NO146385B - STERILE SURGICAL SUTURES, AND PROCEDURE FOR THE PREPARATION OF SUCH SUTURES - Google Patents

Abstract

Sterile surgical sutures, and methods of making such sutures.

Description

The invention relates to sterile surgical suture, as well as

a method for producing such a suture from synthetic polyester. More specifically, the suture consists of a synthetic

tically absorbable copolymer lactide polyester produced by a polymerization where one comonomer is first polymerized and another comonomer is then added.

The use of lactide polyesters in the production of synthetic surgical articles is known in the field. In connection with this, comonomers have often been used to modify

list the characteristics of the different polyesters. The conventional polymerization method for producing the polyesters is by ring-opening polymerization of the relevant cyclic

ke lactides. When producing copolymers, one lactide is usually copolymerized with another. Other cyclic materials have also possibly found use as comonomers. These include other lactones, such compounds as trimethylene carbonate and the like.

Applicable polymerization and finishing methods

there as well as fabrication methods for the surgical articles are also well known in the art. The surgical articles manufactured include both absorbable and non-absorbable articles.

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

It has now been shown that surgical articles of synthetic

technical polyester can advantageously be produced by a polymerization process whereby copolymer lactide polyesters are formed by a ring-opening polymerization whereby the polymerization occurs

runs sequentially or in portions. This is achieved by adding

te the comonomers one after the other or alternately. By directing the polymerization process in a stepwise manner, the in vivo characteristics of the surgical articles can be more broadly modified before the appearance of the usual degree of interference by the ability of the polymer to form dimensionally stable, highly crystalline electrodes.

ler highly-oriented molecular structures.

The method according to the invention can be used

des in two or more steps using two or more comonomers in the polymerization process. In one or more of

steps, two monomers can be used simultaneously. A different catalyst can be used in each step if desired.

It is generally preferred to carry out the successive polymerizations in the same reaction vessel by separately and successively or alternately adding the comonomers thereto. However, if desired, one or more of the repeating polymer segments (ie the reaction product of the separate or alternative monomers) can be prepared and used as such for further chemical reaction to form the polyesters in another reaction vessel of choice, while still preserving the advantages of and staying within the scope of the present invention.

The two lactides which are conventionally preferred for use in the manufacture of surgical articles are L(-)lactide and -glycolide. They are also preferred for use in connection with the present invention. moreover, it is generally preferred here to use them together in a sequential polymerization process.

Other cyclic comonomers which are conventionally used in this connection, e.g. trimethylene carbonate, 2-keto-1,4-dioxane and

one or more of the following compounds can also be used as one of the comonomers for copolymerization with a lactide in carrying out the present invention:/J-propiolactone, tetramethylglycolide, jS-butyrolactone, jf-butyrolactone, <*j-valerolactone, £-caprolactone , pivalolactone and intermolecular cyclic esters of α-hydroxy-butyric acid, α-hydroxyisobutyric acid, α-hydroxyvaleric acid, α-hydroxyisovaleric acid, α-hydroxycaproic acid, α-hydroxy-α-ethylbutyric acid, o-hydroxyisocaproic acid, α-hydroxy-/3- methylvaleric acid, α-hydroxyheptanoic acid, α-hydroxyoctanoic acid, α-hydroxydecanoic acid, α-hydroxymyristic acid, α-hydroxystearic acid, α-hydroxylignoceric acid, α,α-diethylpropiolactone, ethylene carbonate, 2,5-diketo-morpholine, ethylene oxalate, 6,8- dioxabicyclo[3,2,1]-octan-7-one, di-salicylide, trioxane, 3-methyl-1,4-dioxane-2,5-dione, 3,5-dimethyl-1,4-dioxane-2 -on.

One of the preferred areas for application of the present invention concerns the production of sterile, synthetic, absorbable, surgical sutures whereby glycol is used as the predominant lactide comonomer in the production of the polyesters. The current state of the art is such that detailed absorption mechanisms and details of the polymeric structures at the molecular levels are not known with certainty.

One of the preferred embodiments of the invention relates to sequentially copolymerizing lactide [preferably L(-)lactide] with glycolide. The triblock structure formed by sequentially and successively copolymerizing [L(-)lactide], glycolide and L(-)lactide is also of interest. In the latter case, the polyester produced has lactic acid units which are predominant at both ends of the glycolide polymer chain.

It is believed that the three common morphological units, namely spheres, rods (or cylinders) and lamellae, which are well known in AB and ABA type poly(styrene-b-butadiene) (PSB) would be shown in the polyesters of the present invention. In ABA-type PSB films where the molar ratio between styrene units and butadiene units is 80/20, spherical domains have been observed by means of electron micrography. As the molar ratio decreases with relatively larger amounts of butadiene units, the morphology of the microphase separation changes from spheres of butadiene units in a matrix of styrene units to rods of butadiene units in a matrix of styrene units and then to alternating lamellae of the units. If the molar ratio decreases further until the butadiene predominates, the styrene units first present as cylindrical or rod-like microphase separations in a matrix of butadiene units, after which, as the molar ratio decreases further, the styrene units present as spheres in a matrix of butadiene units. For a description of this see M. MatisuOk, S. Sagae and H. Asai, Polymer, 10, p.

79, 1969.

When producing the absorbable sutures in accordance with the present invention, polyester can be used

re where small amounts of a monomer part of an inert homopolymer, e.g. an L(-)lactide moiety is incorporated at one or both ends of a chain of glycolide units. The stable part(s) can be used in relatively small amounts, whereby it is assumed that the morphology

one for the microphase separation e.g. would exist as rods of L(-)lactide units in a matrix of glycolide units or, more preferably, spherical domains of L(-)lactide units in a matrix of glycolide units.

The surgical sutures are produced from the polyesters using the methods conventionally used for the polyesters described in the above-mentioned literature. Likewise, the resulting surgical sutures are used in a conventional manner. The following examples illustrate methods that are useful in connection with the implementation of the present invention. Unless otherwise stated, all parts and percentages are by weight.

Production of poly(trimethylene carbonate).

An ether solution of SnC^^I^O together was prepared

with an ether solution of lauryl alcohol containing 10 mg/ml lauryl alcohol. Sufficient volume of the above-mentioned solutions was added to a polymerization tube so that the final weights of catalyst and lauryl alcohol, after removal of the solvent, were 4.0 mg of SnCl2-2H20 and 250 mg of lauryl alcohol per 20.0 g of trimethylene carbonate.

After the solvent was removed, 20.0 g of trimethylene carbonate was added to the tube. The tube was evacuated and sealed under vacuum. It was then placed in an oil bath at 180°C for 24 hours. It was removed from the oil bath and allowed to cool to room temperature. The tube was opened, the polymer was crushed in a Wiley mill through a 20 mesh screen and dried for 24 hours at 50°C at 0.1 mm Hg. The resulting polymer was formed at 48% conversion and had an I.V. value of 0.34. Percent conversion to polymer was obtained by dividing the weight of polymer after drying by the weight of polymer before drying. I.V. means the intrinsic viscosity of a solution of 0.5 g dried polymer/100 ml hexafluoroacetone sesquihydrate, measured at 30°C.

Example 1

Into a 100 mL three-necked round-bottom flask equipped with an eri glass shaft and a "Teflon" paddle stirrer connected to a stirring motor and a gas inlet tube connected to an argon cylinder was charged 7.0 g of poly(trimethylene carbonate), prepared as indicated above. The flask was purged with argon for 15 minutes. The argon purge was maintained during the following polymerization. The flask was placed in an oil bath of 190°C. The pot contents reached 180 + 2°C within 15 minutes. Then 3.5 g of glycolide was added with stirring, and the oil bath temperature was adjusted so that the temperature of the pot contents was maintained at 180 +_ 2°C for 30 minutes with continuous stirring. The temperature of the oil bath was then

raised so that the temperature of the pot contents after 30 minutes had elapsed was 220 _+ 2°C. Then became

31.5 g of glycolide added while stirring, and the temperature at

the pot contents were kept at 220 + 2°C for 1 1/2 hours with continuous stirring. At this point the oil bath was removed, the tube was stopped and the pot contents were allowed to cool to approximately room temperature under argon purging. This flushing was then stopped. The glass flask was broken, and the polymer was removed and crushed in a Wiley mill through a 20 mesh sieve. 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 1000 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 0.1 mm Hg. The polymer yield was 86%. In I.V. in HFAS was 0.64. The mole percent units derived from trimethylene carbonate in the polymer chain, determined by NMR, was 16.4. This figure corresponds to 14.7% by weight trimethylene carbonate units. The melting point, determined from the peak endotherm in a D.T.A. apparatus, was 218°C.

Accordingly, preferred surgical articles manufactured in accordance with the present invention are sterile synthetic absorbable surgical sutures manufactured from a lactide polyester, this polyester being composed of a copolymer

which have cylindrical or, more preferably, spherical domains of L (-)lactide units in a matrix of glycolide units. The polyesters used may have the relative amounts of glycolide units and L(-)lactide units indicated above. The sutures may be in the form of a sterile surgical needle and suture combination. Conventional suture constructions and sterilization methods can be used. Preferably, a monofilament or polyfilament braided polyester yarn is crimped into the thick end of a surgical needle and the needle attached suture is then sterilized using an antioxidant, e.g. ethylene oxide. Polyesters formed by sequential and consecutive polymerization of L(-)lactide and glycolide are most preferred for use in this connection.

Although the surgical articles according to the present invention are generally applicable in a conventional manner to preserve living tissue in the desired location and condition during a healing process by placing living tissue in this connection, such as in ligation of blood vessels, they are needle-fastened sutures specially adapted for closing wounds in living tissue by suturing the edges of the wound using conventional suturing techniques.

Example 2

30 g of trimethylene carbonate, 3.3 mg of SnCl 2 -2H 2 O and 0.133 g of lauryl alcohol are added to a stirred reactor which is preheated to 153°C under a stream of nitrogen. The temperature is increased over 30 minutes to 180°C. After stirring for a further 30 minutes at the aforementioned temperature, a sample of 2.5 g is taken out, and 17 g of glycolide is added. The temperature is then increased over 30 minutes to 223°C. After stirring for 45 minutes at this temperature, 15 3 g of glycolide are added. Stirring is continued for 1 hour at this temperature. The polymer is then drained, cooled and finely ground to pass through a 10 mesh screen, and dried for 48 hours at 140°C (0.25 mm Hg).

The sample of 2.5 g of poly(trimethylene carbonate) taken at 180°C is dissolved in methylene chloride. The solution is added dropwise to methanol, and the precipitated polymer is collected and dried for 24 hours at 40°C (0.25 mm Hg). The resulting homopolymer had an intrinsic viscosity of 1.32 (30°C, 0.5% solution) in HFAS (hexafluoroacetone sesquihydrate).

The intrinsic viscosity of the final copolymer was 0.81. The concentration of trimethylene carbonate units in the copolymer, determined by NMR analysis, is 17 mol% or 15% by weight. Using a differential scanning calorimeter, the glass transition temperature is 32°C, and the melting endotherm peak is 216°C.

Example 3

The copolymer from Example 2 is extruded at a temperature of 230°C at a rate of 0.227 kg/h, through a 30 ml capillary with a length:diameter ratio of 4:1. The extrudate was run through a quench bath of ambient temperature water and collected on a spool at a speed of 61 m/min.

The resulting extrudate was then drawn through an air chamber at a temperature of 40°C at 3.05 m/min. and a draw ratio of 5.2X, to form a monofilament falling below the USP 6/0 size range.

The physical properties of the drawn fiber were:

Example 4

Samples of the monofilament from Example 3 were implanted subcutaneously in rats. After 21 days, the samples are removed and their direct tensile strength is measured on an Instron Universal Testing Instrument, model 1125 (from the company Instron Corp., USA). The samples retained 45% (on average) of their original tensile strength.

Example 5_

20 g of trimethylene carbonate, 4 mg of SnCl2.2H20 and 0.199 g of lauryl alcohol are added to a stirred reactor that is preheated to 140°C. The mixture is stirred for 2 hours at this temperature under a nitrogen atmosphere. 50 mm Hg vacuum is applied and maintained for 30 minutes. The vacuum is lifted with nitrogen, and 180 g of glycolide, pre-heated at 140°C, is added under a stream of nitrogen. The reactor is heated to 220°C within 30 minutes. The temperature is kept at 220-222°C for 45 minutes. The polymer is drained, cooled, cut into small pieces and dried for 24 hours at 130°C (1 mm Hg).

The intrinsic viscosity of the polymer is 0.86 (30°C, 0.5% solution in HFAS). The concentration of trimethylene carbonate units in the copolymer is 9 mol%, determined by NMR, or 8% by weight. Using a differential scanning calorimeter, the glass transition temperature is 37°C. The melting range is 196-225°C. The peak of the melting endotherm is at 221°C, and /\Hf (the heat of fusion) is 17.6 cal/g. 130 g of polymer is further treated for 3 days at 180°C and 0.2 mm Hg under a nitrogen flow of 56.64 dm 3 /h. The final product weighed 120 g, had

they had an intrinsic viscosity of 0.96 and contained 8.3 mol% (7.4 wt%) trimethylene carbonate units.

Example 6

The copolymer from Example 5 was extruded at a temperature of 230°C through a 1.5 mm capillary with a length:diameter ratio of 4:1. The extrudate was run through a quench bath of ambient temperature water and collected at 15.25 m/min. It was then drawn through an air chamber with temperature

50°C 8X. The physical properties of the drawn fiber were

as follows:

Claims (2)

1. Sterile surgical suture, characterized in that it consists of a synthetic absorbable copolymer lactide polyester produced by a polymerization where one comonomer is first polymerized and another comonomer is then added. 2. Method for producing a sterile surgical suture as stated in claim 1, characterized in that a synthetic absorbable copolymer lactide polyester is used which is produced by adding the comonomers, respectively trimethylene carbonate and glycolide, separately during the polymerization.