DE2162900C2 - Sterile absorbable surgical sutures - Google Patents

Description

The invention relates to sterile surgical suture material in the form of a hidden, preferably colored one Yarn fleeces. its tensile strength 15 days after implantation in living animal tissue is still around 50 and 21 days after implantation it is still about 20% of its original value.

The most common resorbable surgical suture material consists of catgut monofilaments (from Collagen obtained from beef or sheep intestines). Collagen sutures are also made by extrusion from acid-swollen collagen goggles obtained from bovine snakes in a dehydration bath, whereby threads are formed which are then used for the purpose of further orientation of the collagen goggles stretched and combined into a strand. The manufacture of surgical sutures from regenerated collagen is described in US ^{Pat. Nos. I 3} S 31 14 372 and 31 14 593.

Resorbable suture material can also be produced from polyglycolic acid ester according to US Pat. No. 3,297,033 become such seam material! from the homopolymer of a Glykolsäurecstcrs has the disadvantage that it loses its tensile strength too quickly after being implanted in the animal body and in this regard less favorable fct than tanned catgut.

According to US Pat. No. 3,222,181, threads made from homopolymers of polyglycolic acid can be significantly improved in terms of their rate of absorption in vivo by placing them at about 50 to 190 ^{0 for periods of time which, inversely to the temperature in Bertich, vary from about 5 hours to 5 minutes} C treated. Table I of the cited patents ... ririft relates to braided sutures made from heat-bonded Monofilament is produced. According to Table I of the patent mentioned, this seam material! a tensile strength (straight) of 385 N / mm ² and a knot strength of 261 N / mm ² . Fifteen days after implantation in rabbits, the tensile strength of this suture is still 54 N / mm ² or 13.9% of the original tensile strength. Another disadvantage of the polyglycolide Nahlniateriais described in US-PS 32 97 033 is that duss the The color of the extruded threads varies from whitish to light brownish. So bright colors are for surgical Suture material undesirable because of the so-called "chameleon effect". When the suture is in a Surgical cavity is inserted, does it color it)? red quickly. and the surgeon can turn it into a bloody one Environment not easy to distinguish. Numerous processes are known for dyeing textile thread: According to the current regulations of the United States Food & Drug Administration, absorbable However, surgical sutures can only be colored with those dyes approved by this authority allowed are. The problem of staining polyglycolic acid sutures is exacerbated makes it difficult for this suture in the presence of moisture, especially at elevated temperatures, such as they are often used in the dyeing of textile fabrics, are easily hydrolyzed and therefore have tensile strength loses

In a publication by Lichtenstein, Jour. A. Med. Assoc, Vol. 24 (1970), p. 760, it is pointed out that surgical sutures have a high percentage in the latter stages of the healing process retains its original tensile strength. From FR-PS 14 78 694 and US-PS 35 31 561 is surgical Sutures made from copolymers with a predominant proportion of polylactide are known. Here comonomers. like glycolide. be included up to a proportion of 15%; See claim I of the FR-PS and column I, lines 40 ff, the US PS.

Finally, from GB-PS 9 88 939 a process for the polymerization of glycolide, optionally in Presence of a homologue of the general formula given on ropes 1, lines 12 to 16, is known. There Example is lactide. Preferably about 15% Laclid is added to influence the softening point: see page 1, lines 47 to 62.

bo core disclosed in GB-PS invention isi the teaching to avoid the long Polymerisationszciicn the polymerization in a screw extruder and in the presence of tin (II) -siearal rising as catalyst in a temperature range of 80 ⁰ C at the Bcschickungsscitc up to 190 up to 225 ° C depending on the proportion of homologues and then descending again towards the outlet end. A dye can also be added during the polymerization.

b5 According to Example 5, the polymerization in the extruder and then the F ^; Ormgcbung to foils or fillings can be carried out. The polymers obtained are insoluble and not swellable in water and customary solvents. The technical problem (ie the task) on which the present invention is based is to provide a

Resolvable suture material suitable for surgical purposes based on L (-) - lactide and glycolide provide that has the greatest possible original tensile strength and knot strength, its Tensile strength as much as possible even after application during wound healing for about 21 days is maintained and is rapidly absorbed after these 21 days.

The solution to this problem results from claim 1.

The suture of the invention consists of an annealed copolymer prepared as follows will: At least 85 mole percent, but not more than 90 mole percent, glycolide will be with not less than 10 mole percent, but not more than 15 mole percent, of L (-) - lactide in the presence of tin (II) caprylate as a catalyst implemented and then by extrusion, raking, heat treatment and sterilization to a suture material processed, which is characterized in that its tensile strength 15 or 21 days after to Maintains implantation to an improved extent. Furthermore, this suture material can be by adding 0.1 to 03% by weight of l-hydroxy-4-p-toluidino-anthraquinone in the monomer mixture before the polymerization color in the mass without sacrificing the high level of tensile strength retention.

This advantage of retaining a large part of the original tensile strength 15 to 21 days after the Implantation into living tissue appears to be the case for the above-described copolymers of L {-) - lactide and Glycolide when extruded, drawn, braided, heat treated by the methods described below and sterilized to be characteristic.

In contrast to copolymers with a predominant lactide content, the copolymer is not in benzene soluble. For this reason, hexafluoroisopropanol is used as the solvent to determine the viscosity

To further explain the invention, reference is made to the drawings.

Fig.! shows a device for extruding and stretching the copolymers of U, - V lactide and Glycolide.

2 shows in the form of a diagram the decrease in the tensile strength of braided suture material the copolymer of L (-) -lactide and glycolide after implantation in the animal body.

The curve of FIG. 3 shows the molecular weight distribution of a copolymer used according to the invention from L (-) - lactide and glycolide.

F i g. 4 is a thermogram of the shown by FIG. 3 explained copolymers of L (-) -lactide and glycolide.

F i g. 5 shows, in the form of a diagram, the decrease in the tensile strength of the suture material made from the copolymer from L (-) - lactide and glycolide according to FIGS. 3 and 4 after implantation in the animal ΚοφβΓ.

The copolymer of L (-) - lactide and described for the production of surgical suture material Glycolide is a copolymer that can be obtained by converting not less than 10, but not more than 15 Mole percent L (-) - lactide containing not less than 85 but not more than 90 mole percent glycolide

The L (-) - lactide and glycolide used for polymerization should be pure and dry. The implementation is carried out in a dry vessel under dry nitrogen. Used as a polymerization catalyst tin (II) caprylate. The molar ratio of monomers to catalyst is expediently in the range from about 50,000: 1 to 150,000: 1. A small amount can be used to control molecular weight Add glycolic acid. The ratio of monomers to glycolic acid is in the range from 400: 1 to 2000: 1.

To the polymerization to bring about, the mixture of L (-) lactide and glycolide heated for 5 hours at about 200 ⁰ C, until a sample of the polymer at a concentration O.iprozentiger in hexafluoroisopropanol at 25 ° C Inherent Viscosity certain of about 1, 4 has.

If the copolymer is to be used for the production of colored surgical sutures, 0.1 to 3 percent by weight of 1-hydroxy-4-p-toluidinoanihrachinone is added to the reaction flask before the polymerization to. This dye is evenly distributed in the monomer mixture and hardly has any adverse effect on the polymerization reaction. After the polymerization, the colored polymer can are extruded in the air into a thread-like yarn, which is stretched and bundled with heat before braiding can be. After braiding, the braided yarn is drawn and heat-treated again then sterilized

The apparatus used to extrude the copolymer is shown in FIG. 1 shown the extruder 10 has a supported in the vertical plane hopper 11, which at its lower end in a Cylinder 12 opens. Iti the cylinder 12 is a screw 14 which has a slightly smaller diameter than the cylinder 12, rotatably mounted and is driven via the shaft 18 by a variable speed motor 16.

The strangzupressende, finely divided Copolyrnerisa ¹ .20 is poured through the side arm 21 under dry nitrogen into the hopper, and moisture is kept away from the extruder through a continuous stream of dry nitrogen, which flows through the opening 22 into the hopper and through the opening 24 emanates.

The copolymer powder flows from the bottom of the hopper into the extrusion cylinder, where it is melted and is driven by the screw 14 through the bore 26 into the chamber of a gear pump 28. the The gear pump is set in rotation by a variable-speed motor (not shown) and guides the molten material Copolymer is fed through a bore 30 of the extrusion mold 32 at a metered rate. Immediately in front of the extrusion mold is a filter 34 of classified fine sand particles, which on a Sieve lying.

The extrusion mold has several openings. Preferably, each extrusion die has an angle of incidence of 20 ". At this entry angle a streamlined flow is obtained, which ensures uniformity of the extruded goods guaranteed.

When operating the extrusion press, the temperatures of the screw (zone i), the metering pump (zone 2) and the extrusion mold (zone 3) are constantly controlled by three electric heating devices that control the screw, surround the metering pump or the extrusion mold. In addition, the screw 14 and the metering pump 28 pressure exerted on the copoly rnerisaischiiiel / .c is constantly monitored.

When the copolymers are extruded, the dried copolymer powder is poured into the hopper 11 filled and flows under the action of gravity into the extrusion cylinder 12. The screw 14 promotes the polymer through zone I, where it is melted, and presses the polymerizate (melt at pressure, which can be 20.6 MPa, through the opening 26 in the gear pump 28, which the volume of the through the s extrusion mold 32 metered flowing Polymcrisalschmelze. When passing through the dosing pump (zone 2) and the extrusion mold (zone 3) the temperature of the copolymer melt is controlled.

During normal operation, the screw (zone 1) is set to around 244 ± 3 ° C, the metering pump (zone 2) between 202 and 220 ° C and the extrusion mold (zone 3) between 202 and 230 "C. The extruded filaments

33 are stretched about 200 times after leaving the extrusion mold and open in the air ίο room temperature cooled. The stretching takes place in the first 10 to 13 cm under the extrusion die.

The multi-filament yarn runs around the roll 35, over a roll 36 and is around the galcts 37 and 38 wrapped around to prevent slippage caused by variations in the drawing between the Extrusion die and idler roller 35 could be caused. The yarn coming from the godet 37 is then wound onto drum 40.

As mentioned above, the yarn 33 can be stretched and warmed both before and after braiding will. The braided suture can be sterilized without reducing its tensile strength.

by exposing it to the action of a humid atmosphere composed of a chlorofluorocarbon and ethylene oxide suspends.

The following examples, in which all amounts are by weight unless otherwise specified

refer, describe the production of braided copolymer seam malcrial. that 15 days after the Implantation in the animal body still has at least 50% and 21 days after implantation still at least 20% of its original tensile strength.

example 1

Production of a copolymer from 10 mol percent L (-) -lactide and 90 mole percent glycolide (copolymer A)

One with a paddle stirrer. Stirrer and gas outlet provided ReaktionsgcfäO 1 liter stainless steel is heated under vacuum at 110 ⁰ C, to free the internal surfaces of the vessel "of moisture.

Using dry glass equipment, a mixture of 80.6 g (0.56 mol: 12.2 percent by weight) of pure L (-) - lactide (F. 97-99 ° C: specific rotation value at least 282 °) and 580 g (5.0 mols: 87.8 wt .-%) of pure glycolide (F. 82,5-84.5 ⁰ C). This mixture of 10 mol percent L (-) - lactide and 90 mol percent glycolide is transferred to the reaction vessel under dry nitrogen. The reaction mixture is made using a dry glass syringe

034 ml of a catalyst solution of 0J3molaren 13.41 g of tin (II) caprylate in 100 ml toluene (1.1 χ 10- ⁴ mol) The molar ratio of monomer to catalyst is 50,000: first Then 0.5283 g (6.95 χ 10- ^J mol) of glycolic acid are added. The molar ratio of monomers to glycolic acid is 800: 1.

The reaction vessel is closed and the toluene is distilled off in a high vacuum (13-27 Pa). Then that will Vessel flushed with dry nitrogen by evacuating it twice in succession and filling it with nitrogen will. The vessel is then refilled with dry nitrogen until the pressure in the vessel is approximately 105 kPa

amounts to what one closes the exhaust valve. The vessel and its contents are placed in a silicone bath preheated to 200 ° C. and placed for one hour with stirring

and heated to this temperature for 20 minutes. Then the stirrer is raised above the liquid level and the contents of the vessel are heated to 200 ° C for a further four hours. The vessel is cooled and the Polymerisatmaxsc carried out. The polymer is cooled with solid carbon dioxide, cut into quarters with a hand saw, in a Cumberland mill with solid carbon dioxide and grind for 48 hours at 25 ° C and a pressure of 13 Pa dried. The yield of copolymer A is 617 g. This product has a Shore D hardness of 92-94, a softening temperature in the range of 193-196 ° C and a melting point (pour point) of 218-219 ° C, the inherent viscosity of the copolymer, determined on a 0.1 percent solution in K: xa-

Fluoroisopropanol at 25 ° C. is 155. The polymerization described in this example is repeated four times, in each case 1

Heated with stirring to 200 ° C. for an hour and held at the same temperature for a further 4 hours without stirring. The following results are obtained:

Copolymer B: 621 Yield, g 92-94 Shore D hardness 193-196 Softening point, "C 218-219 60 Melting point. "C 1.55 inherent viscosity Copolymer C: 618 Yield, g 92-94 65 Shore D hardness 194-197 Softening point. ⁰ C 219 Melting point, ⁰ C 134 inherent viscosity

21 62 900 61b Copolymerization D: 92-94 Yield, g 193-197 Shore D office 219-220 Softening Point. "C 1.49 Melting point, ° C inherent viscosity 620 (.! «Polymer K: 92-94 Yield, g 194-197 Shore D hardness 218-219 Softening point, '^ 1.49 Melting point, ° C inherent viscosity

The copolymers A to E are grain sizes in a Cumbcrland mill with solid carbon dioxide ground below 4.75 mm. The mixture is freed of metals with a mild magnet and thoroughly dried in a vacuum oven. The mixture weighs 2883 g and has the following physical characteristics:

, Softening Point, "C 190-195

Melting point. Χ 219 - 217 ° C

inherent viscosity 1.57

The melting index of a sample of the mixture is determined according to ASTM test standard D 1238-65T with an Extru-Monsplasiometcr. At 235 ° C the melt index is using a weight of 3800 g and an opening of 0.635 mm 0.7 (g / 10 min at 900 seconds).

Example 2 Extrusion of the copolymer from L (-) · lactide and glycolide

30th

The polymer mixture described in Example 1 is produced under dry nitrogen with the method shown in FIG. 1 shown extruded to a 8fädigcn yarn. A filter made of sand with grain sizes below 0.59 mm and over 0.297 mm is on a sieve with a mesh size of 0.25 mm between the metering pump and the extrusion mold 32. The extrusion mold has eight openings, each 0.635 mm in diameter.

The extruder screw generates a pressure of 103 MPa, and this is how the metering pump works. that the Pressure on the extrusion die remains in the range of 2 to 21 MPa. The extrusion speed is 30 g / h.

When pressing the siran, the feed section of the screw (zone 1) is set to 245 ° C. The metering pump (zone 2) opens 2O5 ° C and the extrusion mold (zone 3) kept at 210 "C. The thread yarn is on the bobbin 40 with a Wound at a speed of 213 m / min. 4t

The yarn thus obtained is stretched on a godet heated to 52 to 54 ° C on the 3- to J. 5-fold oriented. The take-up speed of the oriented yarn is 160 m / min. The tensile strength this oriented yarn is 031 N / tex. The oriented yarn is then heat treated by placing the bobbin with the yarn in a 113 "C oven for 20 minutes. After the heat treatment, the Yarn has a tensile strength of 0.5 to 0.52 N / tex.

Example 3 Braiding a yarn

so

The Bfädigc yarn described in Example 2 (total titer 5.55 ± 133 tex) is applied to the bobbins of a 16-spool braiding machine with a 3-core core. The braid is made with a braid density of 51 ± 3 per 25.4 mm. You get a surgical suture material! in the form of a yarn braid. The yarn braid (mean diameter 0368 mm) has a tensile strength of 54.25 N (510 N / mm ^J ) and a knot strength (mean diameter 0371 mm) of 34.72 N (322 N / mm ² ). The braid of yarn is drawn by winding it up on a tensioning device, which is then ^{stretched by 20 1} Vo, so that a braid is obtained which has been drawn to 1.2 times. The tensioning device with the stretched braid still in place is heat-treated ^{in an oven at 105 ° C. for 24 hours.}

Example 4 Sterilizing and packaging the surgical suture material

The yarn braid drawn and heat-treated according to Example 3 is used in Surgical sutures cut to appropriate lengths and placed in open, ventilated packages with ethylene oxide sterilized by standing on the braided suture material for 6 hours at a relative humidity of 70% and a temperature of 38 ° C, an atmosphere of a chlorofluorocarbon and ethylene oxide (500 mg Älhylenoxid per liter of gas) can act.

The packs of sterilized braided suture are sealed to keep the material sterile until used. The sterile packaged suture (0328 mm diameter) has a tensile strength (straight) of 50.72 N (600 N / mm ² ) and a dry knot strength (0.333 mm diameter) of 31.98 N (366 N / mm ² ).

The rate of absorption of this product (remaining percentage of the tensile wedge 5 days after implantation in rats) is determined on ten samples with five different test animals. Likewise will the percentage remaining tensile strength is determined at 10.15 and 21 days after implantation. The mean values from ten yarn breaks each, determined with the Instron tensile tester at a sliding block speed of 25.4 mm / min on 12.7 mm samples, are summarized in the table below and in FIG. 2 ίο shown.

Days after implantation

0 5 10 15 21

Tensile strength (straight). N 50.69 44.52 37.95 29.22 10.30 Remaining tensile strength,% 100 87.8 75 57.8 20.3 Example5

Production of a copolymer from L (-) -lactide and glycolide with a content of i-Hydroxy-4-p-toluidino-anthraquinone of 0.1 percent by weight (copolymer F)

A ausgestaltetes with paddle stirrer and gas outlet I-liter reaction vessel made of stainless steel is heated under vacuum at 110 ⁰ C, in order to free the inner surfaces of the vessel of moisture.

Using dry glass equipment, place in a glove box under dry nitrogen a mixture of 80.6 g (0.56 mol; 125 percent by weight) of pure L (-) - Laciid (temperature 97-99 ° C; specific rotation value at least 282 °) and 580 g (5.0 mols: 87.8 percent by weight) of pure glycolide (82.5 F. prepared to 84.5 ⁰ C). This mixture of 10 mol percent L (-) -lactide and 90 mol percent glycolide is transferred to the reaction vessel under dry nitrogen. 0.34 ml of a 0.33 molar catalyst solution of 13.41 g of tin (II) caprylate in 100 ml of toluene (1.11 χ 10 ⁴ mol) are added to the reaction mixture using a dry glass syringe. The molar ratio of monomers to catalyst is 50,000: 1. Then you put 03283 g (6.95XlO- ³ mol) glycolic acid and 0.6611 g (0.1 percent by weight) of l-hydroxy-4-p-toIuidino-anthraquinone. The molar ratio of monomers to glycolic acid is 800: 1.

The reaction vessel is closed and the Toiuo! in a high vacuum abdcsiiüicr '.. Then the vessel with purged with dry nitrogen by evacuating and filling with nitrogen twice in a row. That The vessel is then filled again with dry nitrogen until the pressure in the vessel is about 105 Pa whereupon the exhaust valve is closed.

Tube and contents are used in a pre-heated to 200 ⁰ C silicone bath and heated with stirring eL.e hour and 20 minutes at this temperature. The stirrer is then raised above the liquid level and the contents of the vessel are heated to 200 ° C. for a further 4 hours and 18 minutes. The vessel is cooled and the polymer mass is discharged. The polymer is cooled with solid carbon dioxide, with the hand saw in Quarter cut, ground in a Cumberland mill with solid carbon dioxide and 48 hours at 25 ° C and dried in vacuo at 13 Pa. The yield of copolymer is 620 g. The copolymer obtained in this way has a Shore D hardness of 92-94, a softening temperature in the range of 196-199 "C and a Melting point (pour point) of 217 ° C. The inherent viscosity of the copolymer. determined at 25 ° C on one 0.1 percent solution in hexafluoroisopropanol is 1.43.

so The polymerization described in this example is repeated four times, each time one The mixture is heated to 200 ° C. for an hour with stirring and to the same temperature for a further 4 hours without stirring gets the following results:

CopolymerisatG: 60 Copolymer H: 618 S3 yield, g Yield, g 92-94 Shore D hardness Shore D hardness 195-198 Softening point ° C Softening point. ° C 217-219 Melting point ⁰ C 65 Melting point'C 135 inherent viscosity inherent viscosity 615 92-94 195-193 217-21S 1.4t

21 62 900 621 Copy I: 92-94 Yield, g 195-198 Shore D hardness 215-2If Point of curvature, "C 1.37 Melting point, "C inherent visionosity 621 Copolymeris; it]: 92-94 Yield, g 195-198 Shore D hair 215-216 Softening Point, ° C 1.29 Melting point, "C inherent viscosity

The copolymers I · "to | are in a Cumbcrland mill with solid carbon dioxide to grain sizes of Grind less than 4.75 mm. The mixture is freed of metal with the magnet and thoroughly immersed Vacuum oven dried. The mixture weighs 2879 g and has the following physical characteristics:

- Softening! N ' ⁱ s ⁿ ' jnk ^1. , "C 190! 97

■ · Melting point. "C 217-218

'inherent: e Viseosilül 1.41

ii The Sehmel index of a sample of the mixture, determined according to Example!, is 1.2.

'4 B cis ρ ie I 6

% Extrusion of the copolymer mixture prepared according to Example 5
• i

y \ The copolymer mixture produced according to Example 5 becomes an 8-ply yarn according to Example 2 / u

JM extruded, jo

i | The extruder screw generates a pressure of 10.3 MPa, and the metering pump works so that the

The pressure on the extrusion mold remains in the range of 1 to 19 MPa and the extrusion speed is 30 g / h

ISt is.

Ι «During extrusion, the feed section of the screw (zone 1) is set to 245 ± 2 ° C. the dosing pump (zone 2)

ä on 202-2O7 ° C and the extrusion die (zone 3) is maintained at 203-211 ° C. The 8-ply yarn is placed on bobbin j5

■ y, 4D wound at a speed of 21.3 m / min.

The jam thus obtained is oriented 3.5 times by stretching on a godet heated to 52 ° C.

[| The take-up speed of the oriented yarn is 160 m / min. The oriented yarn then becomes

fg wärmcbchandclt. by placing the coil with the (Jarn in an oven at 113 "C for 20 minutes. After

[h of heat treatment, the yarn has a titer tex of 6.22 ± 0.44 and a tensile strength of 0.46 ± 0:07 N / tex.

^h Example 7

\ i Braiding of the yarn produced according to Example 6

45

The 8-ply yarn produced according to Example 6 (Gcsamitcr 6.22 ± 0.44 tex) is applied to the bobbins of a loosely-wound braiding machine with a 3-ply core. The braid is made with a braiding density of 51 ± 3 per 25.4 mm, and 320 m of surgical suture material is obtained in the form of a braided thread. The yarn braid (mean diameter 0.348 mm) has a tensile strength of 46.3 N (486.2 N / mm ² ) and a knot strength (mean diameter 0343 mm) of 30.7 N (332.4 N / mm ² ).

The braid is stretched by winding it onto a tensioning device, which is then stretched by 20%, so that a braid that is stretched 1.2 times is obtained. The jig with the stretched braid still in place is heat-treated in an oven at 105 ° C. for 24 hours. After the heat treatment, the braid (diameter 0.318 mm) has a tensile strength (straight) of 45.81 N (5793 N / mm - ') and a dry knot strength (diameter 0310 mm) of 27.66 N (366.2 N / mm ^:) .

Example 8
Sterilizing and packaging the surgical suture material obtained according to Example 7

b0

The yarn braid drawn and heat-treated according to Example 7 is used in Surgical sutures cut to appropriate lengths and placed in open, vented packages with ethylene oxide sterilized by standing on the braided suture material for 6 hours at a relative humidity of 70% and a temperature of 38 "C an atmosphere of a chlorofluorocarbon and ethylene oxide (500 mg of ethylene oxide per liter of gas).

The packs of the sterilized braided suture are sealed to keep the material up remains sterile for use. The sterile packaged suture has a tensile strength (straight) of 4434N and a dry knot resistance of 29.14 N.

44.52 39.13 3334 24.42 ') 13.29 100 88 75 55 29.7

The rate of absorption of this product (percentage of tensile strength remaining 5 days after implantation in rats) is determined on ten samples with five different test animals. Likewise will the percentage remaining tensile strength is determined at 10.15 and 21 days after implantation. The mean values from ten yarn breaks each, determined with the Instron tensile strength tester at a glass jaw speed of 25.4 mm / min on 12.7 mm samples. are summarized in the table below and shown in Fig.2 shown.

Days after implantation

0 5 to IS 21

Tensile strength (straight). N
Tensile Strength Remaining,%

*) Average value from nine yarn breaks.

Proken of the sterile braid are hydrolyzed in a solution of potassium hydroxide in methanol

The resulting glycolate and lactate are esterified with methanol and the methyl esters through at the same time Gas chromatography with a heat conductivity detector determines the mean glycolide content (six Samples) is 91.1 percent by weight with a normal deviation of 13- The mean lactide content of the Geficchiä (six samples) is 10.0 percent by weight ms! an NcrmaJ deviation of 033.

Example 9

Production of a copolymer from L (-) -lactide and glykoiid with a content of

1 -hydroxy ^ -p-toluidino-anthraquinone from 03 weight percent (Copolymcrisat K)

One with a paddle stirrer. 1 liter stainless steel reaction vessel equipped with a stirrer motor and gas outlet Steel is heated to 110 ° C under vacuum to remove moisture from the inner walls of the vessel.

jo Using dry glass equipment is under dry nitrogen in the glove box Mixture of 80.6 g (056 mol; 12.2 percent by weight) of pure L (-) - lactide (mp 97-99 ° C: specific rotation value at least 282 °) and 580 g (5.0 mol: 87.8 percent by weight) of pure Glykoiid produced This mixture from IO Mol percent L (-) - lactide and 90 mol percent glycoid are transferred into the reaction vessel under nitrogen The reaction mixture is filled with 034 ml of a 033 molar volume using a dry glass injection syringe

j5 catalyst solution of 13.41 g of tin (II) caprylate in 100 ml of toluene (LI IxIO ⁴ mol) was added. The molar ratio of monomers to catalyst is 50,000: 1. Then 05283 g (6.95 χ 10 'mol) of glycolic acid and 15834 g (03 percent by weight) of i-hydroxy ^ -p-toluidino-anthraquinone are added. The molar ratio of monomers to glycolic acid is 800: 1.

The reaction vessel is closed and the toluene is removed in a high vacuum. The vessel is purged with dry nitrogen by evacuating and filling it with dry nitrogen twice in succession. Then, the vessel is refilled with dry nitrogen until the pressure in the vessel from about 105 kPa, whereupon the exhaust valve closes the vessel with contents is placed in a preheated to 200 ⁰ C silicone bath and Gcfäßinhalt one hour under stirring at this temperature Then the stirrer is raised above the liquid level and the contents are ^{heated to 200 °} C. for a further 4 hours without stirring.

After the vessel has cooled, the copolymer is discharged. The copolymer is intense purple colored. The yield is 626 g. The copolymer is cooled with solid carbon dioxide and with the - Hand saw cut into quarters, which together with solid carbon dioxide in the Ciimbcrland-Mühlc on grain sizes below 4.75 mm, whereupon the product is freed from metal with the magnet ground copolymer is dried for 48 hours at 25 ° C. and 13 Pa. The resulting copolymer has

a Shore D hardness of 92-94. a softening point in the range of 190-195 ° C and a melting point of 219 ° C.

The inherent viscosity of this colored copolymer, determined at 25 ° C. on an 0.1% solution in hexafluoroisopropanol, is 1.41.
The melt index of the colored copolymer, determined according to Example 1, is 1.84.

Example 10
Extrusion of the copolymer prepared according to Example 9

The copolymer prepared according to Example 9 with the g i in F. 1 shown extruded to a 8fädigcn yarn. Between the metering pump 28 and the extrusion mold 32 rests on a sieve of 0.25 mm mesh size classified sand with grain sizes below 059 mm and above 0.297 mm. The extrusion mold has eight openings, each 0.635 mm in diameter.

The extruder screw generates a pressure of 10.3 MPn. and the metering pump works so that the b5 The pressure at the extrusion orifice is in the range of 5 to 20 MPa and the extrusion speed is 30 g / h amounts to.

When extruding, the temperature of the feed section of the screw (Zone I) is reverberated to 241-245 "C. that of the metering pump (zone 2) to 205 "C and that of the injection mold (zone 3) to 204-207" C. That

8-ply yarn is wound onto the bobbin 40 at a speed of 213 m / min

The yarn obtained in this way is oriented by 3.5 times it on a godet heated to 52 ° C stretching The winding speed of the oriented yarn is 160 m / min. The oriented yarn will then heat treated by placing the bobbin with the yarn in an oven at 113 ° C for 20 minutes. After the heat treatment, the tensile strength of the yarn (5.66 ± 0.11 tex) is 0.51 ± 0.06 N / tex.

Example 11 Braiding the yarn produced according to Example 10

The Bfädige yarn produced according to Example 10 (total denier 5.66 ± 0.1 tex) is applied to the bobbins of a loosely-wound braiding machine with a triple core. The braid is made with a braid density of 51 ± 3 per 25.4 mm. A surgical suture material is obtained in the form of a braided thread. The Gani braid (mean diameter 0.340 mm) has a tensile strength of 46.70 N (510.1 N / mm ² ) and a knot strength wedge (mean diameter 0335 mm) of 29.92 N (338.6 N / mm ² ). The braided yarn is stretched by winding it on a tensioning device which is then stretched 20% so that a braid is obtained which has been stretched fifteen times. The jig with the braid still in place is then heat-treated in an ^{oven at 105 ° C. for 24 hours.} After heat bonding, the braid (mean diameter 0.282 mm) has a tensile strength (straight) of 45.42 N (7265 N / mm ² ) and a dry knot strength of 28.45 N (4393 N / mm ² ).

Example 12 Sterilize and package the suture material produced according to Example 11

The drawn and heat-treated yarn braid according to Example 11 is cut into lengths suitable for use as surgical suture material and sterilized in open, ventilated packs with ethylene oxide by being exposed to an atmosphere for 6 hours at 70% relative humidity and 38 ° C Chlorofluorocarbon and ethylene oxide (500 mg ethylene oxide per liter of gas) is exposed.

The packs of the sterilized braid are closed so that the material remains sterile until it is used. The sterile packaged suture has a tensile strength wedge (straight) of 49.54N and a Dry knot strength of 27.25 N.

The rate of absorption of this product (percentage of tensile strength remaining 5 days after implantation in rats) is determined on ten samples with five different test animals. Likewise will the percentage remaining tensile strength wedge was determined at 10.15 and 21 days after implantation. The mean values js from ten yarn breaks each, determined with the Inslron tensile testing device at a glass jaw speed wedge of 25.4 mm / min on 12.7 mm samples, are summarized in the table below and in FIG. 2 shown.

40

Days after implantation

0 5 10 15 21

Tensile strength (straight). N 49.52 40.50 35.89 ") 25.69 14.51 Remaining tensile strength. % 100 81.6 72.4 51.8 29.2

*) Average of nine breaches.

Example 13 (comparative experiment)

Absorption speed of a sterile braided suture from the Glycolic acid homopolymer

Individually packaged polyglycolic sealant is used. The suture, approximately 152 cm long and 0.328 mm in diameter, has a tensile strength (straight) of 43.06 N (511.7 N / mm ² ) and a dry knot strength (diameter 0.328 mm) of 30.90 N (364.2 N / mm ² ).

The rate of absorption of this product (percentage of tensile strength remaining 5 days after Implanting in rails) is determined by implanting eight samples in eight different test animals will. Likewise, the percentage of remaining tensile strength wedge will be 10, 15 and 21 days after implantation certainly. The mean values from eight yarn breaks, determined with the Instron tensile tester at one mi Sliding jaw speeds of 25.4 mm / min on 12.7 mm samples are summarized in the table below and shown in FIG. 2 shown.

Days after implantation

0 5 10 15 21

, Tensile strength (straight), N 4638 4235 29.42 17.65 3.23

Remaining tensile strength. % 100 923 63.2 373 6.88

As FIG. 2 shows, the braided suture material described in Examples 1 to 12 consists of a Copolymer of 10 mol percent L (-) - lactide and 90 mol percent glycolide from the braided suture material Polyglycolic acid for the percentage of remaining 15 and 21 days after implantation Far superior to the original tensile strength.

Example 14

j. Production of a copolymer from L (-) - lactide and glycolide with a content of

1,4-bis- (p-toluidino) -anthraquinone of 0.1 percent by weight (copolymer L)

Following the procedure of Example 5, a green-colored copolymer is prepared by adding 0.1 percent by weight of 1,4-bis (p- ^ ₀ toluidinoj-cmhrachinon to the reaction mixture of 10 mol percent L (-) - lactide and 90 mol percent glycolide Copoylmcrisai has an inherent viscosity of 1.41 and a melt index (determined according to Example 1) of 03.

The green-colored polymer can be extruded, drawn, braided, heat-treated, sterilized and packaged as surgical sutures.

Likewise, for coloring the surgical suture material according to the invention, any non-toxic _2S dye can be used which retains its color and color strength under the conditions of the polymerization and does not impair the polymerization reaction.

Many of the dyes listed in the regulations of the Federal Food, Drug, and Cosmetic AcU of 1938 as being used for food, drugs and cosmetics cannot be used because they impair copolymerization by using copolymers of L (-) - lactide and glycolide of low Molekularge-J ₀ weight receives a low inherent viscosity and have a low Zugcfestigkeit. Other non-toxic dyes themselves suffer under the conditions of the polymerization and then do not exhibit the desired bright color.

Example 5 Production of a copolymer from L (-) - lactide and glycolide (copolymer M)

A 1 liter stainless steel reaction vessel equipped with a paddle stirrer, stirrer motor and gas outlet Steel is heated to 110 ° C in a vacuum to remove moisture from the inner walls.

A mixture of 80.6 g (0.56 Mole; 12.2 percent by weight) of pure L (-) - lactide (m.p. 97-99 ° C; specific rotation value max. 282 ") and 580 g (5.0 moles: 87.8 percent by weight) of pure glycolide (m.p. 82.5-84.25 "C). This mixture of 10 Mol percent L (-) - lactide and 90 mol percent glycolide are poured into the reaction vessel under dry nitrogen The reaction mixture is transferred using a dry glass syringe with 034 ml of a

_4S 033 molar catalyst solution of 13.41 g of tin (II) caprylal in 100 ml of toluene (1.11 10 * mol) was added. The molar ratio of monomers to catalyst is 50,000: 1. Then 03283 g (635 χ 10 'mol) of glycolic acid are added. The molar ratio of monomers to glycolic acid is 800: 1.

The reaction vessel is closed and the toluene is distilled off in a high vacuum. The vessel is with purged dry nitrogen by evacuating it twice in succession and filling it with dry nitrogen

J becomes _0. The vessel is then refilled with dry nitrogen until the pressure in the vessel is 105 kPa, whereupon the outlet valve is closed.

Now the vessel and its contents are placed in a silicone bath heated to 200 "C" and the contents of the vessel Heated to this temperature for 1 hour while stirring. Then the stirrer is above the liquid level and heating to 200 ° C continued for a further 4 hours. The vessel is cooled and the polymer

_{; 5} mass discharged. The polymer is cooled with solid carbon dioxide, cut into quarters with a hand saw, ground with solid carbon dioxide in a Cumberland mill and dried at 25 ° C. and 13 Pa for 72 hours. The yield of Copolymerisal M is 545.9 g or 82.9%. The product has a melting point (pour point) of 234 ° C. The inherent viscosity of the copolymer. determined at 25 ° C. on a 0.1 percent solution in hexafluoroisopropanol, is 1.54.

j. The melt index of a sample of the product, determined according to Example 1, is 036 (g / 10 min at 900 seconds).

Example 16 Extrusion of the copolymer prepared according to Example 15

The copolymer M prepared according to Example 15 is extruded under dry nitrogen with the aid of a screw extruder to give an 8-filament yarn. Between the metering pump and the extrusion mold rests on a sieve with 0.177 mm mesh size a filter made of classified sand with grain sizes of less than

62 900

0.42 mm and more than 0.25 mm. Pie extrusion mold has eight openings, each 0.635 mm in diameter.

The screw of the ^ extruder produces a Pnick of 13.7 MPa, and the _s metering pump operates, the pressure dag in the extrusion die in l ^ rich is of "L030 to 687 kPa. During extrusion of / is iufühfungsabschnitt of the screw of the extruder to 245 ° C, the metering pump 210 ^b 'C and the S'trangpreßforrp to 215 ° C. Das8fädige yarn with a Gesphwindigkeit vpn 213 m / min wound. "'

The yarn obtained in this way is oriented by drawing it 4.5 times on a godet heated to 57 "C. The oriented yarn is then heat-treated by heating the bobbin with the yarn in an oven maintained ^{at 105 ° C. for 45 minutes} is. the tensile strength after heat treatment (6:08 tex) is 0, ^ 22 N / TCX.

10 Example 17

Braiding the yarn produced according to Example 16

The 8-ply yarn (6.08} ex) produced according to Example 16 is applied to the bobbins of a loosely-wound braiding machine with a 3-fold core ± 3 each 25.4 mm are produced, and one obtains a surgical hiajitmateriaj in Fprni'eines p'ari} fencing of size 2 / Q (average size 0 345 mm) with a tensile strength of 61.4 {(S (655.1 j N / mrn, ² ) jincj a knot strength of 37.87 N (403.5 N / mm ² ). The yarn braid is sealed hot by winding it on a tensioning device which is heated by '°% in an oven slightly above room temperature. is expanded so that one is 11 times

) p

an oven slightly above room temperature is expanded by '°%, so that a temperature of 1.1 times 20 l

Versirecktes braid gets the jig with the stretched braid in place and Sttyie is then 24 |

Heat-treated for hours at 105 ° C in an oven in an inert atmosphere ■ Example 18 Sterilize and pack the braid produced according to Example 7

The yarn braid stretched and heat-treated according to Example 17 is cut into lengths suitable for use as surgical suture material and sterilized in open, ventilated packs with ethylene oxide by exposing it to the action of an atmosphere at 25 ° C and 100% relative humidity for 3 hours. which contains 1000 mg of ethylene oxide per liter. The sterilization process is repeated by exposing the product to the action of the gas atmosphere for a further 3 hours at 25 ° C under the same conditions. The packs are then degassed for 16 hours at 40 ^° C. under vacuum (66 pa) and then closed. The sterile packaged suture material (diameter 0335 mm) has a knot strength of 36.00 N (407.6 N / mm ² ), according to the method described in "United States Pharmacopoeia" Volume XVJl, page 921. The tensile strength wedge (straight) of the sterile suturing material (diameter 0335 mm) is 57.00 N (645.5 N / mm ² ).

The rate of absorption of this product (percentage of remaining tensile strength 7, 14, 21 and 28, respectively) Days after implantation in rats) is determined by implanting ten samples in five different test animals. The mean values from ten yarn breaks, determined with the Instron tensile strength test device at a speed of 25.4 mm / min on 12.7 mm specimens, are listed below and in F i g. 5 shown

Days after the implant tone
0 7 47.56
8432 14th 21 28 55.60
100 36.77
65.09 23.63
41.88 9.61
17.06

Tensile Strength (Straight), N. Tensile Strength Remaining,%

A representative sample of the braided suture material is examined by classification chromatography to provide information on the molecular weight and the molecular weight distribution of the copolymer Fig. 3 is a graphic representation of the values thus obtained for the curve length distribution. Man notes that the ratio of the weight average molecular weight to the number average molecular weight is 72,000: 33,000 or about 2.1: 1.

A representative sample of the sterile braided suture material of this example is examined with the differential scanning calorimeter. The thermograms are shown in FIG. 4 shown From the curve A it can be seen that the freezing temperature of the wärmebchandtcn. braided suture material (No. 10) is 55 ⁰ C. The melting point indicated by 12 is 205 ^° C. After melting, the suture material is cooled, whereupon a second thermogram (curve B) is made. The freezing temperature (# 14) of this chilled material is 43 ° C. The crystallization temperature (No. 16) asks 112 ° C and the melting point (No. 18) 205 ° C. bo

Example 19 Production of a copolymer from L (-) -Laclid and glycolide (copolymer N)

A equipped with paddle stirrer, stirrer and CiasauslaS 1-l.iter-Reaktionsgcfäß stainless steel is heated under vacuum at 110 ⁰ C, to remove the moisture from the inner walls to.

A mixture of 126.7 g (0.88

Mole; 17.93 percent by weight) of pure L (-) - lactide and 580g (5.0 mol: 82.07 percent by weight) of pure glycolide (m.p. 82.5-84.5 ° C). This mixture of 15 mol percent M -) lactide and 85 mol percent glycolide is transferred to the reaction vessel under dry nitrogen. Using a dry glass injection needle, 0.36 ml of a 0.33 molar catalyst solution of 13.41 g of tin (II) caprylic in 100 ml of toluene (1.18 χ 10 ⁴ mol) is added to the reaction mixture. The molar ratio of monomers to catalyst is 50,000: 1. Then 0.5586 g (735 χ 10- 'mol) of glycolic acid are added. The molar ratio of monomers to glycolic acid is 800: 1.

The reaction vessel is closed and the toluene is distilled off in a high vacuum. Then the jar with purged dry nitrogen by evacuating it twice in succession and filling it with dry nitrogen

ίο will. The vessel is then filled again with dry nitrogen until the pressure in GcfäQ is 105 kPa, whereupon the exhaust valve is closed.

The vessel with contents is placed in a preheated to 200 "C silicone bath and the contents heated 55 minutes under stirring at 193 to 200 ⁰ C. Then the stirrer is raised above the liquid level of the reaction mixture and the mixture further 4 hours and 5 minutes at 200 "C heated. The reaction vessel turns off removed from the silicone bath and left to cool overnight. The response container with its contents is then displayed solid carbon dioxide and the polymer is discharged from the reaction vessel, with the hand saw in Quarter cut, ground together with solid carbon dioxide in a Ciimbcrland mill and at 25 "C and dried at 13 Pa in a vacuum. The yield is 512.4 g. This product has a Shore D Haric of 90 — Si and a melting point (pour point). 225 "C. The inherent viscosity of the (Onolymerisais. Determined

> o at 25 ° C in an oxygen percent solution in 1 xafluoroisopropanol. is 1.51.

The melting index of a sample of the polymer N dried in vacuo is determined by the method of Example 1 at 235 "C with a weight of 3800 g and an opening of 0.635 mm, is 033 (g / 10 min at 900 see).

Example 20 Extrusion of the copolymer prepared according to Example 19 The copolymer N prepared according to Example 19 is mixed under dry nitrogen with that in Example 1

The screw extruder shown is extruded into a I2fädigcn yarn. Between the dosing pump and

the extrusion mold 32 rests on a sieve with a mesh size of 0.149 mm, a filter made of classified

Sand with grain sizes between 0.177 and 0.149 mm. The extrusion mold has twelve openings of 0508 mm each Diameter.

The extruder screw exerts a pressure of 10J MPa. and the metering pump works so that the Pressure on the extrusion die is in the range of 5.2 to 13.7 MPa.

During extrusion, the feed section of the extruder screw (zone I) is kept at 245 ° C, the metering pump (zone 2) at 220 "C and the extrudate (zone 3) at 230" C. The 12fädigc yarn is on the Coil 40 wound up.

The yarn obtained in this way is oriented by pre-stretching it to 43-fold on a godet heated to 54 "C will. The tensile strength of this oriented yarn 4.44 ± 035 tcx is 0352 N / icx.

Example 21

Braiding the yarn produced according to Example 20 ■ t5

The 2-ply yarn (total liters 4.44 ± 035 tex) is put on the bobbins of a 16-spool braiding machine triple core applied. The braid is made with a braid density of 49 ± 3 per 25.4 mm, and a surgical suture material is obtained in the form of a yarn sheet.

The yarn braid (mean diameter 0.330 mm) has a tensile strength of 38.75 N (1483 N / mm ³ ) and a knot strength of 2334 N (275.7 N / mm ² ). The yarn surface is stretched. by being wound around a jig, which is then stretched by 15%, so that a tangled on the l, 15fachc braid receives the clamping device having thereon the above-stretched braid is then for 24 hours in the oven at 105 ⁰ C wärmebehandelL

Example 22 Sterilize and package the suture material produced according to Example 21

The yarn sheet stretched and heat-wrapped according to Example 21 is used in surgical suture material bO cut to suitable lengths and sterilized in open, ventilated packs with ethylene oxide by 6 Hours at 25 ° C and a relative humidity of 70% of the action of an atmosphere of a chlorofluorocarbon and ethylene oxide (500 mg ethylene oxide per liter of gas) is exposed. The packs are 1 Degassed under vacuum (66 Pa) at 40 ° C and then sealed to seal the surgical sutures up to the hour Use to keep sterile.

t> 5 The sterile packaged suture material (mean diameter 0.29 mm) has a tensile strength (straight) of 45.62 N (6943 N / mm ² ) and a dry knot strength of 28.45 N (431.64 N / mm ² ) .

The rate of absorption of this product (the one remaining 7 days after implantation in rats percentage of the tensile strength) is determined by implanting 12 samples in twelve different test animals

re determined. In the same way, the percentage remaining tensile strength will be 14, 21 and 28 days after the Implantation determined. The mean values from wolf yarn breaks, determined with the Instron strength meter at a sliding jaw speed of 24.4 mm / min on 12.7 mm tubes. result from the following Tabel.

Eradicate me from the Imphinuilion

0 7 14 21 28

Tensile strength (straight), N 42.95 37.66 25.40 16.57 6.28 to

Remaining tensile strength,% KX) 79.5 59.1 38 ,! 14.6

Samples of the sterile braid are hydrolyzed in a solution of potassium hydroxide in methanol The glycolate and acetate formed in the process are esterified with methanol and the methylsieres through at the same time Gas chromatography determined with a thermal conductivity monitor. 13 mean glycolide content of six r> Sample is 86.8 percent by weight with a normal deviation of 1.4. The mean lactide content of the six analyzed samples of the braid is 14.7 percent by weight with a normal deviation of 0.2.

I iici All ') Släii ZciCnriüiigCil

Claims (2)

Patent claims: 1. Sterile absorbable surgical suture material in the form of a stretched, preferably colored Yarn braid, which consists of a tempered copolymer of L (-) -lactide and glycolide characterized in that the proportion of L (-) - lactide units is 10 to 15 percent by weight, that the copolymer has an inherent viscosity of at least 1.4 determined in a 0.1 percent solution in Hcxafluorisopropanol at 25 ° C before extrusion and that the surgical suture material after sterilization has a knot strength of at least 345 N / mm ² and a tensile strength (just ^ of at least 552 N / mm ² , which 15 days after implantation in animal tissue is still 50 percent to and 21 days after implantation is still at least 20 percent of its original value. 2. Surgical suture material according to claim 1, characterized in that the copolymer in its Mass with 0.1 to 1) 3 percent by weight of i-hydroxy-4-p-ioIuidino-anihraquinone or with 0.1 percent by weight 1,4-Bis (p-toluidino) anthraquinone is colored