GB1590261A - Isomorphic copolyoxalates and sutures thereof - Google Patents

Description

(54) ISOMORPHIC COPOLYOXALATES AND SUTURES THEREOF (71) We, ETHICON, INC., a Corporation organised under the laws of the State of New Jersey, United States of America, of Somerville, New Jersey, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: This invention relates to isomorphic polyoxalate polymers, synthetic absorbable sutures comprising oriented fibers thereof, a method of closing a wound in living tissue of a non-human animal using a suture as just mentioned, surgical prostheses comprising a fabric manufactured at least in part from synthetic absorbable fibers of the said polymers, and surgical prostheses comprising solid surgical aids cast or machined from absorbable polymers as first mentioned.

Absorbable suture materials have traditionally been natural collagenous materials obtained from sheep or beef intestine, commonly known as catgut. More recently, it has been proposed to manufacture synthetic absorbable sutures from polyesters of hydroxycarboxylic acids, notably polylactide, polyglycolide, and copolymers of lactide and glycolide.

Such synthetic absorbable sutures are described in.U.S.P. 3,636j956, U.S.P. 3, 297,033 and elsewhere in the literature. Polyesters of succinic acid have also been suggested for at least partially bioresorbable surgical articles as disclosed for example in U.S.P. 3,883,901.

Among the requirements of an ideal absorbable suture are that it should have good handling properties, should approximate and hold tissue for proper healing with minimal tearing and tissue damage, should have adequate straight tensile and knot strength, should be controllably uniform in properties including dimensional stability within the body, should be sterilizable, should be absorbable by living tissue, preferably at a constant rate regardless of the place in the body or the condition of the patient and without causing such unfavorable tissue reactions as walling off, granuloma formation or excessive edema, and finally should be capable of being properly and easily tied into surgical knots.

While multifilament sutures manufactured from polymers of lactide and glycolide fulfill the above requirements to a large degree, monofilament sutures of these materials are considerably less flexible than catgut and these synthetic sutures are accordingly generally limited to a multifilament, braided construction. Sutures of glycolide polymers are also not suitable for sterilization by radiation without suffering severe degradation of physical properties.

We have discovered that copolyoxalate copolymers having isomorphic sequences can be melt extruded into pliable, monofilament fibers whic have good in vivo strength retention and are absorbed in animal tissue without significant adverse tissue reaction. The fibers have good tensile and knot strength, and can be sterilized by gamma radiation without serious loss of these properties. In addition, monofilament sutures of the polymers of the present invention have a high degree of softness and flexibility not found in many synthetic absorbable sutures of the prior art.

The preparation of polyoxalate polymers is described in the art. Carothers et al, J. Amer.

Chem. Soc. 52, 3292 (1930) for example, describes the ester interchange reaction of diols such as ethylene glycol, 1,3-propanediol, or 1,4-butanediol with diethyl oxalate to yield a mixture of monomer, soluble polymer and insoluble polymer. The reaction of oxalic acid and an alkylene glycol to form polyester resins is described in U.S. 2,111,762, while the preparation of polyesters of fiber-forming quality from dicarboxylic acids and diols is described in U.S. 2,071,250-1 and 2,952,652. Isomorphic polymers including polyester copolymers have been discussed in the literature (Isomorphism in Synthetic Macromolecular Systems, G. Allegra and I. W. Bassi, Adv. Polymer Sci. 6, 549 (1969)). The particular isomorphic copolyoxalates of the present invention however, have not previously been known, nor has their preparation or use as synthetic absorbable sutures been suggested heretofore.

It is accordingly an object of the present invention to provide polymers of isomorphic copolyoxalates and articles made therefrom. A further object of this invention is to provide synthetic absorbable sutures of isomorphic copolyoxalates. It is a yet further object of this invention to provide surgical aids and prostheses fabricated of fibers, or cast or machined from blocks, of isomorphic copolyoxalate pblymers.

Highly crystalline isomorphic polyoxalate polymers are prepared by reacting mixtures of cyclic and linear diols with dialkyl oxalate, preferably in the presence of an inorganic or organometallic catalyst. The diols comprising the reaction mixture have the same carbon chain length separation between terminal OH groups of 6 or 8 carbon atoms. The cyclic diol may be trans 1,4-cyclohexane dialkanol or p-phenylene dialkanol and comprises from 5 to 95 mol percent, and preferably from 40 to 75 mol percent of the total diol reactant.

Copolymers prepared by the transesterification reaction of the two diols and diethyl oxalate are melt extruded into highly crystalline filaments suitable for use as synthetic absorbable sutures. Drawn and oriented filaments are characterized by high tensile and knot strength, a Young's modulus in most cases of less than about 600,000 psi providing a high order of filament softness and flexibility, and good strength retention and minimal tissue reaction in vivo.

In the subsequent description, reference will be made to the accompanying drawing, in which Figure 1 is a perspective view of a needle-suture combination; Figure 2 is a perspective view of a needle-suture combination within a hermetically sealed container; Figure 3 illustrates a screw machined from the polymer of the present invention; Figure 4 is a cross-sectional view of a composite yarn containing filaments of different composition; and Figure 5 is a plan view of a surgical fabric knitted from fibers of the present invention.

According to the present invention, we provide isomorphic polyoxalate polymers comprising units of cyclic and linear oxalates and having the general formula -[-O-R-O-CO-CO-]- wherein each R is (CH2)n - A - (CH2)n I or - (CH2) W 2n II with from 5 to 95 mol percent, and preferably from 40 to 75 mol percent, of the R units being I; A is trans 1,4-cyclohexylene or p-phenylene, n is 1 or 2 and is the same for I and II, and x is the degree of polymerization resulting in a fiber forming polymer having a molecular weight greater than 10,000.

Polymers of the present invention are conveniently prepared by an ester interchange reaction between the afore-described mixture of diols and a C1-C4 alkyl ester of oxalic acid, preferably in the presence of an ester interchange catalyst. The preferred ester of oxalic acid is diethyl oxalate. The ester interchange is most preferably conducted in two stages wherein the reactants are first heated with stirring under a nitrogen atmosphere to form a prepolymer with the removal of ethanol, followed by postpolymerization under heat and reduced pressure to obtain a final polymer of the desired molecular weight and fiber forming quality. Polymers with low or moderate degrees of polymerization are postpolymerized in the liquid state or as finely-divided solid particles, depending on their melting temperature range.

The polyrner is melt extruded through a spinnerette in a conventional manner to form one or more filaments which are subsequently drawn about 4X to 6X in order to achieve molecular orientation and improve tensile properties. The resulting oriented filaments have good tensile and dry knot strength and good in vivo strength retention.

It is well documented that the crystallinity and hence suitability for fiber-formation in both the AB and AA-BB type polyesters decreases significantly when the mol fraction of the major comonomer sequence decreases below about 80%. In some instances, if the comonomer sequences are isomorphic, chains composed of slightly less than 80% of the major sequences can pack into a crystalline form. However, randomly constructed copolyester chains based on almost equal amounts of the isomorphic comonomer sequences are generally found to be non-crystalline and poor fiber formers. Contrary to this general rule, the isomorphic copolyesters of the present invention display an unexpectedly high level of crystallinity of about 45% in a 50/50 copolyester. The polymers of the present invention are also unusual in that all copolymers through the entire composition range of from 5 to 95% of each isomorphic comonomer demonstrate levels of crystallinity comparable to those encountered in the parent homopolymers; namely between 30 and 50% depending on the thermal history. A similarly striking observation characteristic of these copolyesters is their display of melting endotherms, as shown by DSC, for the crystalline regions of all copolymers within the composition range of from about 5 and 95 mol % of each isomorphic comonomer. Constructed curves of the melting temperature versus composition did not reveal any positive eutectic composition in these systems. The X-ray and DSC data suggest strongly the uncommon presence of almost complete isomorphism in the copolyesters of the present invention.

Dimensional stability and tensile strength retention of the oriented filaments may be enhanced by subjecting the filaments to an annealing treatment. This optional treatment consists of heating the drawn filaments to a temperature of from about 40 to 1300C, most preferably from about 60 to 1100C while restraining the filaments to prevent any substantial shrinkage. The filaments are held at the annealing temperature for a few seconds to several days or longer depending on the temperature and processing conditions.

In general, annealing at 60 to llO"C for up to about 24 hours is satisfactory for the polymers of the present invention. Optimum annealing time and temperature for maximum fiber in vivo strength retention and dimensional stability is readily determined by simple experimentation for each fiber composition.

Filaments of the present invention may be used as sutures in either a monofilament or a multifilament construction. Multifilament sutures are preferably braided but may also be twisted or covered in accordance with common practice. For use as sutures, it is necessary that the fibers be sterile, and sterilization may be accomplished by exposing the fibers to Cobalt 60 gamma radiation or to ethylene oxide. Such sterilization techniques are well known and commonly practiced in suture manufacture.

Since the function of a suture is to join and hold severed tissue until healing is well along, and to prevent wound separation as a result of movement or exercise, a suture must meet certain minimum standards of strength. It is particularly important that strength be maintained when knots are tied and during the actual procedure of drawing tight a suitable knot. Sutures prepared from oriented filaments of the present invention are characterized by a straight tensile strength of at least about 30,000 psi and a knot strength of at least about 20,000 psi, although significantly higher strengths may be obtained.

The preparation of high molecular weight oriented filaments of isomorphic polyoxalates is further illustrated by the following examples where all percentages are on a molar basis unless otherwise noted. The following analytical methods were used to obtain the data reported in the examples. Inherent viscosity (njnh) was obtained on polymer solutions (1 gram/liter) in chloroform or hexafluoro-2-propanol (HFIP). The infrared spectra of polymer films (cast from CHCl3 or HFIP) were recorded on a Beckman Acculab 1 spectrophotometer. The NMR spectra of the polymer solutions in CHC13 were recorded on an MH-100 or CFT-20 spectrophotometer. A DuPont 990 DSC apparatus was used to record the glass transition (Tg), crystallization (Tc) and melting (tom) temperatures of the polymers under nitrogen, using about 5 mg samples and a heating rate of 10 C/min. or as otherwise specified. The thermogravimetric analysis (TGA) data of the polymers were recorded under nitrogen using a DuPont 951) TGA apparatus and a heating rate of 10 or 20"C/min. with about 10 mg samples. A Philips vertical goniometer with graphite crystal monochromatized copper K, radiation was used to obtain the X-ray powder and fiber diffraction patterns of the polymers. Crystallinity was determined by the method of Hermans and Weidinger and the diffractometer patterns were resolved with a DuPont 310 curve analyzer.

In vitro hydrolysis of polymer discs (about 1.2 g, 2.2 cm diameter) and monofilaments (7-25 mil) was conducted at 37"C in phosphate buffer comprising a solution of 27.6 g sodium dihydrogenphosphate monohydrate in 1000 ml water adjusted to pH 7.25 with sodium hydroxide.

In vivo absorptio,l (muscle) was determined by implanting two 2 cm segments of monofilament fiber into the left gluteal muscles of female Long Evans rats. The implant sites were recovered after periods of 60, 90, 120 and 180 days and examined microscopically to determine the extent of absorption. In vivo absorption (subcutaneous) is a non histological technique in which continuous observation of the biological degradation of segments of suture is made by implanting two segments of suture, 2 cm long, into the abdominal subcutis of young female rats. The implants are readily visible when the skin is wetted with propylene glycol and extent of absorption can be determined by subjective visual examination.

In vivo strength retention was determined by implanting segments of sutures in the posterior dorsal subcutis of female Long Evans rats for period of 5 to 30 days. The sutures were recovered at the designated periods and pull-tested for straight tensile strength.

In vitro strength retention was determined by placing segments of sutures in the afore-defined buffer at 500C for periods of 2 to 4 days. The sutures were recovered at the designated periods and pull-tested for straight tensile strength.

EXAMPLES General Polymerization Procedure Diethyl oxalate was heated with selected diols in a mechanically-stirred reactor using a stannous alkanoate or organic titanate catalyst. The reaction was conducted under a nitrogen atmosphere at suitable temperatures until a substantial portion of the calculated amount of ethanol was obtained. Postpolymerization of the resulting prepolymer was then continued under reduced pressure using a suitable heating scheme. At the end of the postpolymerization period, the molten polymer was allowed to cool slowly at room temperature, isolated, ground and dried at 25"C to 80"C (depending on the polymer Tm) in vacuo for at least one day. Alternatively, the prepolymer can be postpolymerized partially in the liquid state, cooled, and then post-polymerized further in the solid state as finely divided particles. Detailed experimental conditions for the preparation of representative samples of isomorphic polyoxalates and important properties of the resulting polymers are presented below.

EXAMPLE I 95/5 Poly (trans 1, 4- Cycloh exylenedicarbinyl-co-hexamethy lene Oxalate): Distilled diethyl oxalate (19.0 g, 0.130 mol), recrystallized trans 1,4cyclohexanedimethanol (19.8 g, 0.137 mol), 1,6-hexane-diol (0.856 g, 0.00724 mol) and stannous octoate (0.33 M in toluene; 0.080 ml, 0.026 mmol) were added under dry and oxygen-free conditions to a glass reactor equipped for magnetic stirring. The prepolymer was formed by heating the mixture at 1200C for 3 hours under nitrogen at 1 atmosphere while allowing the formed ethanol to distill, followed by heating at 1600C for 2 hours. The prepolymer was then heated in vacuo (0.05 mm Hg) at 220"C for 1 hour, and the postopolymerization completed by heating at 215"C for an additional 6 hours. The polymer was then allowed to cool to room temperature, isolated and ground, and finally dried in vacuo at room temperature.

Polymer Characterization: ninth in CHl3 = 0.50 DSC (20"C/min.): Tm = 210 C Polymer Melt-Spinning: The polymer was spun using an Instron Rheometer with a 30 mil die at 207"C.

In Vitro Evaluation: The undrawn fibers lost 21 and 66 percent of their initial mass after immersion in phosphate buffer at 37"C for 42 and 127 days, respectively.

EXAMPLE II 85/15 Poly (1,4-Cyclohexylenedicarbinyl-co-hexamethylene Oxalate): Distilled diethyl oxalate (58.4 g, 0.400 mols), recrystallized trans 1,4cyclohexanedimethanol (less than 1% cis isomer; 53.9 g, 0.374 mols), 1,6-hexanediol (7.8 g, 0.066 mol), and stannous octoate (0.33M in toluene; 0.40 ml, 0.13 mmol) were added under dry and oxygen-free conditions to a glass reactor equipped for mechanical stirring. The mixture was heated at 120 and 1500C for 2 and 3 hours, respectively, under nitrogen at one atmosphere while the formed ethanol distilled. The prepolymer was allowed to cool, then reheated to 200"C under reduced pressure (0.1 mm Hg). Temperatures of 200, 220 and 230"C were maintained for 2, 3 and 4 hours while the collection of distillates continued. The resulting polymer (inh in CHC13 = 0.49) was cooled, isolated, ground (2 mm screen size), and then dried in vacuo at room temperature. Portions (30 g) of this ground polymer were postpolymerized in the solid state in glass reactors equipped for magnetic stirring by heating in vacuo (0.1 mm Hg) at 185"C for 22 hours.

Polymer- Characterization: ninth in CHCl3 = 1.14 DSC (20"Cimin.): Tm = 187"C Polymer Melt-Spinning: The polymer was spun at 230"C using an Instron Rheometer with a 40 mil die. The fiber was quenched in ice water, wound, dried and subsequently drawn.

Fiber Properties: Fibers drawn 5X in two stages, 4X at 620C followed by 1.25X at 1190C exhibited the following properties: diameter = 8.5 mils, straight tensile strength = 8.39 x 104 psi; knot tensile strength = 5.06 x 104 psi; modulus = 6.61 x 105 psi; elongation = 15%.

In Vivo Evaluation: Sterilized (via y-radiation, 2.5 Mrads), drawn monofilament (8.5 mils) retained 89, 75, 10 and zero percent of its initial breaking strength (4.8 Ibs.) after subcutaneous implantation in rat muscle for 3, 7, 14 and 21 days respectively. Drawn filaments implanted into the gluteal muscles of rats elicited median tissue responses in the slight range throughout a 180 day post-implantation period. Filaments drawn 4X at 600C followed by 1.25X at 1100C and having a straight tensile of 6.76 x 104 psi showed indications of initial degradation 20 to 26 weeks after implantation.

In Vitro Evaluation: Fibers drawn 4X at 600C (exhibiting a straight tensile of 4.33 x 104 psi) lost 40 percent of their initial mass after immersion in phosphate buffer at 370C for 84 days.

EXAMPLE III 80/20 Poly (1,4- Cyclohexylen edicarbinyl-co-hexamethylene Oxalate): Distilled diethyl oxalate (43.8 g, 0.300 mol), recrystallized trans 1,4cyclohexanedimethanol (cis isomer content = 1.0%, 36.3 g, 0.252 mol), 1,6-hexane-diol (7.4 g, 0.063 mol), and stannous oxalate (12.4 mg., 0.060 mmol) were added under dry and oxygen-free conditions to a glass reactor equipped for mechanical stirring. The prepolymer was formed by heating the mixture at 1200C for 2 hours under nitrogen at 1 atmosphere while allowing the formed ethanol to distill, followed by 1600C for 2.5 hours. The mixture was allowed to cool, then reheated in vacuo (0.1 mm Hg) to 140"C and maintained until the prepolymer melted. The temperature was then increased to 1900C, maintained for 30 minutes, then raised to 200"C for 1.5 hours. The melt post-polymerization of the stirred polymer was completed by heating at 220"C for 4.5 hours. The polymer was cooled, isolated, ground (screen size = 2 mm) and dried in vacuo at room temperature. To obtain the final product, the ground polymer was post-polymerized in the solid state in a glass reactor equipped for magnetic stirring by heating at 1800C in vacuo (0.05 mm Hg) for 24 hours while allowing the formed diols to distill.

Polymer Characterization: Ninh in CHCl3 = 1.33 DSC (20"C/min.): Tm = 205"C Polymer Melt-Spinning: The polymer was spun at 240"C using an Instron Rheometer equipped with a 40 mil die.

The extruded filaments were quenched in ice water, wound, then dried at room temperature in vacuo, and subsequently drawn 4X.

Fiber Properties: Diameter = 9.0 mils; straight tensile strength = 7.31 x 104 psi; knot tensile strength = 3.46 x 104 psi; modulus = 7.7 x 105 psi; elongation = 15%.

In Vivo Evaluation: Sterilized (by y-radiation, 2.5 Mrads), fibers (9.0 mil) retained 85, 20 and zero percent of their initial breaking strength (4.2 Ibs.) after subcutaneous implantation in rat muscles for 3, 7 and 14 days, respectively. These fibers were also implanted into the gluteal muscles of rats to determine tissue response and absorption characteristics. The median tissue response elicited by the samples was in the slight range after 5 days post implantation and in the minimal range after 42 days; absorption of the samples was first noted at 120 days and by 180 days approximately fifty percent of the material had been absorbed.

EXAMPLE IV 80/20 Poly (1,4- Cyclohexylenedicarbinyl-co-hexamethylene Oxalate): Distilled diethyl oxalate (23.4 g, 0.160 mol), recrystallized trans 1,4cyclohexanedimethanol (cis isomer content = 6.3%; 20.0 g, 0.139 mol), 1,6-hexanediol (4.1 g, 0.035 mol) and Tyzor OG (Tyzor OG, a titanium glycolate catalyst manufactured by E. I.

DuPont de Nemours and Co., Wilmington, Delaware, 19898) (0.117M in toluene, 0.28 ml, 0.033 mmols) were added under dry and oxygen-free conditions to a glass reactor equipped for magnetic stirring. A prepolymer was formed by heating the mixture at 1200C for 19 hours under nitrogen at 1 atmosphere while allowing the formed ethanol to distill. The pressure was then reduced (0.05 mm Hg) and heating at 1200C continued for 30 minutes longer. The temperature was then increased and maintained at 1800c, 1900C and 200"C for 2, 5 and 2 hours, respectively, while removing excess and formed diols. The polymer was allowed to cool, isolated, ground, and dried in vacuo at room temperature.

Polymer Characterization: ninth in CHCl3 = 0.46 DSC (10 C/min.): Tm = 171 C TGA (10 C/min. under N2): 0.25% weight lost at 275 C Polymer Melt-Spinning: The polymer was spun using an Instron Rheometer with a 30 mil die at 172 C. The extruded filaments were quenched in ice water, dried in vacuo at room temperature, and finally drawn 5X at 43 C.

Fiber Properties: Ninh in CHCl3 = 0.42 X-ray: Major reflections correspond to 8.9 (W), 4.84 (M), 4.41 (S) and 3.42 (W) d-spacings; 26% crystallinity. (Undrawn filaments were found to be 22% crystalline which increased to 31% by annealing at 70 C for one hour).

Physical Properties: Diameter = 11.1 mils; straight tensile strength = 2.07 x 104 psi; elongation = 35%.

In Vivo Evaluation: The rate of absorption and tissue response of drawn filaments was determined by implantation into the ventral abdominal subcutis of Long-Evans rats. Some evidence of filament degradation was noted 11 to 14 weeks after implantation, with the bulk of the fiber being absorbed by 20 to 23 weeks. No tissue reaction to the implants was noted at any period.

ln Vitro Evaluation: The drawn fibers exhibited a 43% decrease in mass after immersion in the phosphate buffer at 37 C for 28 days.

EXAMPLE V 67/33 Poly (trans 1, 4-cyclohexylenedicarbinyl-co-hexamethylene Oxalate): Distilled diethyl oxalate (40.0 g, 0.274 mol), recrystallized trans 1,4 cyclohexanedimethanol (25.9 g, 0.180 mol), 1,6-hexane-diol (10.6 g, 0.0897 mol), and stannous octoate (0.33 M in toluene; 0.16 ml. 0.053 mmol) was added to a glass reactor equipped for mechanical stirring. The prepolymer was formed by heating the mixture under nitrogen at 1200C for 9 hours, followed by 125 C for 9 hours while collecting the distillates.

The prepolymer was cooled, then reheated in vacuo (0.03 mm Hg) and maintained at 80, 120,150, 170 and 1800C for 1, 2, 2, 3 and 1.5 hours, respectively. The postpolymerization of the polymer melt was completed by heating at 195 C for 6 hours while continuing to stir and remove distillates. The polymer was cooled, isolated, ground, and then dried at room temperature.

Polymer Characterization: ninth in CHCl3 = 0.49 DSC (20 C/min.): Tm = 179 C Polymer Melt Spinning: The polymer was spun at 175 C using an Instron Rheometer with a 30 mil die. The resulting fibers were subsequently drawn 4X at 50 C.

Fiber Properties: Diameter = 9.3 mils straight tensile strength = 2.65 x 104 psi, knot tensile strength = 2.21 x 104 psi, modulus = 3.7 x 105 psi.

In Vivo Evaluation, Tissue Reaction: Two centimeter long samples of sterilized (by y-radiation, 2.5 Mrads) drawn fiber were implanted subcutaneously in the abdominal wall of young female Long Evans strainrats. At intervals of 3, 14, 28, 56 and 90 days, two rats were sacrificed for examination of implants.

The skin containing the fibers was excised and affixed to plastic sheets for preservation in formalin. Two tissue blocks were cut transver; ely from each site and embedded in paraffin for histologic preparation. Eight stained sampies were examined at each interval for tissue reaction to the fibers. Only mild foreign body reactions were detected.

In Vivo Evaluation, Absorption: Fiber segments sterilized by y-radiation (2.5 Mrads) approximately 2 em in length were inserted into the ventral abdominal subcutis of Long Evans rats (100 g, female) to determine the rate of absorption of the drawn fibers. One to two rats were sacrificed after various periods after implantation. The skin containing the implant sites was removed and dried. These preparations were examined and evaluated using both dissecting and transmission microscopes. Estimates of the amount of implant remaining were based on the length of the segment or fragments remaining and the decrease in the surface area made by palpating the implant in the dried hide and comparing it with a one week old preparation.

Implants were fragmented at one week; migration and clumping of fragments was noted at subsequent kill periods. Evidence of degradation was first seen 16 weeks after implantation.

Palpable fragments, in diminishing amounts, were present until 30 weeks. Quantitatively, about 100, 75, 45, 40, 20, 15 and 5 or less percent of the suture remained after 14, 16, 20, 23, 26, 30 and 36 weeks.

EXAMPLE VI 50/50 Poly (trans 1, 4-cyclohexyldicarbinyl-co-hexamethylene Oxalate): Distilled diethyl oxalate (38.0 g, 0.260 mol), recrystallized trans 1,4cyclohexanedimethanol (20.2 g, 0.140 mol), 1,6-hexane-diol (16.5 g, 0.140 mol), and stannous octoate (0.33 M in toluene, 0.16 ml, 0.053 mmol) were added under dry and oxygen-free conditions to a mechanically stirred glass reactor. Under nitrogen at one atmosphere, the mixture was heated to and maintained at 1200C for 20 hours, while allowing the formed strength = 36.400 psi, elongation = 31%.

EXAMPLE VIII 30/70 Poly (trans 1, 4-cyclohexylenedicarbinyl-co-hexamethylene Oxalate): Distilled diethyl oxalate (36.5 g, 0.250 mol), recrystallized trans 1,4cyclohexanedimethanol (11.5 g, 0.0797 mol), 1,6-hexane-diol (22.4 g, 0.190 mol), and stannous octoate (0.33 M in toluene; 0.16 ml, 0.053 mmol) were added under dry and oxygen-free conditions to a mechanically stirred reactor. The mixture was heated to and maintained at 125, 140 and 1600C for 2, 2 and 1 hour, respectively, under nitrogen at one atmosphere while allowing the formed ethanol to distill. The prepolymer was cooled and then reheated in vacuo (0.1 mm Hg) and maintained at 150 and 185"C for 16 and 3 hours, respectively. The postpolymerization was completed by maintaining the polymer at 200"C for 5.5 hours while continuing to remove the diols under vacuum. The polymer was then cooled, isolated, ground and dried in vacuo at room temperature.

Polymer Characterization: ninth in CHCl3 = 0.82 DSC (20"C/min): Tm = 85"C Polymer Melt Spinning: The polymer was spun at 125"C using an Instron Rheometer with a 40 mil die. The fiber was quenched in ice water, wound, dried in vacuo at room temperature, and subsequently drawn 5.6X at room temperature, followed by annealing at 55"C.

Fiber Properties: Diameter 8.3 mils, straight tensile strength 5.18 x 104 psi, knot tensile strength 3.51 x 104 psi, modulus 2.11 x 105 and elongation 50%.

In Vivo Evaluation: Sterilized (by y-radiation, 2.5 Mrads), drawn fibers (9.8 mil diameter; 3.64 x 104 psi straight tensile strength; 2.34 x 104 psi knot tensile strength; 1.47 x 105 psi modulus; and an elongation of 45%) were implanted into the gluteal muscles of rats to determine their absorption and tissue response characteristics at 5, 21, 42 and 150 days post implantation.

At the 42 day period, there was no evidence of any morphologic changes of the implant sites indicating absorption. At the 150 day period, the fibers had a median value of 2 percent suture cross sectional area remaining (with a range of 0 to 20 percent).

Foreign body tissue responses to the samples were in the slight range at 5, 21 and 42 day periods and in the minimal range at the 150 day period.

In Vitro Evaluation: Drawn fibers possessing physical properties similar to those of fibers used in the in vivo testing exhibited a 100% decrease in their initial mass after 141 days of immersion in phosphate buffer at 37"C.

EXAMPLE IX 5/95 Poly (trans 1, 4-cyclohexylenedicarbinyl-co-hexamethylene Oxalate): Distilled diethyl oxalate (19.0 g, 0.130 mol), recrystallized trans 1,4cyclohexanedimethanol (1.0 g, 0.0069 mol), 1,6-hexane-diol (16.3 g, 0.138 mol), and stannous octoate (0.33 M in toluene; 0.08 ml, 0.026 mmol) were added under dry and oxygen-free conditions to a glass reactor equipped for magnetic stirring. The prepolymer was formed by heating the mixture at 1200C for 3 hours under nitrogen at one atmosphere while allowing the formed ethanol to distill, followed by 1600C for 2 hours. The prepolymer was heated and maintained at 2050C for 8 hours in vacuo (0.05 mm Hg). The polymer was then cooled, isolated, ground, and dried at room temperature.

Polymer Characterization: Ninh in CHCl3 = 0.88 DSC (20"C/min): Tm = 69"C TGA (20 C/min. under N2): Less than 0.5% weight loss at 2750C was recorded.

Polymer Melt Spinning: The polymer was spun in an Instron Rheometer using 30 mil die at 850C. The fibers were quenched in ice water and subsequently drawn 5X at room temperature.

Fiber Properties: Diameter = 14.7 mils, straight tensile strength = 1.36 x 104 psi, knot tensile strength = 1.41 x 104 psi, modulus = 4.8 x 104 psi, elongation = 90%.

In Vitro Evaluation: The drawn fibers exhibited a 93 percent decrease in their initial mass after immersion in phosphate buffer at 370C for 42 days.

EXAMPLE X 58/42 Poly (1, 4-phenylenedicarbinyl-co-hexamethylene Oxalate): Diethyl oxalate (14.6 g, 0.100 mols), recrystallized 1,4-benzenedimethanol (6.9 g, 0.050 mols, 1,6-hexane-diol (8.3 g, 0.070 mols), and Tyzor TOT (Tyzor TOT, a tetraalkyl titanate catalyst manufactured by E. I. DuPont de Nemours and Co., Wilmington, Delaware, 19898) catalyst (0.4 ml of a 1% solution) were added under dry and oxygen-free conditions to a glass reactor equipped for stirring. The prepolymer was formed by heating under nitrogen at one atmosphere at 140"C for 4 hours while allowing the formed ethanol to distill. The mixture was then heated in vacuo (0.1 mm Hg) at 1650C for 22 hours while continuing to remove distillates. A postpolymerization was conducted at 180, 190, and 200"C for 2, 1 and 4 hours respectively. The polymer was cooled, ground and dried.

Polymer Characterization: ninth in HFIP = 0.48 DSC (10 C/min): Tm = 1700C TGA (100C/min in N2): Less than 1% cumulative weight loss experienced at 2500C.

Polymer Melt Spinning: The polymer was spun at 166"C using an Instron Rheometer equipped with a 30 mil die.

In Vitro Evaluation: Immersion of a molded disc, 2.2 cm in diameter, for 8 and 78 days in phosphate buffer at 37"C resulted in a loss of 3 and 99 percent of the initial mass, respectively.

EXAMPLE XI 56/44 Poly (1,4-phenylenedicarbinyl-co-hexamethylene Oxalate): Dibutyl oxalate (20.2 g, 0.100 mols), 1,4-benzene-dimethanol (8.3 g, 0.060 mols), 1,6-hexane-diol (5.6 g, 0.047 mols), and tetraisopropylorthotitanate catalyst (0.3 ml, of a 0.01M solution) were added under dry and oxygen-free conditions to a glass reactor equipped for magnetic stirring. The prepolymer was formed by heating at 140 and 1600C for 1 and 17 hours respectively under nitrogen at one atmosphere while allowing the formed butanol to distill. The pressure was reduced (0.2 mm Hg) while continuing to heat at 1600C for an additional hour. The postpolymerization of the polymer melt was completed by heating at 1800C and 200"C for 2 and 3.5 hours, respectively, while continuing to remove distillates. The polymer was cooled, and isolated.

Polymer Characterization: Ninh in HFIP = 0.42 DSC (10 C/min): Tm = 165"C TGA (100C/min in N2): Less than 1% cumulative weight loss experienced at 2500C.

In Vitro Evaluation: Immersion of a molded disc, 2.2 cm in diameter, for 7 and 77 days, in phosphate buffer at 37"C resulted in a loss of 3 and 56 percent of the initial mass, respectively.

EXAMPLE XII 50/50 Poly (1,4-phenylenedicarbinyl-co-hexamethylene Oxalate): In a manner similar to that employed in Examples X and XI, the above identified copolymer having the following characteristics was produced: DSC (10 C/min): Tm = 175"C TGA (10 C/min, in N2): Less than 1% cumulative weight loss experienced at 2500C.

In Vitro Evaluation: Immersion of a molded disc, 2.2 cm in diameter, for 8 and 78 days in phosphate buffer at 37"C resulted in a loss of 6 and 54 percent of the initial mass, respectively.

Mixtures of the copolymers of polyoxalates described in the foregoing examples, and combinations of these polymers with up to about 50 percent by weight of poly (alkylene oxalates) and other compatible polymers which produce non-toxic and absorbable polymers, are included within the present invention.

It is to be understood that inert additives such as coloring materials and plasticizers can be incorporated in the sutures. As used herein, the term "inert" means materials that are chemically inert to the polymer and biologically inert to living tissue, i.e., do not cause any of the adverse effects previously discussed. Any of a variety of plasticizers such as, for instance, glyceryl triacetate, ethyl benzoate, diethyl phthalate, dibutyl phthalate and bis-2-methoxyethyl phthalate can be used if desired. The amount of plasticizer may vary from 1 to about 20 percent or more based on the weight of the polymer. Not only does the plasticizer render the filaments of the present invention even more pliable, it also serves as a processing aid in extrusion and thread preparation.

Filaments of the present invention are adversely affected by moisture and are accordingly preferably stored in hermetically sealed and substantially moisture-free packages, a preferred form of which is shown in Figure 2. In Figure 2, there is shown a suture package 14 having disposed therein a coil of suture 12, one end of which is attached to needle 13.

The needle and suture are positioned within a cavity 16 that is evacuated or filled with a dry atmosphere of air or nitrogen. The illustrated package is fabricated of two sheets of aluminum foil or an aluminum foil-plastic laminate and heat sealed or bonded with adhesive at the skirt 18 to hermetically seal the cavity and isolate the contents of the package from the external atmosphere.

Filaments of the present invention may be used as monofilament or multifilament sutures, or may be woven, braided, or knitted either alone or in combination with other absorbable fibers such as poly (alkylene oxalate), polyglycolide or poly (lactide-coglycolide), or with non-absorbable fibers such as nylon, polypropylene, polyethyleneterephthalate, or polytetrafluoroethylene to form multifilament sutures and tubular structures having use in the surgical repair of arteries, veins, ducts, esophagi and the like.

Multifilament yarns that contain isomorphic copolyoxalate filaments of the present invention together with nonabsorbable filaments are illustrated in Figure 4 wherein the nonabsorbable fiber is represented by the hatched fiber cross-section 19. In Figure 4, the fibers 20 are extruded from polymers of the present invention as described above. The relative proportions of absorbable filaments 20 and nonabsorbable filaments 19 may be varied to obtain the absorption characteristic desired in the woven fabric or tubular implants.

Composite fabrics of absorbable and nonabsorbable materials fashioned by textile processes including weaving, knitting and nonwoven felting are describd in U.S.P.

3,108,357 and U.S.P. 3,463,158. Methods of weaving and crimping tubular vascular prostheses are described in U.S.P. 3,096,560. Similar techniques may be used in the manufacture of surgical aids wherein nonabsorbable fibers are combined with absorbable fibers composed of the polymers of this invention. The surgical utility of "bi-component filaments" containing absorbable and nonabsorbable components is descrbed in U.S.P.

3,463,158 the teaching of which is incorporated herein by reference. Monofilaments of the polymers of the present invention may be woven or knitted to form an absorbable fabric having the structure illustrated in Figure 5, useful surgically in hernia repair and in supporting damaged liver, kidney and other internal organs.

The polymers of the present invention are also useful in the manufacture of cast films and other solid surgical aids such as scleral buckling prostheses. Thus, cylindrical pins, screws as illustrated in Figure 3, reinforcing plates, etc., may be machined from solid polymer having in vivo absorption characteristics depending upon the polymer composition and molecular weight.

WHAT WE CLAIM IS: 1. Isomorphic polyoxalate polymers comprising units of cyclic and linear oxalates and having the general formula -[-O-R-O-CO-CO-], wherein each R is (CW)n - A - (CH2)n - I or - (CH2) 4 +2n II and from 5 to 95 mol percent of the R units are I; A is trans 1,4-cyclohexylene or p-phenylene, n is 1 or 2 and is the same for I and II, and x is the degree of polymerization resulting in a fiber forming polymer having a molecular weight greater than 10,000.

2. The polymer of Claim 1 wherein n is 1 and A is trans 1,4-cyclohexylene.

3. The polymer of Claim 1 wherein n is 2 and A is trans 1,4-cyclohexylene.

4. The polymer of Claim 2 wherein units of formula I comprise from 40 to 75 mol percent of the R groups.

5. The polymer of Claim 1 wherein n is 1 and A is p-phenylene.

6. The polymer of Claim 1 wherein n is 2 and A is p-phenylene.

7. A synthetic absorbable suture comprising oriented fiber of an isomorphic polyoxalate polymer as claimed in Claim 1.

8. A suture of Claim 7 wherein said fiber is a monofilament.

9. A suture of Claim 7 wherein said fiber is a multifilament.

10. A suture of Claim 9 wherein said multifilament fiber is a braid.

11. A suture of Claim 7 wherein n is 1 and A is trans 1,4-cyclohexylene.

12. A suture of Claim 7 wherein n is 2 and A is trans 1,4-cyclohexylene.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (27)

1. **WARNING** start of CLMS field may overlap end of DESC **.

   14 having disposed therein a coil of suture 12, one end of which is attached to needle 13.

   The needle and suture are positioned within a cavity 16 that is evacuated or filled with a dry atmosphere of air or nitrogen. The illustrated package is fabricated of two sheets of aluminum foil or an aluminum foil-plastic laminate and heat sealed or bonded with adhesive at the skirt 18 to hermetically seal the cavity and isolate the contents of the package from the external atmosphere.

   Filaments of the present invention may be used as monofilament or multifilament sutures, or may be woven, braided, or knitted either alone or in combination with other absorbable fibers such as poly (alkylene oxalate), polyglycolide or poly (lactide-coglycolide), or with non-absorbable fibers such as nylon, polypropylene, polyethyleneterephthalate, or polytetrafluoroethylene to form multifilament sutures and tubular structures having use in the surgical repair of arteries, veins, ducts, esophagi and the like.

   Multifilament yarns that contain isomorphic copolyoxalate filaments of the present invention together with nonabsorbable filaments are illustrated in Figure 4 wherein the nonabsorbable fiber is represented by the hatched fiber cross-section 19. In Figure 4, the fibers 20 are extruded from polymers of the present invention as described above. The relative proportions of absorbable filaments 20 and nonabsorbable filaments 19 may be varied to obtain the absorption characteristic desired in the woven fabric or tubular implants.

   Composite fabrics of absorbable and nonabsorbable materials fashioned by textile processes including weaving, knitting and nonwoven felting are describd in U.S.P.

   3,108,357 and U.S.P. 3,463,158. Methods of weaving and crimping tubular vascular prostheses are described in U.S.P. 3,096,560. Similar techniques may be used in the manufacture of surgical aids wherein nonabsorbable fibers are combined with absorbable fibers composed of the polymers of this invention. The surgical utility of "bi-component filaments" containing absorbable and nonabsorbable components is descrbed in U.S.P.

   3,463,158 the teaching of which is incorporated herein by reference. Monofilaments of the polymers of the present invention may be woven or knitted to form an absorbable fabric having the structure illustrated in Figure 5, useful surgically in hernia repair and in supporting damaged liver, kidney and other internal organs.

   The polymers of the present invention are also useful in the manufacture of cast films and other solid surgical aids such as scleral buckling prostheses. Thus, cylindrical pins, screws as illustrated in Figure 3, reinforcing plates, etc., may be machined from solid polymer having in vivo absorption characteristics depending upon the polymer composition and molecular weight.

   WHAT WE CLAIM IS: 1. Isomorphic polyoxalate polymers comprising units of cyclic and linear oxalates and having the general formula -[-O-R-O-CO-CO-], wherein each R is (CW)n - A - (CH2)n - I or - (CH2) 4 +2n II and from 5 to 95 mol percent of the R units are I; A is trans 1,4-cyclohexylene or p-phenylene, n is 1 or 2 and is the same for I and II, and x is the degree of polymerization resulting in a fiber forming polymer having a molecular weight greater than 10,000.
2. 2. The polymer of Claim 1 wherein n is 1 and A is trans 1,4-cyclohexylene.
3. 3. The polymer of Claim 1 wherein n is 2 and A is trans 1,4-cyclohexylene.
4. 4. The polymer of Claim 2 wherein units of formula I comprise from 40 to 75 mol percent of the R groups.
5. 5. The polymer of Claim 1 wherein n is 1 and A is p-phenylene.
6. 6. The polymer of Claim 1 wherein n is 2 and A is p-phenylene.
7. 7. A synthetic absorbable suture comprising oriented fiber of an isomorphic polyoxalate polymer as claimed in Claim 1.
8. 8. A suture of Claim 7 wherein said fiber is a monofilament.
9. 9. A suture of Claim 7 wherein said fiber is a multifilament.
10. 10. A suture of Claim 9 wherein said multifilament fiber is a braid.
11. 11. A suture of Claim 7 wherein n is 1 and A is trans 1,4-cyclohexylene.
12. 12. A suture of Claim 7 wherein n is 2 and A is trans 1,4-cyclohexylene.
13. 13. A suture of Claim 11 wherein from about 40 to 75 mol percent of the R units are of

    formula I.
14. 14. A suture of Claim 7 wherein n is 1 and A is p-phenylene.
15. 15. A suture of Claim 7 wherein n is 2 and A is p-phenylene.
16. 16. A suture of Claim 7 having a surgical needle attached to at least one end thereof.
17. 17. A needle and suture combination of Claim 16 packaged in a sterile and dry environment within a hermetically sealed and substantially moisture impervious container.
18. 18. The method of closing a wound in living tissue of a non-human animal, which comprises using as an absorbable suture a sterile, oriented fiber of an isomorphic copolyoxalate polymer as claimed in Claim 1.
19. 19. The method of Claim 18 wherein said fiber is a monofilament.
20. 20. The method of Claim 18 wherein said fiber is a multifilament.
21. 21. The method of Claim 20 wherein said multifilament fiber is a braid.
22. 22. The method of Claim 18 wherein n is 1 and A is trans 1,4-cyclohexylene.
23. 23. The method of Claim 18 wherein n is 2 and A is trans 1,4-cyclohexylene.
24. 24. The method of Claim 22 wherein units of formula I comprise from 40 to 75 mol percent of the R groups.
25. 25. The method of Claim 18 wherein A is p-phenylene.
26. 26. A surgical prosthesis comprising a fabric manufactured at least in part from synthetic absorbable fibers of an isomorphic polyoxalate polymer as claimed in Claim 1.
27. 27. A surgical prosthesis comprising a solid surgical aid cast or machined from an absorbable isomorphic polyoxalate polymer as claimed in Claim 1.