AU738400B2

AU738400B2 - Absorbable polyalkylene diglycolates

Info

Publication number: AU738400B2
Application number: AU20097/97A
Authority: AU
Inventors: Kevin Cooper; Angelo G. Scopelianos
Original assignee: Ethicon Inc
Current assignee: Ethicon Inc
Priority date: 1996-01-18
Filing date: 1997-05-07
Publication date: 2001-09-20
Anticipated expiration: 2016-01-18
Also published as: AU2009797A

Description

I

-1- P/00/0011 Regulation 3.2

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

Name of Applicant: ETHICON, INC.

Actual Inventors: Kevin Cooper and Angelo G. Scopelianos Address for service in Australia: CARTER SMITH BEADLE 2 Railway Parade Camberwell Victoria 3124 Australia Invention Title: ABSORBABLE POLYALKYLENE DIGLYCOLATES The following statement is a full description of this invention, including the best method of performing it known to us 1A- ABSORBABLE POLYALKYLENE DIGLYCOLATES Technical Field The field of art to which this invention relates is polymers, more specifically, biocompatible, absorbable homopolymer and copolymers as well as blends.

Especially, homo- and co-polymers and blends of poly(alkylene diglycolate)s and aliphatic polyesters of lactide, glycolide, e-caprolactone, p-dioxanone, and trimethylene carbonate.

Background of the Invention Polymers, including homopolymers and copolymers, which are both biocompatible and absorbable in vivo are well known in the art. Such polymers are typically used to manufacture medical devices which are implanted in body tissue and absorb over o* time. Examples of such medical devices manufactured from these absorbable biocompatible polymers include suture anchor devices, sutures, staples, surgical tacks, clips, plates and screws, drug delivery devices, adhesion prevention films and foams, 15 and tissue adhesives, etc.

S"Absorbable, biocompatible polymers useful 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 20 aliphatic polyesters, polyanhydrides, poly(orthoester)s, and the like. Natural polymers typically absorb by an enzymatic degradation process in the body, while synthetic absorbable polymers typically degrade by a hydrolytic mechanism.

Synthetic absorbable polymers which are typically used to manufacture medical devices include homopolymers such as poly(glycolide), poly(lactide), poly(ecaprolactone), poly(trimethylene carbonate) and poly(p-dioxanone) and copolymers such as poly(lactide-co-glycolide), poly(e-caprolactone-co-glycolide), and Melbourne\003851230 Printed 10 July 2001 (9:01) -2 poly(glycolide-co-trimethylene carbonate). The polymers may be statistically random copolymers, segmented copolymers, block copolymers, or graft copolymers. It is also known that both homopolymers and copolymers can be used to prepare blends.

U.S. Patents 3,997,512, 4,048,256, 4,076,798, 4,095,600, 4,118,470, and 4,122,129, describe several biocompatible, absorbable, low Tg, aliphatic polyesters known as poly(alkylene diglycolate)s. These polymers are prepared from the polycondensation of diglycolic acid and glycols such as ethylene glycol, diethylene glycol, 1,2propylene glycol, 1,3-propylene glycol, and the like. These film forming, nonbranched, non-crosslinked, linear polymers have found use in drug delivery.

S* However, there is a constant need in this art for new polymer compositions having improved properties when formed into medical devices. For example, there is a great need for soft, flexible, elastomeric, low melting or liquid polymers for use as tissue S adhesives and sealants, bone waxes, cartilage replacements, adhesion prevention 15 barriers, and soft tissue augmentation fillers.

Consequently, for applications such as bone waxes or cartilage replacement, it would be highly desirable to have a polymeric material having characteristics such as S.pliability, and elasticity as found in highly branched or crosslinked gels.

20 Furthermore, materials used for biomedical applications such as defect fillers, and tissue adhesives and sealants require characteristics such as hydrophilicity, ease of application low viscosity liquid) and quick setting times water or light curing).

Accordingly, what is needed in this art are novel polymeric materials which are liquid or low melting, soft, flexible, and elastomeric.

Surprisingly, we have discovered that by selecting appropriate combinations of poly(alkylene diglycolate) homo- or co-polymers, or by postpolymerizing/crosslinking pendant acrylate groups on poly(alkylene diglycolate)s, or Melbourne\003851230 Printed 10 July 2001 (9:01) -3by preparing copolymers or blends of poly(alkylene diglycolate)s with aliphatic polyesters such as poly(e-caprolactone), poly(p-dioxanone), and poly(trimethylene carbonate), materials with a wide range of unique physical characteristics, such as those described above, useful as tissue adhesives and sealants, bone wax, cartilage replacement, adhesion prevention barriers, and soft tissue augmentation fillers can be prepared.

Disclosure of the Invention Accordingly, novel, absorbable, biocompatible, poly(alkylene diglycolate) homo- and co-polymers and copolymers or blends with aliphatic polyesters are disclosed.

More specifically, the poly(alkylene diglycolate) copolymers of the present invention are prepared by a condensation polymerization using a dicarboxylic acid and saturated, aliphatic alcohol monomers. That is, the dicarboxylic acid or ester of diglycolic acid in conjunction with saturated, aliphatic di-, tri-, and tetra-functional alcohols as well as hydroxyl terminated poly(ethylene glycol)s PEG's).

Additionally, for copolymers which comprise saturated, aliphatic diols such as ethylene glycol, 1,3-propanediol, and the like, as well as saturated, aliphatic tri- and tetra-functional alcohols, and hydroxyl terminated PEG's, the use of saturated, 20 aliphatic diols will be limited so as to lead to polymers where about 25 to 50 mole percent, more preferably 40 mole percent, of the repeating units contain saturated, aliphatic multifunctional alcohols or hydroxyl terminated PEG's.

In another aspect of the present invention is a biomedical device, especially implantable devices such as tissue adhesives and sealants, bone wax, cartilage replacement, adhesion prevention barriers, and soft tissue augmentation fillers made from the above-described polymers and blends. Most importantly, biomedical devices comprising the crosslinked hydrogels of the present invention are useful for such devices. A hydrogel, for the purposes of this invention, is defined as a crosslinked or highly grafted polymer, copolymer or polymer blend, which when placed in an Melboume\003851230 Printed 10 July 2001 (9:01) -4aqueous or buffered physiological solution at a concentration of lg/100 ml at a temperature of 37°C is swollen by the solution, but not dissolved, for a time frame as to make it useful for biomedical applications such as drug delivery or soft tissue defect fillers.

The foregoing and other features and advantages of the invention will become more apparent from the following description and examples and accompanying drawings.

Brief Description of the Drawings FIG. 1 illustrates a synthetic process for the preparation of poly(alkylene diglycolate) branched and crosslinked polymers.

FIG. 2 illustrates the physical characteristics of branched and crosslinked poly(alkylene diglycolate) polymers as a function of reaction time and mole percent of S.trifunctional alcohol glycerol) used.

Description of the Preferred Embodiments 15 The aliphatic poly(alkylene diglycolate)s useful in the practice of the present invention will typically be synthesized by conventional techniques using conventional processes.

For example, in a condensation polymerization, a dicarboxylic acid (diglycolic acid) and an alcohol glycerol) is polymerized in the presence of a catalyst at elevated temperatures and reduced pressures. The catalyst is preferably tin based, although any S. 20 conventional catalyst may be used, stannous octoate, and is present in the monomer mixture at a sufficiently effective molar ratio of monomer to catalyst, e.g., ranging from about 10,000/1 to about 100,000/1, or other conventional molar ratios.

The reaction is typically carried out at a temperature range from about 80 0 C to about 220°C, preferably from about 160 0 C to about 200 0 C, under an inert atmosphere until esterification of diglycolic acid is complete, followed by polymerization under reduced pressure until the desired molecular weight and viscosity are achieved.

Suitable saturated, aliphatic alcohols for the preparation of poly(alkylene diglycolate) polymers include, but are not limited to, glycerol, pentaerythitol, trimethylolpropane, slightly to substantially water soluble hydroxyl terminated poly(ethylene glycol)s of Melboure\003851230 Printed 10 July 2001 (9:01) weight average molecular weight of about 100 grams per mole to about 40,000 grams per mole, ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,4-butylene glycol, dipropylene glycol, 1,5-pentanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol, and the like. It should be noted that the term substantially water soluble as used herein is defined as meaning that the solubility of the poly(ethylene glycol) in an aqueous solution is greater than 1 gram per 100 mL of water, whereas the term slightly water soluble is defined as meaning that the solubility of the poly(ethylene glycol) in an aqueous solution is less than 1 gram per 100 mL of water. An aliphatic saturated alcohol is defined as an alcohol in which all carbon-carbon bonds are single in nature and no carbon-carbon ring structures are present. That is, no double or triple carboncarbon bonds or cyclic rings are found in the chemical structure. Hence, the structure of the aliphatic saturated alcohols of the present invention is:

R

4

-(CHR

1

-CHR

2 )n-R 3 where R 1

R

2 are hydrogen or methyl, ethyl or propyl or hydroxyl and combinations 15 thereof, and R 3 and R 4 are hydrogen or hydroxyl and combinations thereof, and where n is an integer from about 1 to about *oo The aliphatic polyesters useful in the practice of the present invention will typically be synthesized by conventional techniques using conventional processes. For example, in 20 a ring opening polymerization, the aliphatic lactone monomers are polymerized in the presence of a conventional organometallic catalyst and an initiator at elevated temperatures. The organometallic catalyst is preferably tin based, stannous octoate, and is present in a sufficiently effective amount in the monomer mixture, preferably at a molar ratio of monomer to catalyst ranging from about 10,000/1 to about 100,000/1. The initiator is typically an alkanol, a glycol, a hydroxyacid, or an amine, or any conventional initiator and is present irn the monomer mixture in a sufficiently effective amount, preferably at a molar 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 80 0 C to about 220 0 C, preferably from about 160°C to about 200 0 C, until the desired molecular weight and viscosity are achieved.

Melboume\003851230 Printed 10 July 2001 (9:01) -6- The copolymers of poly(alkylene diglycolate)s and aliphatic polyesters useful in the practice of the present invention will typically be synthesized by conventional techniques using conventional processes. For example, a preformed poly(alkylene diglycolate) of weight average molecular weight of about 100 to about 100,000 grams per mole and a preformed aliphatic polyester of weight average molecular weight of about 100 to about 100,000 grams per mole are transesterified in the presence of a conventional organometallic catalyst at elevated temperatures. The organometallic catalyst is preferably tin based, stannous octoate, and is present in a sufficiently effective amount in the mixture at a molar ratio of polymer to catalyst ranging from about 10,000/1 to about 100,000/1. The transesterification is typically carried out at a temperature range from about 80 0 C to about 220 0 C, preferably from about 160 0 C to S: about 200 0 C, until the desired molecular weight and viscosity are achieved.

S: Under the above described conditions, the homopolymers and copolymers of poly(alkylene diglycolate)s and aliphatic polyesters, will typically have a weight average molecular weight of about 2,000 grams per mole to about 200,000 grams per mole, more typically about 5,000 grams per mole to about 100,000 grams per mole, and preferably about 10,000 grams per mole to about 70,000 grams per mole. These molecular weights are sufficient to provide an effective inherent viscosity, typically 20 between about 0.05 to about 3.0 deciliters per gram more typically 0.1 to about 2.5 dL/g, and most preferably 0.2 to about 2.0 dL/g as measured in a 0.1 g/dL solution of hexafluoroisopropanol (HFIP) at 25 0

C.

The poly(alkylene diglycolate) homo- and co-polymers will typically consist of about 25 mole percent to about 50 mole percent, and more preferably about 40 mole percent to about 50 mole percent of repeating units with saturated, aliphatic tri- and/or tetrafunctional alcohols and/or hydroxyl terminated poly(ethylene glycol)s, with the remaining portions consisting of repeating units with saturated, aliphatic diols. The lower limit of multi-functional saturated, aliphatic alcohols and poly(ethylene glycol)s 0 in the homo- and co-polymers is desirable because the addition of 25 mole percent Melboume\003851230 Printed 10 July 2001 (9:01) -7leads to polymers which have fewer branches or crosslinks, but which, surprisingly and unexpectedly, still form hydrogels, and provides for materials which are useful in applications such as injectable defect fillers and tissue adhesives and sealants due to their low viscosities.

Articles such as medical devices are molded from the polymers, copolymers and blends of the present invention by use of various conventional injection and extrusion molding processes and equipment equipped with dry nitrogen atmospheric chamber(s) at temperatures ranging from about 160'C to about 230'C, more preferably 170 0 C to about 220 0 C, with residence times of about 1 to about 10 minutes, more preferably about 2 to about 5 minutes.

otO 6• The polymers and blends 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 medical and surgical devices, including wound closure devices. The preferred devices are hydrogels useful as injectable defect fillers, tissue adhesives and sealants, preformed defect fillers, bone waxes, and

S

cartilage replacements. Most importantly, biomedical devices comprising the ~crosslinked hydrogels of the present invention are useful for such devices. A hydrogel, for the purposes of this invention, is defined as a crosslinked or highly grafted polymer, copolymer or polymer blend, which when placed in an aqueous or buffered physiological solution at a concentration of lg/100 ml at a temperature of 37°C is swollen by the solution, but not dissolved, for a time frame as to make it useful for biomedical applications such as drug delivery or soft tissue defect fillers.

Alternatively, the polymers and blends 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 materials of the present invention may be spun as multifilament yam and woven or knitted to form sponges or gauze, (or non-woven sheets may be prepared) or used in conjunction with Melboume\003851230 Printed 10 July 2001 (9:01) -8other 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 tying up and supporting damaged surface abrasions, particularly major abrasions, or areas where the skin and underlying tissues are damaged or surgically removed.

Additionally, the polymers and blends can be molded to form films which, when sterilized, are useful as adhesion prevention barriers. Another alternative processing technique for the polymers and blends of the present invention includes solvent casting, particularly for those applications where a drug delivery matrix is desired.

0 Additionally, ultrathin coatings of about 1 to about 1000 microns can be applied to S 15 tissue surfaces, including the lumen of tissue such as a blood vessel. Once applied, the coating can be cured to secure it to the tissue, making such coatings useful in the 0**o*9 treatment or prevention of restenosis or the prevention of adhesions.

9 9 In more detail, the surgical and medical uses of the filaments, films, foams, coatings 0 *000 20 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. burn dressings Melbourne\003851230- Printed 10 July 2001 (9:01) -9 j. orthopedic pins, clamps, screws, and plates k. clips 1. staples m. hooks, buttons, and snaps n. bone substitutes o. needles p. intrauterine 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 15 w. stents x. suture anchors y. injectable defect fillers z. preformed defect fillers al. tissue adhesives and sealants b2. bone waxes c3. cartilage replacements d4. tissue coatings It will be appreciated by those skilled in the art that unsaturated groups can comprise the polymers of the present invention, but only unsaturated groups found in pendant acrylate groups.

Examples The following examples are illustrative of the principles and practice of this invention, although not limited thereto. Numerous additional embodiments within the scope and spirit of the invention will become apparent to those skilled in the art. The examples Melbourne\003851230 Printed 10 July 2001 (9:01) 10 describe new polymers and blends of poly(alkylene diglycolate)s and aliphatic polyesters, potentially useful as biomedical devices.

In the synthetic process, the poly(alkylene diglycolate) homo- and co-polymers are prepared by a method consisting of reacting a diacid diglycolic acid) and various saturated, aliphatic multi-functional alcohols via a condensation polymerization at temperatures of 150C to 220 0 C for 1 to 12 hours under an inert atmosphere, followed by reaction under reduced pressures for 1 to 24 hours, until the desired molecular weight and viscosity are achieved.

Furthermore, the aliphatic polyesters are prepared by a method consisting of reacting lactone monomers via a ring opening polymerization at temperatures of 80 0 C to 220 0

C

for 1 to 24 hours under an inert nitrogen atmosphere until the desired molecular weight and viscosity are achieved.

S In the examples which follow, the blends, polymers and monomers were characterized S"for chemical composition and purity (NMR, FT-IR), thermal analysis (DSC), melt rheology (melt stability and viscosity), and molecular weight (inherent viscosity).

20 FT-IR was performed on a Nicolet FT-IR. Polymer samples were melt pressed into thin films. Monomers were pressed into KBr pellets. 'H NMR was performed on a 300 MHz NMR using CDC13 or HFAD as a reference.

Thermal analysis of blends, polymers and monomers was performed on a Dupont 912 Differential Scanning Calorimeter (DSC) at a heating rate of 10 0 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 0 C/min. under a nitrogen atmosphere. Isothermal melt stability of the polymers was also determined by a Rheometrics Dynamic Analyzer RDA II for a (9:01) -11 period of 1 hour at temperatures ranging from 160 0 C to 230 0 C under a nitrogen atmosphere.

Inherent viscosities dL/g) of the blends and polymers were measured using a bore Cannon-Ubbelhode dilution viscometer immersed in a thermostatically controlled water bath at 25°C utilizing chloroform or HFIP as the solvent at a concentration of 0.1 g/dL.

Melt viscosity was determined utilizing a Rheometrics Dynamic Analyzer RDA II at temperatures ranging from 160 0 C to 230 0 C at rate of l°C/min. to 10 0 C/min. at frequencies of ls' 1 to 100s-' under a nitrogen atmosphere.

S S Several synthesis and blend examples will be described in the following few pages.

Parts and percentages where used are parts and percentages as specified as weight or 15 moles.

EXAMPLE 1 *•g Synthesis of a 25:75 (mol/mol) poly(1,3-propylene diglycolate -co- 2-hydroxy-l,3propylene diglycolate) copolymer To a flame dried 250 ml 1-neck round bottom flask equipped with an overhead mechanical stirrer, vacuum adapter, 750 adapter, distillate bend with a vacuum take-off and a 50 ml collection flask, 50 grams (3.73x10 1 moles) of diglycolic acid, 14.2 grams (1.86x10' moles) of 1,3-propanediol, 51.5 grams (5.59x10 1 moles) of glycerol, and 8.64 microliters (7.45x10- 6 moles) of a 0.33 M solution of stannous octoate catalyst were added.

The assembly was then placed in a high temperature oil bath at 175 0 C under a stream of nitrogen. The stirred monomers quickly began to melt. The low viscosity melt increased in viscosity. Stirring of the high viscosity melt was continued for 5 hours.

LMelbourne\003851230 Printed 10 July 2001 (9:01) -12 A strong vacuum was then placed on the system and a high volume of distillate (water, excess alcohol) began to evolve, and was collected. After 2 hours, the melt became very viscous. The reaction was allowed to continue for a total reaction time of 24 hours.

The 25:75 (mol/mol) rubbery, crosslinked (mol/mol) poly(propylene diglycolate -co- 2-hydroxy-l,3-propylene diglycolate) copolymer was removed from the bath, cooled to room temperature under a stream of nitrogen, and isolated. The polymer was insoluble in chloroform and hexafluroisopropanol, indicating a high degree of crosslinking or branching.

EXAMPLE 2 15 Synthesis of a 60:40 (mol/mol) poly(1,3-propylene diglycolate -co- 2-hydroxy-1,3propylene diglycolate) copolymer To a flame dried 250 ml 1-neck round bottom flask equipped with an overhead mechanical stirrer, vacuum adapter, 750 adapter, distillate bend with a vacuum take-off 20 and a 50 ml collection flask, 50 grams (3.73x10 moles) of diglycolic acid, 34.06 grams (4.48x10 moles) of 1,3-propanediol, 27.48 grams (2.98x10 moles) of glycerol, and 8.64 microliters (7.45x10-6 moles) of a 0.33 M solution of stannous octoate catalyst were added.

A strong vacuum was then placed on the system and a high volume of distillate (water, excess alcohol) began to evolve, and was collected. After 2 hours, the melt became Melboume\003851230 Printed 10 July 2001 (9:01) 13 very viscous. The reaction was allowed to continue for a total reaction time of 24 hours.

The 60:40 (mol/mol) rubbery, crosslinked (mol/mol) poly(propylene diglycolate -co- 2-hydroxy-1,3-propylene diglycolate) copolymer was removed from the bath, cooled to room temperature under a stream of nitrogen, and isolated. The polymer was insoluble in chloroform and hexafluroisopropanol, indicating a high degree of crosslinking or branching.

EXAMPLE 3 Synthesis of a 75:25 (mol/mol) poly(l,3-propylene diglycolate -co-2- hydroxy-1,3propylene diglycolate) copolymer 15 To a flame dried 250 ml 1-neck round bottom flask equipped with an overhead mechanical stirrer, vacuum adapter, 750 adapter, distillate bend with a vacuum take-off Sand a 50 ml collection flask, 50 grams (3.73x10-1 moles) of diglycolic acid, 42.6 t*o grams (5.59x10' moles) of 1,3-propanediol, 17.17 grams (1.87x10' 1 moles) of glycerol, and 8.64 microliters (7.45x10 6 moles) of a 0.33 M solution of stannous ,t 20 octoate catalyst were added.

The assembly was then placed in a high temperature oil bath at 175°C under a stream of nitrogen. The stirred monomers quickly began to melt. The low viscosity melt increased in viscosity. Stirring of the high viscosity melt was continued for 5 hours.

A strong vacuum was then placed on the system and a high volume of distillate (water, excess alcohol) began to evolve, and was collected. After 2 hours, the melt became very viscous. The reaction was allowed to continue for a total reaction time of 24 hours.

Melbourne\003851230 Printed 10 July 2001 (9:01) -14 The 75:25 (mol/mol) rubbery, crosslinked (mol/mol) poly(propylene diglycolate -co- 2-hydroxy-l,3-propylene diglycolate) copolymer was removed from the bath, cooled to room temperature under a stream of nitrogen, and isolated. The polymer was insoluble in chloroform and hexafluroisopropanol, indicating a high degree of crosslinking or branching.

EXAMPLE 4 Synthesis of a 90:10 (mol/mol) poly(1,3-propylene diglycolate -co- 2-hydroxy-1,3propylene diglycolate) copolymer To a flame dried 250 ml 1-neck round bottom flask equipped with an overhead mechanical stirrer, vacuum adapter, 750 adapter, distillate bend with a vacuum take-off and a 50 ml collection flask, 20 grams (1.49x10' moles) of diglycolic acid, 20.4 S 15 grams (2.68x10' moles) of 1,3-propanediol, 2.8 grams (2.98x10 2 moles) of glycerol, and 3.5 microliters (2.98x10 6 moles) of a 0.33 M solution of stannous octoate catalyst were added.

*5*S The assembly was then placed in a high temperature oil bath at 175 0 C under a stream 20 of nitrogen. The stirred monomers quickly began to melt. The low viscosity melt increased in viscosity. Stirring of the high viscosity melt was continued for 5 hours.

The 90:10 (mol/mol) rubbery, partially crosslinked poly(propylene diglycolate -co- 2hydroxy-1,3-propylene diglycolate) copolymer was removed from the bath, cooled to 1i230 Printed 10 July 2001 (9:01) 15 room temperature under a stream of nitrogen, and isolated. Inherent viscosity using HFIP as a solvent was 0.96 dL/g.

EXAMPLE Synthesis of a 50:40:10 (mol/mol/mol) poly(1,3-propylene diglycolate -2-hydroxy- 1,3-propylene diglycolate-ethylene oxide) terpolymer To a flame dried 250 ml 1-neck round bottom flask equipped with an overhead mechanical stirrer, vacuum adapter, 750 adapter, distillate bend with a vacuum take-off and a 50 ml collection flask, 50 grams (3.73x10' moles) of diglycolic acid, 28.39 grams (3.73x10-1 moles) of 1,3-propanediol, 27.48 grams (2.98x10' moles) of glycerol, 37.3 grams of a 1,000 grams per mole hydroxyl terminated poly(ethylene oxide) and 8.64 microliters (7.45x10 6 moles) of a 0.33 M solution of stannous octoate 15 catalyst were added.

The 50:40:10 (mol/mol/mol) poly(1,3-propylene diglycolate-2-hydroxy-1,3-propylene diglycolate-ethylene oxide) terpolymer was removed from the bath, cooled to room temperature under a stream of nitrogen, and isolated. The polymer was insoluble in chloroform and hexafluroisopropanol, indicating a high degree of crosslinking or branching.

Melboume\003851230 Printed 10 July 2001 (9:01) -16 The polymers of the present invention have many advantages over the polymers of the prior art. For example as shown in FIG. 2, by incorporation of a trifunctional alcohol glycerol) into the repeating units of a poly(alkylene diglycolate) (FIG. it is possible to obtain polymers with a wide variety of physical characteristics.

Highly branched or crosslinked poly(alkylene diglycolate)s can be synthesized by use of larger proportions of multi-functional alcohols. Furthermore, and surprisingly and unexpectedly, by incorporation of more than 25 mole percent, for example, of glycerol, materials can be formed which, when placed in a buffered solution at 37 0

C,

swell without dissolving for a period of 1 week or more, while polymers with less than mole percent glycerol are too lightly crosslinked and immediately dissolve as seen in the Table.

TABLE

o Swelling Behaviour as a Function of Days In-Vitro of Poly(1,3-propylene diglycolate-co-3-hydroxy-1,3-propylene diglycolate)s Swelling and Wt. Loss "Swelling and Wt. Loss *o

S

PPDG-HPDG* One-day Four-day 7-day Example 1 (25:75) 10s 28s Example 2 (60:40) 5s 20s 43s Example 3 (75:25) 5s 16s Example 4 (90:10) 48w 78w 93w Example 5 (50:40:10)** 10s 22s *PPDG-HPDG (mol/mol)-poly(1,3-propylene diglycolate-co-2-hydroxy-1,3propylene diglycolate) Poly (1,3-proplylene diglycolate-2-hydroxy-1,3-propylene diglycolare-ethylene oxide (mol/mol/mol) Swelling (swelling wt original wt./original wt)xl00. Denoted as small "s" Wt loss denoted as small "w" Melboume\003851230 Printed 10 July 2001 (9:01) -17 This solubility behavior is also demonstrated by the lack of solubility of Examples 1, 2, 3, and 5 in chloroform and HFIP, which have more than 25 mole percent glycerol, but the good solubility of Example 4, which readily dissolves in HFIP for IV characterization.

Hence, these surprising and unexpected hydrogel physical characteristics, found for the poly(alkylene glycolate)s with higher proportions of aliphatic, saturated multifunctional alcohols such as glycerol, allow for a variety needs to be met for a wide range of medical devices. For example, there is a great need for polymers for use as bone waxes, and cartilage replacements. Materials for such applications should be pliable and elastic. As described above, highly branched or crosslinked, elastomeric compositions of poly(alkylene diglycolate)s, alone or in combination with other *bioabsorbable aliphatic polyesters (FIG. could be utilized for such applications, S..while polymers with 10 mole percent or less of multi-functional saturated, aliphatic i 15 alcohols dissolve too quickly to be useful for such devices.

Although useful for drug delivery applications, linear, low Tg, poly(alkylene diglycolate)s do not have the characteristics of elasticity or toughness, due to a lack of crosslinks or branching, required for biomedical devices such as preformed implants 20 cartilage replacements).

Therefore, the branched or crosslinked poly(alkylene diglycolate)s of the present invention yield a broad range of properties such as elasticity and toughness, which can not be found with linear poly(alkylene diglycolate)s. This allows the branched or crosslinked polymers of the present invention to be utilized in a variety of medical devices where linear poly(alkylene diglycolate)s can not be used.

Although this invention has been shown and described with respect to detailed embodiments thereof, it will understood by those skilled in the art that various changes Melboure\003851230 Printed 10 July 2001 (9:01) 18 in form and detail thereof may be made without departing from the spirit and scope of the claimed invention.

0

SOS

SO

S

S.

40@@ 0

S

000@ 5000

S

0 059* 05 6

SO

S *05**0 0

OOS*

S

*S*

5*SO

S

5505

S'S.

0

S

Printed 10 July 2001 (9:01)

Claims

1. An absorbable, biocompatible poly(alkylene diglycolate) comprising the reaction product of: an acid or ester of diglycolic acid; and, an aliphatic, saturated alcohol selected from the group consisting of glycerol, pentaerythitol, trimethylolpropane, hydroxyl terminated poly(ethylene glycol)s, ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,4-butylene glycol, dipropylene glycol, 1,5-pentanediol, 1,6-hexanediol, 1,7-heptanediol, and 1,8- octanediol, wherein the poly(alkylene diglycolate) comprises about 25 mole percent S. to about 50 mole percent of repeating units with aliphatic saturated tri-, tetra-alcohols, and hydroxyl terminated poly(ethylene glycol)s, and wherein the balance of the poly(alkylene diglycolate) comprises repeating units with diol alcohols.

2. The poly(alkylene diglycolate) of Claim 1, wherein the poly(alkylene diglycolate) comprises about 40 mole percent to about 50 mole percent of repeating *06 units with aliphatic saturated tri-, tetra-alcohols, and hydroxyl terminated poly(ethylene glycol)s, and wherein the balance of the poly(alkylene diglycolate) comprises repeating units with diol alcohols. *see

3. An absorbable device for use in medical applications, the medical device comprising a poly(alkylene diglycolate), wherein said poly(alkylene diglycolate) comprises the reaction product of: a) an acid or ester of diglycolic acid; and, b) an aliphatic, saturated alcohol selected from the group consisting of glycerol, pentaerythitol, trimethylolpropane, hydroxyl terminated poly(ethylene glycol)s, ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,4-butylene glycol, dipropylene glycol, 1,5-pentanediol, 1,6-hexanediol, 1,7-heptanediol, and 1,8- octanediol, Melboume\003851230 Printed 10 July 2001 (9:01) wherein the poly(alkylene diglycolate) comprises about 25 mole percent to about 50 mole percent of repeating units with aliphatic saturated tri-, tetra-alcohols, and hydroxyl terminated poly(ethylene glycol)s, and wherein the balance of the poly(alkylene diglycolate) comprises repeating units with diol alcohols.

4. The poly(alkylene diglycolate) of Claim 3, wherein the poly(alkylene diglycolate) comprises about 40 mole percent to about 50 mole percent of repeating units with aliphatic saturated tri-, tetra-alcohols, and hydroxyl terminated poly(ethylene glycol)s, and wherein the balance of the poly(alkylene diglycolate) comprises repeating units with diol alcohols.

5. The poly(alkylene diglycolate) of claim 1 wherein the polymer has a molecular weight such that the inherent viscosity is from about 0.05 dL/g to about dL/g as measured in a solution of hexafluoroisopropanol (HFIP) at a concentration of 15 0.1 g/dL at 25 0 C. S°

6. The poly(alkylene diglycolate) of claim 1 wherein the alcohol is a hydroxyl terminated poly(ethylene glycol) of weight average molecular weight of about 100 grams per mole to about 40,000 grams per mole.

7. Absorbable, biocompatable poly(alkylene diglycolates) or absorbable devices for use in medical applications containing them, substantially as hereinbefore described with reference to the non comparative examples. DATED: 10 July 2001 FREEHILLS CARTER SMITH BEADLE Patent Attorneys for the Applicant: ETHICON, INC Melbourne\003851230 Printed 10 July 2001 (9:01) 4.! 7 O 'j