FI65443C - FOERFARANDE FOER FRAMSTAELLNING AV EN STERIL KIRURGISK SUTUR - Google Patents

Description

65443

The following patents are of interest in this regard: U.S. Patent Nos. 3,268,486 and 3,268,487.

It has now been found that synthetic polyester surgical instruments can be advantageously prepared by a polymerization process in which copolymeric lactide polyesters are formed in ring-opening polymerization, the polymerization being carried out in successive reactions by sequential addition of the comonomers used to form the copolymer chain. By performing the polymerization procedure gradually, the in vivo properties of the surgical instruments produced can be more widely modified before the polymer becomes stable in molecular structure, highly crystalline, or strongly oriented, so that its shape can no longer be influenced.

The process of the invention may be carried out in two or more steps using two or more comonomers in the polymer. In one or more steps, two monomers can be used simultaneously. A different catalyst can be used at each stage if desired.

In general, it is preferred to carry out successive polymerizations in the same reaction vessel by adding the comonomers sequentially; however, if desired, one or more polymer blocks may be prepared separately and used as such for further chemical reaction to form polyesters in a different reaction vessel.

According to the invention, a sterile surgical suture is prepared from a synthetic, absorbable lactide polyester copolymer prepared by first forming a polyester comonomer, preferably trimethylene carbonate, and separately polymerizing the glycolide with the resulting product.

The exact absorption mechanism of sterile lactide-polyester copolymer absorbable surgical instruments (especially sutures) is not known, nor is their structure at the molecular level known with certainty.

One of the preferred embodiments of the present invention relates to the intermittent copolymerization of lactide (preferably L - (-) lactide) with a glycolide. The three-group structures formed periodically and sequentially by copolymerizing L (-) lactide 3 65443, respectively, are also of interest. In the latter case, the polyester formed has lactic acid units predominant at each end of the glycolide polymer chain.

In the preparation of absorbable sutures in accordance with the practice of the above invention, polyesters may be used in which smaller amounts of an inert homopolymer monomer block such as an L (-) lactide block are located at one or both ends of the Glycolide unit chain. The stable block or blocks can be used in relatively small amounts, in which case it is believed that the morphology of the micphase separation would occur, for example, as L - (-) lactide unit rods in the glycolide unit matrix or more preferably as spherical L (-) lactide unit regions in the glycolide unit matrix.

Surgical instruments are made from polyesters using methods commonly used in working with the polyesters set forth in the above reference. The surgical instruments obtained are also used in a conventional manner.

The following examples illustrate the methods of the invention. Unless otherwise specified, all parts and percentages are by weight.

Examples 1-2

An ethereal solution of SnCl 2 was prepared together with an ether solution of lauryl alcohol containing 10 mg / ml of lauryl alcohol. A sufficient volume of the above solutions was added to the two polymerization tubes so that when the solvent was removed, the final weights of catalyst and lauryl alcohol were 20.0 g per L (-) lactide monomer:

Table I

Pipe No. mg SnCl 2 H 2 O mg / lauryl alcohol 1 2.0 125 2 4.0 250

After removal of the solvent, 20.0 g of L (-) lactide was added to each tube. The tubes were deaerated and sealed in vacuo. They were then placed in an oil bath at 180 ° C for 24 hours. They were removed from the oil bath and allowed to cool to room temperature. The tubes were opened, the polymer was ground in a Wiley mill through a 20 mesh screen and dried for 24 hours at 50 ° C in 13.3 Pars. The 65443 polymers obtained from tubes 1 and 2 were formed with 86% and 89% conversion and had a V Inh of 0.33 and 0.27, respectively. Percent conversion to polymer was obtained by dividing the weight of dried polymer by the weight of polymer before drying. Inh means the logarithmic viscosity number of a solution containing 0.5 g of dried polymer / 100 ml of hexafluoroacetone sesquihydrate measured at 30 ° C.

To a three-necked 100 mL round bottom flask equipped with a glass shaft and a Teflon ** (DuPont Company, Wilmington, Delaware, USA) paddle stirrer attached to a stirrer motor and a gas inlet tube connected to an argon tank was added 7.0 g of the poly (L) described above. (-) lactide. Argon gas was bubbled into the flask for 15 minutes. The gas flow was maintained throughout the polymerization. The flask was placed in a 190 ° C oil bath. The contents of the flask reached a temperature of 180 ° to 2 ° C within 15 minutes. 3.5 glycolide was then added with stirring and the temperature of the oil bath was adjusted to maintain the temperature of the contents of the flask at 180 ° to 2 ° C for 30 minutes with constant stirring. The temperature of the oil bath was then raised so that within 30 minutes the temperature of the contents of the flask reached 220 ° C to 2 ° C. The remainder of the Gly-colide, 31.5 g, was then added and the temperature of the contents of the flask was maintained at 220 ° to 2 ° C for 1 1/2 hours with constant stirring. The oil bath was removed, stirring was stopped and the contents of the flask were allowed to cool to approximately room temperature under an argon atmosphere. The introduction of this gas into the flask was then stopped. The glass flask was then broken and the polymer removed and ground in a Wiley mill through a 20 mesh screen. 3.0 g of powdered polymer was prepared for embedding into fibreboards by first dissolving the polymer in 60 ml of 60 ° C hexafluoroacetone sesquihydrate (HFAS). The polymer was precipitated by pouring this solution dropwise into 60 ml of methanol with stirring. The polymer was collected by filtration and extracted with acetone in a Soxhlet extractor for 2 days to remove residual fluorinated solvent. The polymer was then dried in a vacuum oven overnight at 50 ° C at 13.3 Pa. The polymer yield was 95%. ^ ^ n ^ in HFAS was 0.77. The molar percentage of lactic acid units in the polymer chain as determined by NMR was 8.8. The melting point determined from the endothermic peak detected by the differential thermal analysis (DTA) was 218 ° C.

5 65443

A second two-stage copolymer was prepared as follows: To a three-necked 100 ml round bottom flask equipped with a S) glass shaft and a Teflon w paddle stirrer attached to an argon tank was added 4.0 g of poly-L - (-) lactide having an in ^ of 0.27 with stirring. Argon gas was bubbled into this for 15 minutes. This argon gas flow was maintained throughout the next polymerization. The flask was placed in a 190 ° C oil bath. The contents of the flask reached a temperature of 180 ° to 2 ° C in 15 minutes. 3.6 g of glycolide were then added with stirring and the temperature of the oil bath was adjusted to maintain the temperature of the contents of the flask at 180 ° to 2 ° C for 30 minutes with constant stirring. The temperature of the oil bath was then raised so that at the end of 30 minutes the contents of the flask reached 220-2 ° C. 31.4 g of glycolide were then added and the temperature of the contents of the flask was maintained at 220 ° to 2 ° C for 1 1/2 hours with constant stirring. The oil bath was then removed, stirring was stopped and the contents of the flask were allowed to cool to approximately room temperature under a stream of argon gas. The power was then stopped. The glass flask was broken and the polymer was removed and ground in a Wiley mill through a 20 mesh screen. 3.0 g of this polymer was dissolved in 60 ml of hexafluoroacetone sesquihydrate (HFAS) at 60 ° C, and the polymer was precipitated by dropwise addition of this solution to 600 ml of methanol. The polymer was collected by filtration and extracted with acetone in a Soxhlet extractor for 2 days. The polymer was then dried in a vacuum oven overnight at 50 ° C at 13.3 Pa. The polymer yield was 95%. ^ 7 in HFAS was 0.82. The molar percentage of lactic acid units in the polymer as determined by NMR was 5.9. The melting point determined was 5.9. The melting point determined by the DTA endorermic peak was 219 ° C.

Example 3

A sample of poly-L (-) lactide was prepared by the procedure of Examples 1-2 except that a 98% conversion was obtained at 0.5 using 1.2 mg SnCl 2 .28 2 O and 7.5 mg lauryl alcohol. To a three-necked 100 mL round bottom flask equipped with a glass shaft and a Teflon® molass stirrer attached to a stirrer motor and a gas inlet tube connected to an argon tank was added 10.0 g of poly-L (-) lactide. This was purged with argon for 15 minutes. This argon flow was maintained throughout the next polymerization. The flask was placed in a 190 ° C oil bath. The contents of the flask reached a temperature of 180 ° to 2 ° C in 15 minutes. Then 2 g of glycolide was added with stirring and the oil bath temperature was adjusted with 2 g of glycolide with stirring and the oil bath temperature was adjusted to keep the contents of the flask at 180 ° to 2 ° C with continuous stirring for 30 minutes, then the oil bath temperature was raised to 30 minutes. 220 ° - 2 ° C. Then 18.0 g of glycolide was added and the temperature of the contents of the flask was maintained at 220 ° to 2 ° C for 1 1/2 hours with constant stirring. The oil bath was then removed, stirring was stopped and the contents of the flask were allowed to cool to approximately room temperature, passing argon into the flask. The introduction of this gas into the flask was then stopped. The glass flask was broken and the polymer was ground in a Wiley mill through a 20 mesh screen.

20.0 g of this polymer was dissolved in 400 ml of 60 ° C hexafluoroacetone sesquihydrate (HFAS), and the polymer was precipitated by dropping this solution into 4,000 ml of methanol with stirring. The polymer was collected by filtration and extracted with acetone in a Soxhlet extractor for 2 days. The polymer was then dried in a vacuum oven overnight at 50 ° C at 13.3 Pa. The polymer yield was 72%. ^ In HFAS was 0.60. The NMR of the molar polymer of lactic acid units as determined by NMR was 33. The melting point as determined from the endothermic peak determined by differential thermal analysis (DTA) was 219 ° C.

Example 4

To a three-necked 100 mL round bottom flask equipped with a glass shaft and a Teflon® molass stirrer attached to a stirrer motor and a gas inlet tube connected to an argon tank was added 6.0 '0.29 poly-L (-) lactide prepared as in Example 3, except that 1.5 one hour at 200 ° C. Argon was bubbled into the flask for 15 minutes. This argon flow was maintained throughout the subsequent polymerization. The flask was placed in a 200 ° C oil bath and the bath temperature was raised until the temperature of the contents of the flask reached 200 ° -2 ° C. This happened within 15 minutes. 48.0 g of glycolide were then added with stirring and the temperature of the oil bath was raised until the temperature of the contents of the flask was 225 ° to 2 ° C. This happened within 30 minutes. Stirring was continued for 1 1/2 hours at this temperature. 6.0 g of L (-) lactide were then added (stirring the contents of the flask) and stirring was continued for 1 1/2 hours at this temperature. The oil bath was then removed, stirring was stopped and the contents of the flask were allowed to cool to room temperature under argon. This power was then stopped. The glass flask was broken and the polymer was removed and ground in a Wiley mill through a 20 mesh screen. 5.0 g of this polymer was dissolved in 100 ml of hexafluoroacetone sesquihydrate (HFAS), and the polymer was precipitated by dropwise addition of this solution to 1,000 ml of methanol with stirring. The polymer was collected by filtration and extracted with acetone in a Soxhlet extractor for 2 days. The polymer was dried in a vacuum oven overnight at 50 ° C in 13.3 parts. The polymer yield was 82%. ^ ^ ^ In HFAS was 0.81. The molar percentage of lactic acid units in the polymer chain as determined by NMR was 11.2. The melting point as determined by differential thermal analysis (DTA) from the endothermic peak was 216 ° C.

Example 5

To a three-necked 100 mL round bottom flask equipped with a glass shaft and a Teflon® paddle stirrer attached to a stirrer motor and a gas inlet tube connected to an argon tank was added 4.5 g of poly (epsilon-caprolactone) with a ηη of 0.42. The poly (epsilon-caprolactone) polymer was prepared as in Example 1 except that 8.0 mg of SnCl 2 H 2 O and 500 mg of lauryl alcohol were used and epsilon-caprolactone was used instead of L (-) lactide. Argon was bubbled into the flask for 15 minutes. The argon flow was maintained throughout the next polymerization. The flask was placed in a 190 ° C oil bath. The contents of the flask reached 180 ° to 2 ° C within 15 minutes. 1.35 g of glycolide were then added with stirring and the temperature of the oil bath was adjusted to maintain the temperature of the contents of the flask at 180 ° to 2 ° C with constant stirring for 30 minutes, then the temperature of the oil bath was raised to 220 ° to 2 ° C at the end of 30 minutes. . 12.15 g of glycolide were then added with stirring and the temperature of the contents of the flask was maintained at 220 ° to 2 ° C for one hour with constant stirring. The oil bath was removed, stirring was stopped and the contents of the flask were allowed to cool to approximately room temperature under a stream of argon. This power was then stopped. The glass flask was broken and the polymer was removed and ground in a Wiley-8 65443 mill through a 20 mesh screen. 4.0 g of this polymer was dissolved in 80 ml of 60 ° C HFAS and the polymer was precipitated by dropping this solution into 1,000 ml of methanol with stirring. The polymer was collected by filtration and extracted with acetone in a Soxhlet extractor for 2 days. The polymer was then dried overnight in a vacuum oven at 50 ° C at 13.3 Pa. The polymer yield was 73%. ^ ^ In HFAS was 12.3. The molar percentage of Epsilon hydroxycarboxylic acid units in the polymer chain as determined by NMR was 12.3. This corresponds to 12.1 weight percent caprolactone units. The melting point as determined by a differential thermal analysis (DTA) device from the endothermic peak was 218 ° C.

Example 6

To a three-necked 100 mL round bottom flask equipped with a glass shaft and a Teflon ® molass stirrer attached to a stirrer motor and a gas inlet tube connected to an argon tank was added 7.0 g of poly (trimethylene carbonate) with an **) Inh of 0.34. Poly (trimethylene carbonate) was prepared by the method of Example 1 except that trimethylene carbonate was used instead of L (-) lactide and 4.0 mg SnCl 2 .H 2 O was used with 250 mg lauryl alcohol. The conversion was 48%. Argon was bubbled into the flask for 15 minutes. The argon flow was maintained throughout the next polymerization. The flask was placed in a 190 ° C oil bath. The contents of the flask reached 180 ° to 2 ° C within 15 minutes. 3.5 g of glycolide were then added with stirring and the temperature of the oil bath was adjusted to maintain the temperature of the contents of the flask at 180 ° to 2 ° C for 30 minutes with constant stirring. The temperature of the oil bath was then raised so that at the end of 30 minutes the temperature of the contents of the flask was 220 ° to 2 ° C. 31.5 g of glycol were then added with stirring and the temperature of the contents of the flask was maintained at 220 ° -2 ° C for 1 1/2 hours with constant stirring. The oil powder was then removed, stirring was stopped and the contents of the flask were allowed to cool to approximately room temperature under a stream of argon. This power was then stopped. The glass flask was broken and the polymer was removed and ground in a Wiley mill through a 20 mesh screen.

5.0 g of this polymer was dissolved in 100 ml of 60 ° C HFAS and the polymer was precipitated by dropping this solution into 1,000 ml of methanol with stirring. The polymer was collected by filtration and extracted with acetone in a Soxhlet extractor for 2 days. The polymer was dried overnight in a vacuum oven at 50 ° C at 13.3 Pa. The polymer yield was 86%. The inh in HFAS was 0.64. The molar percentage of trimethylene carbonate derivative units in the polymer chain as determined by NMR was 16.4. This figure corresponds to 14.7 weight percent trimethylene carbonate units. The melting point as determined by differential thermal analysis (DTA) from the endothermic peak was 218 ° C.

Example 7 L (-) lactide (1612 g) SnCl 2 .2H 2 O (0.204 g) and lauryl alcohol (4.77 g) were added to a pre-heated reactor preheated to 140 ° C. The reactants were heated with stirring under nitrogen for 30 minutes to 200 ° C and then maintained at this temperature for 2 hours.

The reactor was degassed to 6.665 Pa and the mixture was stirred for 30 minutes, during which time the temperature of the mixture was allowed to drop to 180 ° C.

Normal atmospheric pressure was restored by introducing nitrogen into the reaction vessel and the temperature was raised to 200 ° C for 5 minutes. Molten glycolide (5198 g) preheated to 100 ° C was added and the temperature was raised to 225 ° C for 15 minutes and maintained at this temperature for a further 20 minutes.

The contents of the reactor were emptied and the polymer mass was broken after cooling to room temperature. The polymer was then ground and vacuum dried at 1066-1333 Pa for 11 hours at 140 ° C to remove any volatiles before spinning and determining the viscosity of the polymer.

The logarithmic viscosity number of the polymer was determined to be 1.14 measured at 30 ° C in 0.5% hexafluoroacetone sesquihydrate solution. The molar% of lactic acid units in the final polymer was determined to be 20.3% by NMR. The melting range of the product was defined as 215-223.5 ° C using a hot plate polarizing microscope.

A portion of the dried polymer was added to a small continuous press feeder at about 230 ° C. The press was equipped with a 1.5 mm cylindrical nozzle in length with a diameter of four to one. The compressed pulp was immersed in water and 65,4443 was recovered in 13.4 m per minute. It was then pulled about 4.5 times its original length at 55 ° C in a hot air extractor. A sample of the glycolide homopolymer, ^ ^ ^ 1 * 05, was compressed and drawn in the same manner and then post-treated together with the copolymer fiber prepared above, for 3 hours at 135 ° C at a pressure of 133.3 Pa.

The 0.061 mm diameter copolymer fiber was found to have very good tensile strength retention properties (238.6 MPa) in the exceptionally accelerated strength retention test and initial strength (665.6 MPa) despite its high comonomer content (20.3 mol%). In contrast, a homopolymer fiber having a diameter of 0.053 mm had an initial strength of 965.5 MPa and a corresponding strength obtained in an accelerated test of 174.5 MPa.

As mentioned above, such copolymeric polyesters are believed to be characterized by microphase separations, which are spherical regions in the molten state, prior to orientation, with the chain blocks of lactic acid units partially overlapping in the matrix of glycolic acid units. It is believed that polysers with such microphase separation would exist when the molar percentage placed on the polymer chain of L (-) lactide was at most 25%. Between about 25 percent to about 40 percent to about 40 percent of lactic acid units, it is believed that cylindrical areas of lactic acid units would predominate. This would likewise be the case where lactic acid units predominate at both ends of the polyester chain as a result of periodic and sequential polymerization of L (-) lactide, glycolide and then L (-) lactide.

Although the geometry of the regions in the molten state is theoretical, evidence of the existence of phase separation or precipitation of polymers can be seen by comparing their melting points with the melting point of the main component homopolymer.

Accordingly, preferred surgical devices made in accordance with the present invention are sterile synthetic absorbable surgical sutures made from a lactide polyester, said polyester being formed from a copolymer having cylindrical or, more preferably, spherical L (-) lactide unit regions in a glycolide unit matrix. The polyesters used 11 65443 may have the relative amounts of glycolide units and L (-) lactide units shown above. The sutures may be in the form of a combination of a sterile surgical needle and a suture. Conventional suture construction and sterilization methods can be used. Preferably, the single-stranded or multi-strand braided polyester yarn is crimped at the end of the surgical needle and the sutured suture is sterilized, then using a toxidant such as ethylene oxide. Polyesters formed periodically and sequentially with polymers of L (-) lactide and glycolide are then most preferred in use.

Although the surgical instruments of the present invention are generally useful in conventional ways to hold living tissue in the desired location and connection during the healing process by positioning and securing living tissue, such as ligating blood vessels, needle sutures are particularly suitable for closing living tissue wounds by knitting .

Example 8 To a stirred reactor preheated to 153 ° C was added 30 g of trimethylene carbonate, 3.3 mg of SnCl 2 .2H 2 O and 0.133 lauryl alcohol in a stream of nitrogen. The temperature was then raised to 180 ° C over 30 minutes. Stirring was continued at this temperature for another 30 minutes, then a 2.5 g sample was taken and 17 g of glycolide was added to the mixture. The temperature was raised to 223 ° C for 30 minutes. After stirring for 45 minutes at this temperature, 153 g of glycolide was added and stirring was partitioned for 1 hour at this temperature, then the polymer was removed from the reaction vessel, cooled, ground through a 10 mesh screen and dried for 48 hours at 140 ° C / 0.25 mmHg. A 2.5 g sample of polytrimethylene carbonate taken at 180 ° C was dissolved in methylene chloride. The solution was added dropwise to methanol, the precipitated polymer was collected and dried for 24 hours at 40 ° C / 0.25 mmHg. The resulting homopolymer had an inherent viscosity of 1.32 (30 ° C, 0.5% solution in HFAS). The inherent viscosity of the final copolymer was 0.81. NMR analysis showed that the final product contained 17 mole% or 15% by weight of trimethylene carbonate units. The glass transition point measured by DSC calorimeter at 10 ° C / min was 32 ° C, and the melting endotherm peak was at 216 ° C.

12 65443

Example 9 To a stirred reactor preheated to 140 ° C was added 20 g of trimethylene carbonate, 4 mg of SnCl 2. 2 Η 2 <0 and 199 g of lauryl alcohol, and the mixture was stirred for 2 hours at this temperature under a nitrogen atmosphere. The reaction mixture was then evacuated to 50 mmHg and held for 39 minutes. Nitrogen was then bubbled into the reactor until normal pressure was reached, glycolide (180 g) preheated to 140 ° C under a stream of nitrogen was added, and the reactor was heated to 220 ° C over 30 minutes. It was heated at 220-222 ° C for 45 minutes, then the polymer was removed from the reactor, cooled and cut into small pieces which were dried for 24 hours at 130 ° C / 1 mmHg. The inherent viscosity of the polymer was 0.86 (30 ° C, 0.5% solution in HFAS). The copolymer contained trimethylene carbonate units of 9 mol% or 8% by weight as determined by NMR analysis. The glass transition point measured by DSC calorimeter at 10 ° C / min was 37 ° C and the melting range was 196-225 ° C. The melting endotherm peak was at 221 ° C and the melting point was 17.6 cal / g. 130 g of polymer were further treated for 3 days at 180 ° C / 0.2 mmHg in a nitrogen flow of 0.056 m 2 / h. The final product weighed 120 g, had an inherent viscosity of 0.96 and contained 8.3 mol% (7.4% by weight) trimethylene carbonate units.

The copolymer prepared in Example 8 was extruded at 230 ° C at 226 g / h through a 0.75 mm capillary with a diameter to length ratio of 1: 4. The compact was passed through a water bath at room temperature and recovered at a speed of 61 m / min. It was then drawn through a 40 ° C hot air chamber at 30.5 / min and stretched 5.2 times. The copolymer of Example 9 was similarly extruded through a 1.5 mm capillary, recovered at 15.2 m / min through a 50 ° C hot air chamber stretched 8 times.

2 The tensile strength of the samples in direct drawing was 68.0 N / cm and 2 49.3 N / cm. Elongation at break was 35 and 31%. The knot pull strengths 2 2 were 54.2 N / cm and 37.5 N / cm. Module 1290000 (average).

Samples of 0.096 mm and 0.164 mm in diameter from the extruded product of Example 8 were attached subcutaneously to rats. 21 years