactide) qraft copolymers as described in U. S . Patent 5, 080, 665 .
FIG . 4 illustrate~ a schematic representation of poly ~p-diox~no~c co-lactide) graft copolymers as described in U.S. Patent 5, 080, 665.
FIG. 5 illustrates a synthetic process for the preparation of p-dioxanone-rich, poly(p-~ Y~none-co-lactide) segmented copolymers as described in U.S.
- Patent 4, 643,191.

J

_ ~ 2186~3 FIG. 6 illustrate~ a schematic representation of p-dioxanone-rich, poly(p-dioxanone-co-lactide) segmented copolymers as de~cribed in U.S. Patent 9,643,191.
FIG. 7 illustrates a synthetic process for the preparation of the poly(lactide)-rich, poly(lactide-co-p-dioxanone) segmented copolymers of the present invention .
FIG. 8 illustrates a schematic representation of the poly(lactLde)-rich, poly(lactide-co-p--l;oY~n~ne) segmented copolymers of the present invention.
FIG. 9 schematic representation of the morphologic differences between the lactide-rich, poly(lactide-co-p-dioxanone) segmented copolymers of the present invention, and the poly(p-dioxanone-b-lactide) block copolymers aA de~cribed in U.S. Patent 5,0B0,665 and the p-dioxanone-rich, poly (p-dioxanone-co-lactide) segmented copolymers a~ described in U.S. Patent 9, 643,191.
FIG. 10 shows the compositional differences between the .qegmented poly(lactide-co-p-r~ioY~n~ne) copolymers of the present invention and the copolymers disclosed in U.S.
Patents 4, 643,191 and 5, 080, 665.
FIG. 11 displays the property differences between the segmented poly(lactide-co-p-dioxanone) copolymers of the present invention and U.S. Patents 4,643,191 and 5,080,665, based upon differences in composition and structure .

I

218~3 DQJcription of th~ ProfQrrQd r ~; -t~
The process of the present invention is a one-step, one-.
reaction vessel, two-temperature process in which a s mixture of p-dioxanone monomer and p-dioxanone homopolymer, is formed at low temperatures of from about 100C to about 130C, preferably 110C. The mixture is then reacted with lactide at temperatures from about 120C to about 180C to form copolymers in which segments or sequences are composed of both p-dioxanone and lactide repeating units (FIGS. 5 and 6~. These s~ ted copolymers are, surprisingly and unexpectedly, substantially less crystalline than the block or graft copolymers previously known in the art and, therefore, yield materials with good strength, but shorter BSR
profiles, faster absorption rates, much longer ~lg~7ti~nc and lower stiffness than the block copolymers.
More specifically, the poly(lactide-co-p-~ioYan~ne) segmented copolymers of the present invention are prepared by a process in which a small proportion of p-oy~lon~ monomer in the initial monomer feed of the copolymer is reacted at low temperatures from about 100C to about 130C, preferably about 110C, for a sufficient time effective to cause polymerization, preferably about 4 to about 8 hours, followed by reaction with lactide at higher temperatures of about 140C to about 190C for a sufficient time effective to cause copolymerization, preferably about 1 to about 4 hours .
Furthermore, the segmented poly(lactide-co-p-dioxanone) copolymers will typically consist of about 30 mole 21 86aS3 I ~

percent to about 95 mole percent of repeating units of lactide, more typically about 30 mole percent to about 90 mole percent of repeating units of lactide, and preferably about 30 mole percent to about 50 mole S percent repeating units of lactide.
The aliphatic segmented copolyesters useful in the preparation of the segmented copolymers of the present invention will typically be synthesized in a ring 10 opening polymerization. That is, the aliphatic lactone monomers are polymerized in the presence of a catalytically effective amount of an organometallic catalyst and an initiator at elevated temperatures. The organometallic catalyst is preferably tin based, e.g., 5 stannous octoate, and is present in the monomer mixture at a molar ratio of monomer to catalyst ranging from about 10, 000/1 to about 100, 000/1. The initiator 1J
typically an alkanol, a glycol, a hydroxyacid, or an amine, and is precent in the monomer mixture at a molar 20 ratio of monomer to initiator ranging from about 100/1 to about 5000/1. The polymerization is typically carried out at a temperature range from about 80C to about 240C, preferably from about 100C to about 220C, until the desired molecular weight and viscosity are achieved.
2s Suitable lactone monomers may be selected from the group consisting of glycolide, lactide ~l, d, dl, 3eso), p-dioxanone, delta-valerolactone, beta-butyrolactone, epsilon-decalactone, 2, 5-diketomorpholine, 30 pivalolactone, alpha, alpha-diethylpropiolactone, ethylene carbonate, ethylene oxalate, 3-methyl-1, 4-dioxane-2, 5-dione, 3, 3-diethyl-1, 4-dioY.an-2, 5-dione, gamma-butyrolactone, 1,4-dioxepan-2-one, 1,5--lioYPp~n-2-one, 1, 4-dioxan-2-one, 6, 8-dioxabicycloctane-7-one and ErH-1077 I

218~5~3 g combinations of two or more thereof. Preferred lactone monomers are selected from the group consisting of lactide, and p~ Y~nr~nP.
s More specifically, the segmented copolymers of poly(lactide-co-p-dioxanone) useful in the practice of the present invention will typically be ~ynthe~ized by a process in which p-dioxanone is polymerized in a ring opening polymerization in the presence of an lO organometallic catalyst and an initiator at elevated temperatures. The organometallic catalyst i~ preferabl~
tin based, e . g ., stannous octoate, and is present in the mixture at a molar ratio of polymer to catalyst ranging from about 10,000/l to about lO0,000/l. The initiator is 15 typically an alkanol, a glycol, a hydroxyacid, or an amine, and is present in the monomer mixture at a molar ratio of monomer to initlator ranging from about lO0/1 to about 5000/1.
20 The polymerization is typically carried out at a temperature range from about 100C to about 130C, preferably 110C, for about 4 to about 8 hours, preferably 5 to 6 hour~, yielding a mixture of p-Y:lnr~ne monomer and homopolymer. Then, lactide monomer 25 ls added to the mixture of p-dioxanone monomer and homopolymer and the temperature i8 raised to about 140C
to about 190C, preferably from about 160C to about 185C until the desired molecular weight and viscosity are achieved.
Under the above described conditions, the segmented copolymers of poly~lactide-co-p-dioxanone), will typicallr have a weight average molecular weight of about 20,000 grams per mole to about 300,000 grams per Eq~H-1077 2186~3 mole, more typically about 40, 000 grams per mole to about 200, 000 grams per mole, and preferably about 60,000 grams per mole to about 150,000 grams per mole.
These molecular weights provide an inherent viscosity 5 between about 0.5 to about 4.0 deciliters per gram (dL/g), more typically 0.7 to about 3.5 dL/g, and most preferably 1. 0 to about 3 . 0 dL/g as measured in a 0 .1 g/dL solution of hexafluoroisopropanol ~HFIP) at 25CC.
Also, it should be noted that under the above described lO conditions, the residual monomer content will be less than about 5 wt. %.
The segmented copolymers of poly(lactide-co-p-dioxanone) of the present invention will typically consists of 15 about 30 mole percent to about 9S mole percent, more preferably about 40 mole percent to about 90 mole percent of lactide repeating unit~, and most preferably about 30 mole percent to about 50 mole percent of lactide repeating units. The lower limit of lactide 20 repeating units in the copolymers is desirable because the addition of 30 mole percent leads to copolymer~
which have long BSR profiles, but lower strength. The upper limit of lactide repeating units in the copolymers is desirable because the addition of 95 mole percent 2s leads to copolymers which have long BSR profiles, but higher strength and stiffness. This lead~ to copolymer~
with a desirable range of strength, stiffness and absorption profiles for use in a variety of biomedical applications .
Articles such as medical devices are molded from the segmented copolymers of the present invention by use of various injection and extrusion ~oLding equipment equipped with dry nitrogen al -sph~ric chamber(s) at ErH-1077 I

218~55 3 temperatures ranging from about 160C to about 220C, more preferably 180C to about 220C, with residence times of about 2 to about 10 minutes, more preferably about 2 to about 5 minutes.
The segmented copolymers of the present invention can be melt processed by numerous methods to prepare a vast array of useful devices. These materials can be injection or compression molded to make implantable lo medical and surgical devices, including wound closure devices. The preferred devices are suture anchor devices, staples, surgical tacks, clips, plates and screws, and a~h~cion prevention films and hemostatic foam barriers.
Alternatively, the segmented copolymers of the present invention can be ~.L~u~ to prepare ibers. The fill: -~ thuis produced may be fabricated into sutures or ligatures, attached to surgical needles, packaged, 20 and sterilized by known techniques. The materials of the present invention may be spun as multifili ~ yarn and woven or knitted to form sponges or gauze, lor n~ ven ~heets may be prepared) or used in conjunction with other molded ~ -~ssive structures such as prosthetic 25 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 ~ ts include tubes, including branched tubes, for artery, vein or intestinal repair, nerve 30 splicing, tendon splicing, sheets for tying up and supporting damaged surface abrasions, particularly major abrasions, or areas where the skin and underlying tissues are damage~or surgically removed. Especially, suture 2pplications where Monocryl-like, monofilament ~186553 sutures with excellent tensile properties but longer BSR
profiles than Monocryl are needed, mo~t especially in wound fascia closure applications, where longer absorption times would lead to better tissue fixation.

Additionally, the segmented copolymers of the present invention can be molded to form films which, when ~terilized, are useful as adhesion prevention barriers.
Another alternative processing technique for the copolymers of the present invention includes solvent casting, particularly for those applications where a drug delivery matrix is desired.
Furthermore, the segmented copolymers of the present invention can be processed by conventional techniques to form foams, which are useful as hemostatic barriers, bone substitutes, and tissue scaffold3.
In more detail, the surgical and medical uses of the filaments, films, foams and molded articles of the present invention include, but are not nec.~c~rily limited to knitted products, woven or non-woven, and molded products including:
25 a. burn dressings b. hernia patches c. medicated dressings d. fascial substitutes e. gauze, fabric, sheet, felt or sponge for liver hemosta~is f. gauze bandages g. arterial graft or substitutes h. -bandages for skin surfaces i. burn-dressing3 ErEl-1077 2186~53 j. orthopedic pins, clamps, screws, and plates k. clips l. ~taples m. hooks, buttons, and snaps s n. bone substitutes o. needles p. intrauterine devices q. draining or testing tubes or capillaries r. surgical instruments 10 8. vascular implants or supports t. vertebral discs u. extracorporeal tubing for kidney and heart-lung machines v. artificial skin and others S w. stents x. suture anchors y. in~ctable de~ect fillers z. preformed defect fillers al. tissue adhesives and sealants 20 b2. bone waxeQ
c3. cartilage r~r3 ? ~ t~
d4. hemostatic barriers eS. tissue scaffolds 2 5 ~
The following examples are illustrative of the principles and practice of this invention, although not limited thereto. Numerous additional '-'t- t~ within the scope and spirit of the invention will become apparent to those skilled in the art. The examples describe the novel segmented copolymers of poly(lactide-- - ~ co-p-dioxanone) of the present invention.
_ , ~ ETH-1077 I
I

. ~ 2186~3 In the synthetic process, the high molecular weight aliphatic segmented copolyesters are prepared by a method consisting of reacting p-dioxanone via a ring opening polymerization at temperatures of 100C to 130CC
5 for 4 to 8 hours under an inert nitrogen atmosphere, followed by reaction with lactide at temperatures of 140C to 190C until the desired molecular weight and viscosity are achieved.
lo In the examples which follow, the segmented copolymers and monomers were characterized for ~hPmical composition and purity (NMR, Fr-IR), thermal analysis IDSC~, melt rheology (melt stability and viscosity), and molecular weight (inherent viscosity), and baseline and in vitro 15 mechanical properties ( Instron stress/strain) .
lH NMR was p~Lf~ ~d on a 300 MHz Nt~R using CDCl3 or HEPD
a~ a reference. Thermal analysis of 9-, ted copolymers and monomers was performed on a Dupont 912 Differential 20 Sc~nnin~ Calorimeter lDSC) at a heating rate of 10C/min.
A Fisher-Johns melting point apparatus was also utili7ed to determine melting points of monomers. Thermal gravimetric analysis was performed on a Dupont 951 TG~
at a rate of 10C/min. under a nitrogen al -~here.
25 Isothermal melt stability of the sej ted copolymers was also det~rmined by a Rheometrics Dynamic Analyzer RDA II for a period of 1 hour at temperatures ranging from 160C to 230C under a nitrogen atmosphere.
30 Inherent viscosities (I.V., dL/g) of the segmented copolymers were measured using a 50 bore Cannon-Ubbelhode dilution visco~eter immersed in a thermostatically controlled wa~er bath at 25C utilizing ErH-1077 _ _ _ 21~553 chloroform or HFIP as the solvent at a concentration of 0.1 g/dL.
Melt viscosity was determined utilizing a Rheometrics 5 Dynamic Analyzer RDA II at temperatures ranging from 160C to 230C at rate of 1C/min. to 10C/min. at frequencies of ls~l to lOOs~l under a nitrogen atmosphere.
Baseline and in vitro mechanical properties of lO cylindrical dumbbells of the polymers 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 ..1 1 specimens.
The cylindrical dumbbells were prepared by utilizing a CSI Nini-max injection molder eTlipped with a dry nitrogen ai ~ ric chamber at temperatures ranging from 170C to 220C with a residence time of 3 minutes.
Films were prepared by utilizing a Carver Press at temperatures from 130C to 190C with a residence time of 3 to 5 minutes at a pressure of 15,000 psi.
25 Mechanical properties of the films were performed on an Instron model 1122 at a crosshead rate of 20 in/min.
Speci- gauge length was 1. 5 in ., with a width of 0 . 25 in. and a thickness of 0 . 005 in.
30 Fibers were prepared by a method as described in U.S.
Patent 4, 643,191 which is incorporated by reference. The copolymers were melt extruded in a conventional manner using an INSTRON capillary rheometer or single screw extruder. Rheometer packing temperatures ranged from 2~86~3 about 100C to about 200C with dwell times of about 5 to about 15 minutes and ram speeds of about l to about 3 cm/min . E~ctrusion temperatures ranged f rom about 1 60OC to about 230C .
S
The extrudate was typically drawn at a draw rate of 4 feet per ~inute in a single or mulitstage drawing process with drawing temperatures of about 25C to about 75C, giving a final draw ratio of about 4X to about 8X.
~ibers were also annealed under similar conditions as -described in U.S. Patent 9,643,191. Annealing temperatures were from about 70C to about 190C, preferably 110C, with Anne~lin~ times of about 1 hour to 15 about 10 hours, preferably about 4 to 7 hours.
In vitro ~tudie~ wer~ detP~m~nPd in ~ pho~phate buffer solution (pH~7 . 27 ) at ~ temperature of 37C for periods of 4, 7, 14, 21, and 28 days. Cylindrical du~bbells (8 20 to lO of a total weight of 2.4 to 3.0 grams) or fibers (8 to 10, 6 to 12 inches long) were placed in 100 ml of buffer solution.
Several synthesis exa~ples will be described in the 25 following few pages. Parts and percentages where used are parts and percentages as specified as weight or moles .
~MPIIS 1 Synthesis of a 90:10 (mol/mol) poly(lactide-co-p-~iio~nnn~) segmented copolymer ` ~ 2186~53 To a flame dried 250 ml 2-neck round bottom flask equipped with an overhead mechanical stirrer, nitrogen inlet and glass stopper, 10.21 grams (0.10 moles) of p-dioxanone, 0.1273 grams (1.2x10-3 moles) of diethylene s glycol (DEG) initiator, and 121.2 microliters of a 0.33 M solution of stannous octoate catalyst were added.
The assembly was then placed in a high temperature oil bath at llO~C. The stirred p-dioxanone quickly began to melt. The low viscosity melt quickly increased in viscosity. Stirring of the high viscosity melt waY
continued for 5 hours.
Then, 129.71 grams (0.90 moles) of lactide were added and the temperature was raised to 185C. The lactide quickly began to melt and the reaction mass slowly began to increa~e ln viscosity. Stirring of the high vi3c03ity ~elt was continuedl for another 2 . 5 hours for a total reaction time of 7 . 5 hours .
The 90:10 (l/mol) poly(lactide ~.o p ~ Y~nor~) segmented copolymer was removed from the bath, cooled to room temperature under a stream of nitrogen, isolated and ground. The polymer was then dried under vacuum at 2s 80C for 14 hours and at 110C for 28 hours. The inherent viscosity was 2.05 dL/g as measured in a 0.1 g/dL HFIP
solution at 25C. The copolymer conversion was about 96~ .
E~CAMPL~S 2 Synthesis of a 80:20 (mol/mol) poly(lactide-co-p-dioxanone) segmented copolymer ErH-1077 I

To a flame dried 250 ml 2-neck round bottom flask equipped with an overhead mechanical stirrer, nitroqen inlet and glass stopper, 20.42 grams (0.2 moles) of p-dioxanone, 0.063 qrams (0.6x10-3 moles) of DEG initiator, and 121.2 microliters of a 0.33 M solution of stannous octoate catalyst were added.
The assembly was then placed in a high temperature oil bath at 110C. The stirred p-dioxanone quickly began to melt. The low viscosity melt quickly increased in viscosity. Stirring of the high viscosity melt was continued for 5 hours.
Then, 115.30 grams (0.80 moles) of lactide were added and the temperature was raised to 185C. The lactide quickly began to melt and the reaction mass slowly began to increase in viscosity. Stirring of the high viscoslty melt was continued for another 2 . 5 hours for a total reaction time of 7 . 5 hours .
The 80:20 (~Gol~mol) poly(lactide-co-p-~ Y~nr n-~) segmented copolymer was removed from the bath, cooled to room temperature under a stream of nitrogen, iqolated and ground. The polymer was then dried under vacuum at 80C for 14 hours and 110C for 28 hours. The inherent viscosity was 1. 72 dL/g as measured in a 0 .1 g/dL HFIP
solution at 25C. The copolymer conversion wa~ about 94~ .
.. ! ~
30 1!~UWLE 3 Synthesis of a 70:~ (mol/mol) poly(lactide-co-p-dioxanone) qegmente~ co~olymer ErH-1077 _ _ _ ~18~5~3 . .

To a flame dried 250 ml 2-neck round bottom flask equipped with an overhead mechanical stirrer, nitrogen inlet and glass stopper, 30. 63 grams ~0. 30 moles) of p-dioxanone, 0.063 grams (0.6x10-3 moles) of DEG initiator, and 121.2 microliters of a 0.33 M solution of stannous octoate catalyst were added.

The assembly was then placed in a high temperature oil bath at 110C. The stirred p-dioxanone quickly began to melt. The low viscosity melt quickly increased in vi~3cosity. Stirring of the high viscosity melt was continued for 5 hours.
Then, 100.89 grams (0.70 moles) of lactide were added and the temperature was raised to 185C. The lactide quickly began to melt and the reaction mass slowly began to lncrea~le in viscosity. Stirring of the high vi~co~ity melt wa~ continued for another 2 . 5 hours for a total reaction time of 7 . 5 hours .
The 70:30 (mol/mol) polyllactide-co-p-~ioY~-~one) segmented copolymer was removed from the bath, cooled to room temperature under a stream of nitrogen, isolated and ground. The polymer was then dried under vacuum at 80C for 14 hours and 110C for 28 hours. The inherent viscosity waY 1.86 dLtg as measured in a 0.1 g/dL HFIP
solution at 25C. The copolymer conversion was about 88~ .
. .
3 o ~
Synthesis of a 60:40 (mol/mol) poly(lactide-co-p-dioxanone)-segmented copolymer 218~55'~
. --To a flame dried 250 ml 2-neck round bottom flask equipped with an overhead mechanical stirrer, nitrogen inlet and glass ~3topper, 40.83 grams (0.40 moles) of p-dioxanone, 0.063 grams (0.60x10-3 moles) of DEG
initiator, and 121.2 microliters of a 0.33 M solution of stannous octoate catalyst were added.
The assembly was then placed in a high temperature oil bath at 110C. The 3tirred p-dioxanone quickly began to melt. The low viscosity melt quickly increased in viscosity. Stirring of the high viscosity melt was continued for 5 hours.
Then, 86.48 grams (0.60 moles) of lactide were added and the temperature was raised to 185C. The lactide quickly began to melt and the reaction mass slowly began to increase in viscosity. Stirrimg of the high vi~co~ity melt wa~3 c~ntin~d for another 2.5 hours for a total reaction time of 7 . 5 hours .
The 60:40 (mol/mol~ poly(lactide-co-p--lioYanone) segmented copolymer was removed from the bath, cooled to room temperature under a stream of nitrogen, isolated and ground. The polymer was then dried under vacuum at 80C for 14 hours and 110C for 42 hours. The inherent viscosity was 1.37 dL/g as measured in a 0.1 g/dL HFIP
solution at 25C. The copolymer conversion was about 84% .
E$AMPIlC S
Synthesis of a 50:50 ~mol/mol) poly(lactide-co-p-- - dioxanone) segmented copolymer ` 2186~3 To a flame dried 250 ml 2-neck round bottom fla~k equipped with an overhead mechanical stirrer, nitrogen inlet and glass stopper, 51. 04 grams lO . 50 moles) of p-dioxanone, 0.063 gram~ (0.60x10-3 moles) of D5G
initiator, and 121.2 ~icroliters of a 0.33 M solution of stannous octoate catalyst were added.
The assembly was then placed in a high temperature oil bath at 110C. The stirred p-dioxanone quickly began to lO melt. The low viscosity melt quickly increased in vi~cosity. Stirring of the high viscosity melt was continued for 5 hours.
Then, 72.06 grams (0.50 moles) of lactide were added and 15 the temperature was raised to 185C. The lactide quickly began to melt and the reaction mass slowly began to increase in visco~ity. Stirring of the high ~iscosity melt wa~ continued for another 2 . 5 hours for a total reaction time of 7 . 5 hours .
The 50:50 ~mol/mol) poly(lactid~ co p rii~V~nr~ne) segmented copolymer was removed from the bath, cooled to room temperature under a stream of nitrogen, i~olated and ground. The polyaler was then dried under vacuum at 2s 80C for 42 hours. The inherent viscosity was 1.39 dL/g as mea~ured in a 0.1 g/dL HFIP solution at 25C. The copolymer conversion was about 86~.
~AMPI E 6 Synthesis of a 40:60 (mol/mol) poly(lactide-co-p-dioxanone) ~eg~ented copolymer ETE~-1077 2~1 86~i53 To a flame dried 250 ml 2-neck round bottom flask equipped with an overhead mechanical stirrer, nitrogen inlet and glass stopper, 61.25 grams (0.60 moles) of p-dioxanone, 0. 063 grams (0 . 60x10-3 moles) of DEG
initiator, and 121.2 microliters of a 0.33 M solution of stannous octoate catalyst were added.
The assembly was then placed in a high temperature oil bath at 110C. The stirred p-dioxanone quickly began to melt. The low viscosity melt quickly increased in viscosity. Stirrin~ of the high viscosity melt was continued for 5 hours.
Then, 57 . 65 grams (0 . 40 moles) of lactide were added and the temperature was raised to 185C. The lactide quickly began to melt and the reaction ma~3s slowly began to increai~e in visco~ity. Stirring of the high viscosity melt was continued for another 2 . 5 hours for a total reaction time of 7 . 5 hours .
Th~ 40:60 (mol/mol) poly(lactide co p tl~ov~n~n~) segmented copolymer was removed from the bath, cooled to room temperature u~der a stream of nitrogen, isolated and ground. The polymer was then dried under vacuum at 80C for 42 hours. The inherent viscosity was 1.32 dL/g as measured in a 0 . l g/dL HFIP solution at 25C. The copolymer conversion was about 83~.
~MPLE 7 Synthesis of a 60:40 (mol/mol) poly(lactide-co-p-tlinY~nnne) block copolymer as prepared in U.S. Patent 5, 080, 665 I

ErH-1077 ~,, 2~8~5~ `

To a flame dried 250 ml 2-neck round bottom flask equipped with an overhead mechanical stirrer, nitrogen inlet and glass stopper, gO . 83 grams (0 . 40 moles) of p-dioxanone, 0.063 grams (0.6x10-3 moles) of DEG initiator, and 121.2 microliters of a 0.33 M solution of ~tannous octoate catalyst were added.
The assembly was then placed in a high temperature oil bath at 180~C. The stirred p-dioxanone quickly began to melt. The low viscosity melt quickly increased in viscosity. Stirring of the high viscosity melt was continued for 4 hours.
Then, 86 . 48 grams (0 . 6 moles) of lactide were added and the temperature was raised to 200C. The lactide quickly began to melt and the reaction mass slowly began to increase ln viscosity. Stirring of the high visco~ity melt was cont~nl~ed for another 2 hours for a total reaction time of 6 hours.
The 60:40 ~mol/mol) poly(lactid~ co p dioxanone) block copolymer was removed from the bath, cooled to room temperature under a ~tream of nitrogen, tQolAt~d and ground. The polymer was then dried under vacuum at llO~C
for 24 hours. The inherent visc03ity was 1.35 dL/g as measured in a 0.1 g/dL HFIP solution at 25C. The copolymer conversion was about 86~.
,.
e~MPI~ 8 Synthesis of a poly(lactide) homopolymer To a flame dried 250 ml 2-neck round bottom flask e~-irped with an overhead ~ n;c?l stirrer, nitrogen -218fi5~3 inlet and glass stopper, 144.13 grams (1 mole) of lactide, 0.1139 grams (1.2x10-3 moles) of DEG initiator, and 121.2 microliters of a 0.33 M solution of stannous octoate catalyst were added.
The assembly was then placed in a high temperature oil bath at 185C. The stirred lactide quickly began to melt.
The low viscosity melt quickly increased in viscosity.
Stirring of the high viscosity melt was continued for lO 3 . 5 hours .
The poly(lactide) homopolymer was removed from the bath, cooled to room temperature under a stream of nitrogen, isolated and ground. The polymer was then dried under vacuum at 80C for 14 hours and llODC for 28 hours. The inherent viscosity was 1.56 dL/g as measured in a 0.1 g/dL HFIP 301ul-10n at 25C. The polymer conversion was about 99%.
20 ~p~ 9 Synthesis of a poly(p-dioxanone) homopolymer To a flame dried 250 ml 2-neck round bottom flask 25 ecr-irped with an overhead mechanical stirrer, nitrogen inlet and glass stopper, 102.088 grams ~1 mole) of p-~i; oY~nor~e~ 0. 063 grams (0 . 6x10-3 moles) of DEG initiator, and 121.2 microliters of a 0.33 M solution of stannous octoate catalyst were added.
The assembly was then placed in a high temperature oil bath at llO=C. The stirred p-dioxanone quickly began to melt. The low viscosity melt quickly increa4ed in 2i865~3 viscosity. Stirring of the high viscosity melt was continued for 8 hours.
The poly (p-dioxanone) homopolymer was removed from the s bath, cooled to room temperature under a stream of nitrogen, isolated and ground. The polymer was then dried under vacuum at 70C for 12 hours and 80C for 28 hours. The inherent viscosity was 1.56 dL/g as measured in a 0.1 g/dL HFIP solution at 25C. The polymer conversion was about 829~.
~MPI~S 10 Synthesis of a 85:15 ~mol/mol) poly(p-dioxanone-co-lactide) segmented copolymer as prepared in U.S. Patent 4, 643, 191 To a flame dried 250 ml 2-neck round bottom flask equipped with an overhead m~AhAniAAl stirrer, nitrogen inlet and gla~ stopper, 86.78 grams (0.85 mole) of p-YAnnne~ 0.42 gral!n8 (0.4x10-3 moles~ of DEG initiator, and 101 microliters of a 0.33 ~I solution of 3tannous octoate catalyst were added.
The assembly was then placed in a high temperature oil bath at 110C. The stirred p-~i~YAnr~ne quickly began to melt. The low viscosity melt quickly increased in visco~ity. Stirring of the high viscosity melt was continued for 6 hours.
Theil, 21. 62 grams (0 .15 moles) of lactide were added and the temperature was raised to 140C. The lactide cluickly began to melt and the reactio~ ~ass slowly began to increase in vi~cosity. Stirring of_the high viscosity 218~53 melt was continued for another 4 hours for a total reaction time of 10 hours.
The 85:15 (mol/mol) poly(p-dioxanone-co-lactide) 5 sej ted copolymer was removed from the bath, cooled to room temperature under a stream of nitrogen, isolated and ground. The polymer was then dried under vacuum at 80C for 42 hours . The inherent viscosity was 1. 52 dL/g as measured in a 0.1 g/dL HFIP solution at 25C. The lO copolymer conversion was about 90&.
As discussed above, U.S. Patent 5,080,665 describes poly(lactide-co-p-dioxanone) block or graft copolymers.
U.S. Patent 4, 643, lgl describes p-dioxanone-rich, 15 segmented poly(p-dioxanone-co-lactide~ copolymers.
The preqent invention describe~ poly~lactide~-rich, 9 ~ ~ ted poly ( lact idc co p ti j oV~n~Qp ) copol ymers .
20 ~q shown in FIGS. 1, 2, 3 and 4, block copolymers are copolymers where long blocks of repeating units of each of the homopolymers (i.e., the homopolymers of poly(p-~lioY~n~ne), or poly(lactide)) are connected or linked at a single point. Segmented copolymers, aq shown in FIGS.
25 5, 6, ~, and 8, are copolymers where short s~ -q of repeating units _s~d of both monomeric units are connected or linked at many points.
. .
The differences in the a~an~ t or sequPnceq of the 30 repeating units in the copolymer can lead to dramatic changes in the thermal, chemical, physical, and for absorbable polymers, ~lological properties.
ErH-1077 i -For biocompatible, absorbable aliphatic poly(ester~ 3, the sequence arrangement of repeating units in the polymer chain has a ~trong effect on, for example, absorption rates, BSR profiles, strength, and stiffness.
Table 1 shows the surprising and unexpected changes in physical properties by comparing the poly(lactide-b-p-dioxanone) block copolymers of U. S . Patent 5, 080, 665, the p-dioxanone-rich, poly (p-~li or~none-~o-lactide) segmented copolymers of U.S. Patent 4, 643,191, and the poly (lactide) -rich, segmented poly (lactide-co-p-dioxanone) copolymers of the present invention.

.
-E~H-1077 _ _ 2186~53 ~ 28 ~
~-bl- 1 Pre~rti-~ o~ th~ tld--rieh Poly(l~tid -eo-p-diox~non-) ~-em-nt-d bloelc ee olym~r ~~PU S p~t rtn5tiOn80~n66ds~pnodly(' r t d P dio~l~non~
5 rieh poPiy(p-rl ~ id-) eopoiym r o~ U S P~t-nt ~ 6~3 191 PWPDO PWPDO Poly~l-ctid~) diox-Yn(opn-) PDO/PLA
Pre~rti-J Ex~mpl- 6 Ex-mpl- 7 Ex~ rpl- ~ Ex-~p~- 9 ~x~mpl- 10 Initi-l Compo~ition ~0/60 ~0/60 100/0 0/100 85/15 Imol~) ~ilms 511~ximum Load ~psi) 600 ~S00 2000 7~00 6200 Ultim~t- Str-~s 20(psi) ~600 ~500 2000 7100 6200 ~ Str-in 500 S 3 31~ 750 Perm~n-nt S-~, ~, 6 1 0 279 117 ~t-r br~
25prop~rti-s t 300~ qlongatlon) Pror~e~ti-~
30Cry~t-llinity (~) ¦ <S ¦ 35 ¦ ~0 ¦ S0 ¦ 28 For example, the block copolymers have hish initial ~trength and stiffness. This is caused by the long block~ of polyllactide) homopolymer in the copolymers, which yields highly crystalline polymers. Consequently, 40 the block copolymers have high strength and stiffness.
The segmented copolymers of the present invention, however, are much more elastic. The sequence or arrangement of repeating units is such that the segments 45 are, ~osed of both monomeric units (FIG. 8). Hence, the degree of crystallinity (i.e., percent) is less than that of the block copolymers. This yields a structure ~ where a few crystalline domains act as physical ~ U ~ ~
21~6~S3 , ~

crosslinks between the amourphous regions of the polymer (FIG. 9), yielding the combination of high elongation (%
strain) and low permanent set (Table 1, Example 6). The block copolymers, because of their long blocks of s lactide and p-dioxanone, have a more crystalline morphology (FIG. 9). ~ence, the crystalline domains are too large and can not act as phy-~ical crosslinks between the amorphous domains. This yields polymers with higher strength, but without elastomeric properties (i.e., low 10 elongations or high permanent set, Table 1, Example 7).
In addition, it can be clearly seen that the s~ -ed copolymers of U.S. Patent 4, 643,191 and the homopolymers of poly(lactide) and poly(p-dioxanone) do not possess the unique elastomeric properties of the present invention ~Table 1, Examples 8, 9 and 10) (i.e., high elongation with low permanent set).
C~n~equ~ntl y, these physical characteriqtic~ allow for a variety of needs to be met for a wide range of medical 20 device-~. For example, there is a great need for ab30L~able polymer~ films and foam~ in wound care, Pspe~-iAlly adhesion prevention, hemostatic barriers and tissue scaffolds which require elastic properties.
I

Therefore, it can be seen that there is a need for poly(lactide)-rich, poly(lactide-co-p-~ Yannne) segmented copolymers of the present. The copolymers of the present invention possess unique elastomeric properties which can not be obtained f rom the block copolymers of U.S. Patent 5,080,665 or from the p-dioxanone-rich, poly ~p-dioxanone-co-lactide) segmented copolymers of U.S. Patent 4, 643,191.
!

ErH-1077 -~ 8 6 ~ ~ 3 Although this invention has been shown and described with respect to detailed . '~ ltr ts thereof, it will understood by those ~killed in the art that various changes in form and detail thereof may be made without s departing from the spirit and scope of the claimed invention .

Claims

1. An absorbable, biocompatible segmented copolymer comprising:
a major component comprising about 30 mole percent to about 95 mole percent of repeating units of lactide;
and, a minor component comprising about 70 mole percent to about 5 mole percent of repeating units of p-dioxanone.

2. The segmented copolymer of claim 1 wherein the copolymer has a molecular weight such that the inherent viscosity is from about 0.6 dL/g to about 3.0 dL/g as measured in HFIP at a concentration of 0.1 g/dL.

3. The segmented copolymer of claim 1 wherein the major component comprises about 30 mole percent to about 90 mole percent of repeating units of lactide, and wherein the minor component comprises about 70 mole percent to about 10 mole percent of repeating units of p-dioxanone.

4. The selected copolymer of claim 3 wherein the copolymer has a molecular weight such that the inherent viscosity is from about 0.6 dL/g to about 3.0 dL/g as measured in HFIP at a concentration of 0.1 g/dL.

5. The segmented copolymer of claim 1 wherein the repeating units of lactide comprise about 30 mole percent to about 50 mole percent, and wherein the repeating units of p-dioxanone comprise about 70 mole percent to about 50 mole percent of the copolymer,

6. The segmented copolymer of claim 5 wherein the copolymer has a molecular weight such that the inherent viscosity is from about 0.6 dL/g to about 3.0 dL/g as measured in HFIP at a concentration of 0.1 g/dL.

7. An absorbable device for use in medical applications, the medical device comprising a segmented copolymer, said copolymer comprising:
a major component comprising about 30 mole percent to about 95 mole percent of repeating units of lactide;
and, a minor component comprising about 70 mole percent to about 5 mole percent of repeating units of p-dioxanone.

8. The absorbable device of Claim 7 wherein the segmented copolymer comprises:
a major component comprising about 30 mole percent to about 90 mole percent of repeating units of lactide;
and, a minor component comprises about 70 mole percent to about 10 mole percent of repeating units of p-dioxanone.

9. The absorbable device of Claim 7 wherein the segmented copolymer comprises:
about 30 mole percent to about 50 mole percent of repeating units of lactide; and, about 70 mole percent to about 50 mole percent of repeating units of p-dioxanone.

10. A process for producing a segmented copolymer from the group of lactone monomers- comprising p-dioxanone, and lactide, said process comprising heating a mixture of p-dioxanone monomer, p-dioxanone homopolymer, and lactide, to a sufficient temperature for a period of time to effectively produce a segmented copolymer comprising a major component comprising about 30 mole percent to about 95 mole percent of repeating units of lactide and a minor component comprising about 70 mole percent to about 5 mole percent of repeating units of p-dioxanone.

11. A process for producing a segmented copolymer comprising the steps of:
a) polymerizing p-dioxanone in the presence of a catalytically effective amount of catalyst and an initiator at a sufficient temperature and for a sufficient period of time to yield a first mixture of p-dioxanone monomer and p-dioxanone homopolymer; and, b) adding lactide to the first mixture to form a second mixture; and, c) polymerizing the second mixture at a sufficient temperature and for a sufficient amount of time to form a segmented copolymer comprising a major component comprising about 30 mole percent to about 95 mole percent of repeating units of lactide and a minor component comprising about 70 mole percent to about 5 mole percent of repeating units of p-dioxanone.

12. The process of claim 11 wherein the temperature for the initial polymerization is about 100°C to about 130°C and the time is about 5 to about 6 hours and the temperature for the second polymerization is about 190°C to about 210°C, and the time is about 1 hour to about 4 hours.

13. The process of claim 12 wherein the amount of catalyst utilized comprises from about 10, 000/1 to about 100,000/1, based on the molar ratio of polymer to catalyst, and wherein the catalyst is preferably tin based.

14. The process of claim 13 wherein the catalyst comprises stannous octoate.

15. The process of claim 12 wherein the amount of initiator comprises from about 100/1 to about 5,000/1;
based on the molar ratio of polymer to initiator, and wherein the initiator comprises a member selected from the group consisting of alkanols, glycols, a hydroxyacids, amines, and combinations thereof.

16. The process of claim 12 wherein the lactone monomer added in the second step (b) comprises lactide and the temperature of the polymerization of the second mixture is from about 180°C to about 220°C.

17. The process of claim 16 wherein the segmented copolymer comprises a molecular weight such that the inherent viscosity is from about 0.6 dL/g to about 3.0 dL/g as measured in HFIP at a concentration of 0.1 g/dL.

18. The process of claim 11 wherein the segmented copolymer comprises:
a major component comprising about 30 mole percent to about 90 mole percent of repeating units of lactide and, a minor component comprising about 70 mole percent to about 10 mole percent of repeating units of p-dioxanone.

19. The process of claim 11 wherein the segmented copolymer comprises:
about 30 mole percent to about 50 mole percent of repeating units of lactide and, about 70 mole percent to about 50 mole percent of repeating units of p-dioxanone.

20. An absorbable, biocompatible segmented copolymer comprising:
a major component comprising about 30 mole percent to about 95 mole percent of repeating units of lactide, and, a minor component comprising about 70 mole percent to about 5 mole percent of repeating units of p-dioxanone, wherein said segmented copolymer is the product of the process comprising the steps of:
a) polymerizing p-dioxanone in the presence of a catalytically effective amount of catalyst and an initiator at a sufficient temperature and for a sufficient period of time to yield a first mixture of p-dioxanone monomer and p-dioxanone homopolymer; and, b) adding lactide to the first mixture to form a second mixture; and, c) polymerizing the second mixture at a sufficient temperature and for a sufficient amount of time.