JPH09132638A - Polymer capable of being absorbed by living tissue and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a polymer being capable of being absorbed by living tissues and having excellent mechanical strengths, flexibility and suitable hydrolyzability and to provide a medical molding, especially a monofilament suture, formed therefrom. SOLUTION: A ternary block polymer obtained by polymerizing 20-1,200 pts.wt. ε-caprolactone through ring opening in the presence of 100 pts.wt. hydroxyl-terminated polylactic acid having a weight-average molecular weight of 2,000-500,000, adding 15-1,200 pts.wt. glycollide during or after the ring opening polymerization of ε-caprolactone and polymerizing the glycollide through ring opening, comprising polylactic acid segments, poly(ε-caprolactone) segments and polyglycolic acid segments and having a weight-average molecular weight of 10,000-1,000,000, a process for producing the same and a medical molding formed from the same are provided.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a bioabsorbable polymer, a method for producing the same, and a medical molded article obtained from the bioabsorbable polymer. Specifically, a bioabsorbable polymer having excellent mechanical strength and flexibility such as linear tensile strength and ligation tensile strength and having appropriate hydrolyzability, a method for producing the same, and the bioabsorbable polymer. It relates to a molded article for medical use obtained from coalescence.

[0002]

2. Description of the Related Art Polylactic acid, polyglycolic acid and lactic acid-
Polyester represented by glycolic acid copolymer,
Lactic acid and glycolic acid, which are non-enzymatically hydrolyzed in the living body and are the degradation products thereof, are finally converted into carbon dioxide gas and water by the metabolic pathway and released to the outside of the body. Similarly, polymers such as trimethylene carbonate, p-dioxanone, and lactones such as ε-caprolactone or copolymers thereof are similarly decomposed in the living body and finally become carbon dioxide gas and water and released outside the body. It is known that it will end up.

As a method for producing the above bioabsorbable polymer, glycolide, which is an anhydrous cyclic dimer of glycolic acid, and lactide, which is an anhydrous cyclic dimer of lactic acid, and trimethylene, are used in the presence of a catalyst such as tin octoate. A method of ring-opening polymerization of carbonate, p-dioxanone, ε-caprolactone and the like, or a mixture thereof is known. And, among these bioabsorbable polymers, for example, polyglycolic acid,
Polylactic acid, glycolic acid-lactic acid copolymer, etc.
It is used as a material for aseptic surgical products such as gauze.

However, since polyglycolic acid, polylactic acid, glycolic acid-lactic acid copolymer and the like have high rigidity, when they are used as sutures in the form of monofilaments, they are ligated when sutured to the operated affected area. Is difficult to tie. Therefore, it is usually used as a so-called multifilament by forming many thin monofilaments to have flexibility and braiding them. However, the surface of the multifilament suture is rough, and there is a problem that the surrounding living tissue is damaged when suturing, and a coating agent or the like is applied to make the filament slippery during ligation. Need to
There is also a problem that the manufacturing process becomes complicated and economically disadvantageous.

In view of the above situation, the flexibility of a bioabsorbable polymer typified by polyglycolic acid, polylactic acid, glycolic acid-lactic acid copolymer and the like has been improved to form a surgical suture or the like in the form of a monofilament. As bioabsorbable polymers that can be used, lactic acid-hydroxycaproic acid copolymers, glycolic acid-hydroxycaproic acid copolymers, and the like, and medical molded products molded from them have been proposed.

As a glycolic acid-hydroxycaproic acid copolymer, for example, in JP-A-59-82865, about 20-35% by weight of ε-caprolactone and about 65% by weight are disclosed.
Consisting of a sequence based on ~ 80 wt% glycolide and having a tensile strength of at least 30,000 psi and 35
Disclosed is a sterilized surgical product comprising a polymeric material having a Young's modulus of less than 10,000 psi, and a method of making the polymeric material, a copolymer. Then, as a method for producing the copolymer, a low molecular weight prepolymer of ε-caprolactone and glycolide is produced, the prepolymer includes ε-caprolactone in an amount of more than 50% by weight, and is produced at a temperature lower than 220 ° C. And adding additional glycolide to the prepolymer and allowing the mixture containing the additional glycolide to give a conversion to copolymer of at least 80% at a temperature above 140 ° C. for a time sufficient. A method of polymerizing to give a copolymer having a crystallinity of at least 5% is described.

The glycolic acid-hydroxycaproic acid copolymer disclosed in the above publication and the surgical product formed from the copolymer have excellent flexibility and mechanical strength, and therefore, they are used in the form of monofilament for surgery. There is an advantage that it can be used as a suture. However, they have a too fast hydrolysis rate and are rapidly degraded in vivo. Therefore, it is not satisfactory as a surgical suture or its material for an affected area which has a long healing period.

Further, JP-A-4-226527 discloses a segmented copolymer having at least two different ester bonds and exhibiting bioabsorbability.
The publication discloses a segmented copolymer consisting of a fast transesterification bond consisting essentially of glycolate bonds and a slow transesterification bond selected from the group consisting of trimethylene carbonate and caproate bonds, and at least Using sequential addition of at least two different cyclic ester monomers in two stages, the first cyclic ester monomer being carbonates and lactones,
A method for producing the above segmented copolymer is disclosed, in which lactides are used as the second cyclic ester monomer, and after the copolymer melt is formed, it is further heated for transesterification. The segmented copolymer is said to exhibit significantly different physical properties than random or block copolymers.

However, this segmented copolymer, as shown in the publication, has a lower melting point of the polymer as the segmentation proceeds, and
Crystallinity decreases. Therefore, according to the findings of the present inventors, the segmented copolymer does not exhibit sufficient tensile strength when converted into a monofilament as a suture. Also, according to the findings of the present inventors, this segmented copolymer is, because of its low crystallinity, hydrolyzed in the body too fast, and has a long healing period as a surgical suture or a material for the same. Is not satisfactory.

As the lactic acid-hydroxycaproic acid copolymer, for example, in JP-A-64-56055, a copolymer containing 95 to 65 mol% of lactic acid units and 5 to 35 mol% of hydroxycaproic acid units. A biodegradable medical molded article formed of a polymer and a method for producing the same are disclosed. Since the copolymer and the molded article for medical use disclosed in this publication have flexibility, there is an advantage that they can be used as a surgical suture in the form of a monofilament. But,
The mechanical strength is low, and the rate of decomposition in vivo is too slow, so that it is present in the body longer than necessary, which is not preferable.

[0011]

SUMMARY OF THE INVENTION The object of the present invention is to overcome the above-mentioned problems, have excellent mechanical strength and flexibility, and have appropriate hydrolyzability, such as surgical monofilament sutures and other materials. The present invention provides a bioabsorbable polymer suitable as a product, a method for producing the bioabsorbable polymer, and a medical molded article obtained from the bioabsorbable polymer.

[0012]

Means for Solving the Problems As a result of intensive studies aimed at solving the above-mentioned problems, the present inventors have unexpectedly synthesized and isolated polylactic acid having a hydroxyl group at the terminal in advance, In the presence of the polylactic acid, ε-caprolactone is first subjected to ring-opening polymerization, and then glycolide is added to the reaction system to carry out ring-opening polymerization to obtain a bioabsorbable copolymer capable of achieving the above object, and The present inventors have found that the bioabsorbable copolymer is suitable as a material for a monofilament suture, and have reached the present invention.

That is, in the present invention, in the presence of 100 parts by weight of polylactic acid having a hydroxyl group at the terminal and having a weight average molecular weight of 2000 or more and 500,000 or less, first, ε-
A polylactic acid segment obtained by ring-opening polymerization of 20 to 1200 parts by weight of caprolactone, and then ring-opening polymerization by adding 15 to 1200 parts by weight of glycolide during or after the ring-opening polymerization of ε-caprolactone. It comprises a poly (ε-caprolactone) segment and a polyglycolic acid segment, and has a weight average molecular weight of 10,000 to
It is a ternary block copolymer of 1,000,000. The ternary block copolymer of the present invention has a molecular weight of 10,0.
00 to 1,000,000. Considering the mechanical strength, hydrolysis rate, productivity, processability, etc. of the ternary block copolymer, a more preferable molecular weight range is 50,000.
~ 400,000.

One of the ternary block copolymers provided by the present invention is a copolymer having a structure represented by the following formulas (1) and (2).

Embedded image (In the formula, x, y and z represent positive numbers, and x: y: z =
100: a: b, a is 13 to 810, and b is 20 to 1593. Further, P is a hydrogen atom, or an alkyl group having 1 to 18 carbon atoms or a carbon alkylene group, and Q is a hydrogen atom or a monovalent or polyvalent metal atom.)

Another aspect of the present invention is a bioabsorbable medical molded article molded from the above ternary block copolymer. A preferred embodiment of the bioabsorbable medical molded article of the present invention is a monofilament suture.

Further, in another invention of the present invention, in the presence of 100 parts by weight of polylactic acid having a hydroxyl group at the terminal and having a weight average molecular weight of 2000 or more and 500,000 or less, first, 20 to 1200 parts by weight of ε-caprolactone is used. Part is subjected to ring-opening polymerization, and then the ring-opening polymerization is carried out by adding 15 to 1200 parts by weight of glycolide during or after the ring-opening polymerization of the ε-caprolactone. The polylactic acid segment, poly (ε-caprolactone) Weight average molecular weight of 50,000 to consist of a segment and a polyglycolic acid segment
It is a method for producing a ternary block copolymer of 1,000,000.

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below. The molecular weights (weight average molecular weight, Mw) of polylactic acid, ε-polycaprolactone, polyglycolic acid, copolymers and the like in the present invention are values measured by the method described in Examples below.

The bioabsorbable polymer of the present invention is prepared by previously synthesizing and isolating polylactic acid having a specific molecular weight, mixing the polylactic acid with ε-caprolactone (hereinafter simply referred to as caprolactone), and mixing the polylactic acid with the polylactic acid. In the presence thereof, first, a predetermined amount of caprolactone is subjected to ring-opening polymerization, and then a predetermined amount of glycolide is sequentially added to the reaction system to carry out ring-opening polymerization.

The molecular weight of the polylactic acid used in the present invention affects the mechanical strength and hydrolyzability of the resulting copolymer. That is, if the molecular weight of polylactic acid is too low, for example, the mechanical strength of the obtained copolymer will be low and the hydrolysis rate will be high. On the other hand, if the molecular weight of polylactic acid is too high, the melt viscosity of polylactic acid will be too high.
In the polymerization of caprolactone in stages, it becomes difficult to uniformly disperse and mix polylactic acid and caprolactone. This means that the production of polylactic acid or poly (ε-caprolactone) (hereinafter simply referred to as polycaprolactone) homopolymer without addition of caprolactone is increased, and the desired ABC is increased.
Since it becomes difficult to obtain a mold block copolymer, it becomes difficult to balance desired physical properties such as strength, flexibility, and decomposition rate. From this viewpoint, the molecular weight of the polylactic acid used is preferably about 2000 or more and 500,000.
0 or less, more preferably 5,000 or more and 30
10,000 or less, more preferably 10,000 or more 1
It is 50,000 or less.

The polylactic acid may be one produced by dehydration polycondensation of lactic acid or one produced by ring-opening polymerization of lactide. The lactic acid used for dehydration polycondensation may be D-lactic acid or L-lactic acid. For example, polylactic acid produced by dehydration polycondensation using only L-lactic acid usually contains 80 to 99.9% by weight of L-lactic acid unit and 0.1% of D-lactic acid unit due to racemization during the polymerization reaction. Approximately 20% by weight is contained.

Lactide includes L-lactide, which is a cyclic dimer of L-lactic acid, and D, which is a cyclic dimer of D-lactic acid.
-Lactide, meso-lactide in which D-lactic acid and L-lactic acid are dimerized cyclically, and DL-lactide, which is a racemic mixture of L-lactide and D-lactide, include ring-opening polymerization of any of these lactides in the present invention. Polylactic acid obtained by the above method can also be used. The content ratio of L-lactic acid unit and D-lactic acid unit of polylactic acid affects the crystallinity of the obtained copolymer.
Considering mechanical properties such as tensile strength, those containing 90 to 99.9% by weight of L-lactic acid unit and 0.1 to 10% by weight of D-lactic acid unit are preferably used.

The polylactic acid used in the present invention is a polylactic acid having a hydroxyl group at the terminal. Polylactic acid having a hydroxyl group at one end is prepared by carrying out polymerization in the above ring-opening polymerization of lactide using a hydroxyl group-containing compound such as water, alcohols, hydroxycarboxylic acid, etc. as an initiator (chain regulator). be able to. It can also be prepared by the dehydration polycondensation method of lactic acid described above. Further, polylactic acid having hydroxyl groups at both ends can be prepared by ring-opening polymerization of lactide using a dihydroxy compound such as ethylene glycol as an initiator.

The polylactic acid synthesized by the above method is preferably isolated from the synthetic reaction system by a known method such as a reprecipitation method. Furthermore, it is preferable to remove unreacted monomers such as lactide and lactic acid along with the isolation operation.
A preferable residual amount of the unreacted monomer is 10% by weight or less based on the obtained polylactic acid. More preferably 5%
It is particularly preferably 3% or less. When the removal of the unreacted monomer is insufficient only by the isolation operation such as the reprecipitation method, it is preferable to reduce the amount of the unreacted monomer by operations such as reprecipitation purification, solvent extraction, and heating / reducing pressure.

The polylactic acid used in the present invention usually has a distribution in molecular weight, as in general synthetic polymers.
The molecular weight distribution is generally represented by the ratio (Mw / Mn) of the weight average molecular weight and the number average molecular weight. For example, the polylactic acid produced by the dehydration polycondensation method has a relatively wide molecular weight distribution and Mw / Mn of about 2 to 6. Further, for example, polylactic acid obtained by the ring-opening polymerization method of lactide has Mw / Mn of about 1.2 to 4. In the production method of the present invention, polylactic acid having a narrow molecular weight distribution may be used, but from the viewpoint of mechanical properties (strength, flexibility, etc.) of the resulting copolymer and the decomposition rate in vivo, polylactic acid is used. The molecular weight distribution of is preferably medium, and the value of the ratio of the weight average molecular weight to the number average molecular weight is
It is preferably 2 or more and less than 6.

Further, the polylactic acid used in the method for producing the copolymer of the present invention has a hydroxyl group at the terminal and is 200
Any polylactic acid having a weight average molecular weight of 0 or more and 500,000 or less may be used, and may have any of branched, comb, star polymer, and dendrimer structures.

The form of polylactic acid used as a raw material is preferably pellet or powder in consideration of the ease of dispersion and mixing of polylactic acid and caprolactone. Particularly preferred is a powder form.

The polylactic acid used in the present invention may contain a structural unit other than the lactic acid unit as long as the properties of the polylactic acid are not substantially impaired. The structural unit that can be contained is not particularly limited, and examples thereof include hydroxycarboxylic acid units such as hydroxycaproic acid units, glycolic acid units, hydroxybutyrate units, and hydroxyvalerate units, diol units, dicarboxylic acid units, and the like. Although the amount depends on the type of the structural unit contained, it is less than about 20 mol% considering that the properties peculiar to polylactic acid are not substantially impaired.

It is important to control the amount of water contained in the polylactic acid and caprolactone used. This is because, in the stage of caprolactone ring-opening polymerization, the presence of such water facilitates the formation of a caprolactone homopolymer, resulting in unfavorable changes in physical properties. The water content is preferably 0.1 to 200 ppm. Caprolactone may be dried by using, for example, molecular sieves, and further distilled to remove water. It is advisable to remove water from the polylactic acid by drying under reduced pressure at a temperature of, for example, room temperature to 120 ° C. Moreover, since the water content of glycolide used affects the molecular weight of the copolymer obtained, the water content is preferably 0.1 to 200 ppm. Glycolide is preferably dried at room temperature to 50 ° C. under reduced pressure, or sludge is slid in a hydrophilic non-alcoholic organic solvent that does not dissolve glycolide to remove water.

Further, lactide, caprolactone, glycolide and other lactones usually include free hydroxycarboxylic acids such as glycolic acid, hydroxycaproic acid and lactic acid. Since free hydroxycarboxylic acid affects the molecular weight of the obtained copolymer, its content is preferably reduced as much as possible, and is preferably in the range of about 10 to 500 ppm. More preferably 10 to 200
ppm.

The bioabsorbable polymer of the present invention is prepared by first caprolactone 2 in the presence of 100 parts by weight of the above polylactic acid.
It can be produced by ring-opening polymerization of 0 to 1200 parts by weight, and then sequentially adding 15 to 1200 parts by weight of glycolide to the reaction system for ring-opening polymerization. The ratio of the three components used is, when converted to the molar ratio of the repeating constitutional units of the produced copolymer, 13 to 810 parts by mol of hydroxycaproic acid unit and 20 to 1593 parts by mol of glycolic acid unit with respect to 100 parts by mol of lactic acid unit. Is.

The amount of caprolactone used affects in particular the flexibility of the copolymer obtained. When the amount of caprolactone used is increased, the flexibility of the obtained copolymer is improved. The amount of polylactic acid and glycolide used affects, among other things, the mechanical strength of the copolymer obtained. When the amount of polylactic acid and glycolide used is small, the mechanical strength tends to decrease, and conversely, when they are large, the mechanical strength tends to improve.

The amount of polylactic acid, caprolactone and glycolide used affects the hydrolysis rate of the resulting copolymer. If the amount of polylactic acid or caprolactone used is too large, the hydrolysis tends to be slow, and if the amount of glycolide used is large, the hydrolysis tends to be too fast. From such a viewpoint, polylactic acid, caprolactone and glycolide are used in the respective proportions as described above, and by adding them into the reaction system in the above method and order, the mechanical strength,
A bioabsorbable copolymer having an appropriate balance of flexibility and hydrolyzability can be obtained.

Further, as a bioabsorbable polymer suitable for a bioabsorbable monofilament suture, in order to have more suitable tensile strength, flexibility and hydrolyzability, the proportions of polylactic acid, caprolactone and glycolide used are appropriate for the monofilament. Use of caprolactone in an amount of 15% or more of the total amount (polylactic acid amount + caprolactone amount + glycolide amount) in order to exert sufficient flexibility and to make the hydrolysis rate of the monofilament moderate. The total amount of polylactic acid and caprolactone is 30
It is more preferable that the content is not less than% and not more than 90%.

In the present invention, in addition to the above three raw materials, other lactone may be used together with caprolactone or glycolide as a monomer for copolymerization. Examples of other lactones include β-propiolactone, β-butyrolactone, β-valerolactone, δ-valerolactone,
p-dioxanone, 3-methyl-1,4-dioxane-
2,5-dione, trimethylene carbonate and the like can be mentioned. Considering the object of the present invention, the amount of these other lactones used is preferably 10 parts by weight or less based on 100 parts by weight of polylactic acid.

In the production method of the present invention, strength, flexibility,
In order to obtain a copolymer having a balanced decomposition rate, it is preferable that the amount of caprolactone in the first step remaining as an unreacted monomer is smaller than that of glycolide in the addition of glycolide in the second step. Preferably, the amount of residual caprolactone is 10% by weight or less based on the amount of glycolide added in the second stage. As a method of reducing unreacted caprolactone in the reaction system immediately before the addition of glycolide in the second step, for example, a method of increasing the conversion rate of caprolactone by carrying out the polymerization of caprolactone in the first step under appropriate and sufficient reaction conditions. , First
A method of removing unreacted caprolactone by heating the reaction system under reduced pressure conditions from the latter half of the polymerization reaction of the step or immediately before the polymerization reaction of the second step after the completion of the polymerization reaction can be mentioned. In the above method, the conversion rate can be increased to about 99% by appropriately adjusting the amount of catalyst, the reaction temperature, and the reaction time. In the production method of the present invention, in order to obtain a copolymer having physical properties such as preferable mechanical strength and decomposition rate, it is preferable to increase the conversion rate of caprolactone in the first step to at least 70% or more. It is preferably 80% or more, particularly preferably 90% or more.

The method of adding glycolide to the reaction system is not particularly limited. However, the melt obtained by polymerizing caprolactone in the presence of polylactic acid has a high viscosity,
On the other hand, the added glycolide becomes a low-viscosity melt in the reaction system. Therefore, if a large amount of glycolide is added to the system at one time, the two are not mixed well and the reaction tends to be non-uniform. This makes the addition of the polyglycolic acid segment in the copolymer non-uniform, and the desired physical properties cannot be expected. Therefore, a preferable method of adding glycolide is to continuously or intermittently add a predetermined amount of glycolide little by little such that the amount of glycolide added per minute does not exceed 20% of the total weight of polylactic acid and caprolactone. It is a method of adding it.

The conversion rate of glycolide affects the mechanical strength of the resulting copolymer. Therefore, ring-opening polymerization is preferably performed until the conversion rate of glycolide becomes 95% by weight or more.

The proportions of polylactic acid, caprolactone and glycolide used, and the method and order of addition of these three components to the reaction system affect the mechanical strength, flexibility and hydrolyzability of the resulting copolymer. . In order to impart excellent mechanical strength, flexibility and the like to the resulting copolymer and to impart appropriate hydrolyzability, it is important to add each to the reaction system according to the above method and sequence.

Examples of the method for ring-opening polymerization of caprolactone and glycolide in the presence of polylactic acid include a bulk polymerization method, a solution polymerization method and a suspension polymerization method. However, in consideration of prevention of mixing of organic solvent, suspension stabilizer, etc., the bulk polymerization method carried out in a molten state is preferable. The ring-opening polymerization of caprolactone or glycolide is preferably 130 ° C. or higher and 270
It can be performed in the range of less than ° C. Particularly, the polymerization temperature of caprolactone is preferably higher than the temperature at which the coexisting polylactic acid melts. At a temperature at which polylactic acid is not completely melted, the polymerization of caprolactone often does not start from the terminal hydroxyl group of polylactic acid, and the by-product of the caprolactone homopolymer increases, which is not preferable. On the other hand, if the polymerization is carried out at an excessively high temperature, the produced polymer is decomposed, which is not preferable. Considering this point, the preferable polymerization temperature range of caprolactone is about 170 to 250 ° C. Similarly, the preferable polymerization temperature range of glycolide is about 150 to 250 ° C. Usually, it is preferable to carry out in an atmosphere of an inert gas such as nitrogen.

The ring-opening polymerization time is not particularly limited, but it is important for the ring-opening polymerization of caprolactone to be carried out without adding glycolide until the conversion of caprolactone reaches at least 70% by weight. In the above temperature range, the time required to reach such conversion is usually 0.
It takes about 2 to 10 hours. The ring-opening polymerization of glycolide is preferably carried out until the conversion rate of glycolide becomes 95% by weight or more. Glycolide is preferably 0.1
It is preferable to add the solution over 2 hours, more preferably 0.1 hour. Thus, the conversion rate of glycolide is 9
It reaches 5% by weight or more. In order to add glycolide to the reaction system, it is preferable to heat the glycolide at 100 to 150 ° C. and handle it in a molten state.

The conversion of caprolactone and glycolide to the copolymer can be determined, for example, by adding hexafluoro-
It is dissolved in 2-propanol and the residual monomers are quantitatively calculated by using gas chromatography.

In order to complete any ring-opening polymerization in a short time and obtain a high molecular weight copolymer, it is preferable to use a polymerization catalyst. Examples of the polymerization catalyst include stannous octoate, tin tetrachloride, zinc chloride, titanium tetrachloride, iron chloride, boron trifluoride ether complex, aluminum chloride, antimony trifluoride, lead oxides, and other mainly polyvalent metals. And a tin compound or a zinc compound is preferably used. Stannous octoate is particularly preferred. The amount of the polymerization catalyst used is 0.0 with respect to the total weight of the raw materials charged.
It is preferably about 01 to 0.03% by weight.

The copolymer obtained by the ring-opening polymerization is depressurized in the molten state, or after cooling and pulverizing, the unreacted monomer is removed by heating under reduced pressure. When removing unreacted monomer by depressurizing the molten state, 200
~ 240 ° C, final 1 over 0.2-1 hour
Examples include a method of depressurizing and degassing at a pressure of 3,300 Pa or less and maintaining the state for 0.3 to 2 hours. 13
It is preferable to reduce the pressure to about 0 Pa.

When the copolymer is cooled and pulverized and then heated under reduced pressure to remove the unreacted monomer, the shape of the copolymer is preferably as fine as powder or pellet. . 1 at 40-130 ° C
Depressurize and degas at a pressure of 3,300 Pa or less,
It is preferable to continue depressurization and deaeration for 5 to 72 hours. 1
It is preferable to reduce the pressure to about 30 Pa. In any method, stirring may be performed or non-stirring may be performed.

One of the features of the method for producing a ternary block copolymer of the present invention is that polylactic acid having a hydroxyl group at the terminal is previously synthesized and isolated, and caprolactone is subjected to ring-opening polymerization in the presence of the polylactic acid. There is. This has an important meaning as a method for producing a ternary block copolymer having appropriate strength, flexibility and hydrolyzability. That is, it is a method of preliminarily synthesizing polylactic acid having a desired or known structure (molecular weight, molecular weight distribution, optical activity, etc.) and then isolating it, and using the polylactic acid in a predetermined amount to produce a ternary block copolymer Therefore, the structure of the polylactic acid segment, which greatly affects the mechanical strength and hydrolyzability, is well defined (tailor
-made) block copolymers can be produced.

The ternary block copolymer of the present invention can be produced by another production method, for example, ring-opening polymerization of lactide is first carried out to produce polylactic acid, and then polylactic acid is isolated from the reaction system. In comparison with a method in which caprolactone is added to the reaction system to form a copolymer, and glycolide is further added thereto to perform ring-opening polymerization (hereinafter referred to as continuous three-stage polymerization method) Excellent in terms.

In the continuous three-stage polymerization method, the temperature when the second-stage caprolactone is added is kept at least 200 in order to maintain the molten state of the polylactic acid produced in the first stage.
Must be kept above ℃. In this case, according to the knowledge of the present inventors, at a temperature of 200 ° C. or higher, about 1 due to the equilibrium between polylactic acid and lactide (polymer ← → monomer).
0% or more of lactide monomer is mixed. If the lactide monomer is mixed during the second stage polymerization of caprolactone, the second segment of the ternary block copolymer becomes a random copolymer segment in which lactic acid units and caprolactone units are mixed. This is not preferable because it leads to deterioration of mechanical strength and physical properties such as stickiness at room temperature.

Further, in the continuous three-stage polymerization method, since caprolactone, which is a low-viscosity liquid at room temperature, is added to molten high-temperature, high-viscosity polylactic acid, the mixture and dispersion of both tend to be non-uniform, resulting in polylactic acid terminal. Of polycaprolactone) does not proceed favorably and the content of the caprolactone homopolymer is increased, resulting in deterioration of physical properties, which is not preferable.

According to the production method of the present invention, first, ring-opening polymerization of caprolactone is carried out in the presence of polylactic acid having a hydroxyl group at the terminal, whereby a segment of polycaprolactone is grown from the terminal hydroxyl group of polylactic acid to give polylactic acid. -A polycaprolactone AB type block copolymer is formed. Then, by sequentially adding glycolide thereto and subjecting it to ring-opening polymerization, a polymer chain of glycolide (polyglycolic acid segment) is formed from the terminal hydroxyl group of the polycaprolactone chain.
Grows. Therefore, for example, when polylactic acid having a hydroxyl group at one end is used, ABC type 3 of polylactic acid (A) -polycaprolactone (B) -polyglycolic acid (C) is used.
The original block copolymer is formed. Further, for example, by using polylactic acid having hydroxyl groups at both ends, CBAB
A C-type ternary block copolymer is produced.

The molecular weight of the obtained bioabsorbable polymer is related to mechanical strength, hydrolyzability and the like. Therefore, the molecular weight of the bioabsorbable polymer of the present invention is 50,000 to 1,000.
It is preferably about 10,000. Surgical suture,
When used as a bone reinforcement, the molecular weight is usually 5
It is about 10,000 to 1,000,000. It is preferably 50,000 to 400,000.

Thus, one of the preferred bioabsorbable polymers provided by the present invention is 13 to 810 parts by mol of hydroxycaproic acid unit and 20 to 1593 parts by mol of glycolic acid unit per 100 parts by mol of lactic acid unit. A polylactic acid segment (A), a polycaprolactone segment (B), and a polyglycolic acid segment (C) containing a compound represented by Formula (1) (Chemical Formula 3) are ABC type or CB type.
-A-B-C type, molecular weight of 50,000-
It is a 1,000,000 ternary block copolymer.

Embedded image

In the polymer produced by the production method of the present invention, in addition to the above ternary block copolymer, a small amount of caprolactone homopolymer, glycolic acid homopolymer, polycaprolactone-polyglycolic acid (BC type). Block copolymer, and a small amount of polylactic acid, polylactic acid-polycaprolactone (AB type or BAB type) block copolymer, polylactic acid-polyglycolic acid (AC type or CAC)
(Type) block copolymer and the like may be mixed.

The amount of these by-produced polymers is the amount of impurities such as polylactic acid, caprolactone, glycolide as a raw material, water and hydroxycarboxylic acid, and the mixing of polylactic acid and caprolactone in the first step of the reaction is uniform. And the uniformity of mixing of the polymer and glycolide at the time of adding glycolide in the second step. The amount of the by-produced polymer is, for example, by dissolving and extracting the by-produced polymer from the ternary block copolymer by Soxhlet extraction, dissolving the ternary block copolymer in a good solvent, and dissolving the by-produced polymer. Add a solvent that does not dissolve the ternary block copolymer,
This can be known by a method such as reprecipitation of only the ternary block copolymer.

The bioabsorbable polymer of the present invention produced as described above is molded into a medical molded article by a known method. Examples of medical molded products include monofilament sutures, bone reinforcing plates, surgical nets, and sustained-release agents.

The method for producing the monofilament suture is as follows:
There is no particular limitation and a known method can be applied. For example, the bioabsorbable polymer of the present invention is kneaded and melted using an extruder or the like equipped with a spinning die, and molded into a monofilament fiber through a spinneret. Then, the fibers may be stretched and oriented, and the oriented fibers may be annealed and further heat-treated.

As the molding conditions of the monofilament, the spinning temperature may be higher than the melting point of the copolymer and lower than the decomposition temperature. Usually, it is preferably 120 to 250 ° C. The stretching temperature is selected on the basis of the glass transition temperature of the filament, but normally it is preferably about 15 to 80 ° C. More preferably, it is 25 to 70 ° C. The draw ratio is preferably 3 to 20 times in the length direction of the filament. More preferably, it is 3 to 10 times. The stretched filaments are preferably annealed and heat-treated in order to make properties such as tensile strength, dimensional stability, and hydrolyzability uniform. Annealing is carried out under relaxation of 0.5 to 10% or under tension, preferably at 40 to 130 ° C. for 0.01 seconds to 30 seconds.
It is preferable to carry out for about a second.

After annealing, heat treatment is performed at 40 to 150 ° C. for 1
Under tension at a reduced pressure of 30 to 100,000 Pa,
It is preferably carried out for 1 to 72 hours. The more preferable temperature for the heat treatment is 50 to 125 ° C. The preferred pressure is 130 to 16,000 Pa, more preferably 1
It is 30 to 8,000 Pa. The thickness of the monofilament-like suture of the present invention is not particularly limited, but the diameter is usually 0.005 to 1 mm. Preferably 0.02 to 0.
8 mm. The monofilament suture of the present invention is
It is preferable to attach a suturing needle to at least one end, if necessary.

In a preferred embodiment of the invention, the surgical monofilament suture of the invention comprises at least 2
Linear tensile strength of 00 MPa, at least 170 MPa
It has a ligation tensile strength of. Young's modulus is 2.1 GPa or less. The hydrolyzability, that is, the residual rate of linear tensile strength in vivo (ratio to the original tensile strength) is 10 to 90 after 6 days under the conditions described below.
%. In a preferred embodiment, it is 20-80%. In a more preferred embodiment, it is 30 to 70%. Further, the monofilament-like suture of the present invention has good ligation stability, and the knot of the ligature once made does not become loose. The methods for evaluating and measuring these characteristics will be described in detail in Examples below.

[0059]

The present invention will be described below in further detail with reference to examples. The molecular weights of polylactic acid and copolymers shown in Examples, ε-caprolactone, glycolide, and lactide conversion rates, copolymer composition, copolymer melting point, linear tensile strength, Young's modulus, after hydrolysis The linear tensile strength residual rate and ligation stability were measured by the following methods.

(1) Molecular Weight of Polylactic Acid and Tertiary Block Copolymer etc. Polylactic acid is dissolved in chloroform, and the other polymers are dissolved in hexafluoro-2-propanol (hereinafter referred to as HFP) to give a concentration of 0.2. A solution of wt% was prepared, and the solution was subjected to gel permeation chromatography (manufactured by Showa Denko KK, model: GPC-SYSTEM21, hereinafter, G
It was measured using a PC). The weight average molecular weight (Mw) is calculated using polystyrene as the polylactic acid and polymethylmethacrylate as the standard substance for the other polymers.

(2) ε-caprolactone, glycolide,
And conversion of lactide The generated polymer is dissolved in HFP, and the content of ε-caprolactone, glycolide, and lactide in the polymer (residual monomer amount) is measured by capillary gas chromatography, and the calculation is performed.

(3) Copolymer composition (parts by weight) Nuclear magnetic resonance apparatus (manufactured by JEOL Ltd., model: FX-90)
Using Q), a mixed solvent of HFP and deuterated chloroform (volume mixing ratio: HFP: CDCl ₃ = 2: 1) is used as a solvent, and ¹ H nucleus is measured in a range of ¹ to 9 ppm.
From the respective resonance intensities of the methyl group (5.2 ppm) based on lactic acid, the methylene group (2.4 ppm) based on hydroxycaproic acid, and the methylene group (4.8 ppm) based on glycolic acid, each composition ratio in the sample (parts by weight) ). Less than,
It is called 1 H-NMR analysis.

(4) Copolymer melting point (° C.) Differential scanning calorimeter [manufactured by RIGAKU, model: DSC
-8230] is used to measure the melting point indicated by the peak of the differential scanning calorimeter operating at a heating rate of 10 ° C. per minute.

(5) Linear tensile strength (MPa), Young's modulus (GPa) According to the method specified in JIS L-1069, the chuck width of the tensile tester is 40 mm and the tensile speed is 100 mm / mi.
Measure with n. The linear tensile strength indicates the maximum load (N) until the sample breaks. Young's modulus is the stress (load) −
It is calculated from the gradient of the initial linear elastic region of the strain curve by the following formula. Young's modulus = (tan θ × L · C · S) / (H × A) [wherein, θ: stress (load) -angle (°) between the initial linear portion of the strain curve and the strain axis (X axis), L : Chuck width (m
m), C: chart speed (mm / min), S: load per graduation of stress axis (N / mm), H: tensile speed (m
m / min), A: sample cross-sectional area (mm ² )]

(6) Residual rate of linear tensile strength after hydrolysis (%) The sample (monofilament) was immersed in a phosphate buffer solution having a pH of 7.27 and a temperature of 50 ° C. for 6 days, dried, and then The linear tensile strength is measured by the method described in the item 5) and is shown as a percentage (%) with respect to the value when not soaked.

(7) Stability of ligation A sample (monofilament) was wrapped twice around a glass tube having a diameter of 20 mm to make a surgical knot, and then left at a temperature of 23 ° C. and a relative humidity of 50% for a predetermined period of time. Visually observe the change over time in the looseness of the knot. The ligation stability of the sample is evaluated by the degree of looseness of the ligature of the ligature of the sample on the glass tube. The evaluation criteria are as follows. Rank A: A state in which the knot has no looseness and is in close contact with the glass tube. Rank B: A state in which the knot is loose but adheres to the glass tube. Rank C: A state in which the knot is loosened greatly and the knot is separated from the glass tube.

Example 1 A 1 L reactor which was equipped with a mechanical stirrer and a vacuum degasser and heated and dried under reduced pressure was powdered and had a molecular weight of 86,0.
100 parts by weight of polylactic acid (hereinafter, referred to as PLA) which is 00, 100 parts by weight of ε-caprolactone (hereinafter, referred to as CL), and stannous octoate of 0.015 with respect to CL.
The amount charged was wt.%. Inside the reactor, 30 ℃, 130
The mixture was degassed under reduced pressure at ˜1,300 Pa for about 2 hours to remove toluene (solvent of stannous octoate). Then
Nitrogen was aerated to about 101,000 Pa. After bubbling nitrogen through for about 5 minutes, the reaction mixture was heated to 220 ° C. over about 20 minutes in a nitrogen atmosphere and kept at this temperature for 2 hours. At this time, the conversion rate of CL to the copolymer was about 9
8%.

Next, 100 parts by weight of molten glycolide (hereinafter referred to as GLD) heated to about 110 ° C. was continuously added into the reactor over about 10 minutes, and vigorously stirred for 5 minutes. After that, the reaction temperature is set to 2 while gently stirring.
The temperature was raised to 35 ° C. and the state was maintained for about 1 hour. GLD
The conversion rate of the copolymer was about 99% by weight. The pressure inside the reactor was gradually reduced to remove unreacted residual monomers. The composition, molecular weight, and melting point of the obtained copolymer were measured by the above methods, and the results are shown in Table 1 (Table 1).

Next, the obtained copolymer was melt extruded at 240 ° C. using an extruder to form a monofilament. The obtained monofilament was stretched 7.4 times in the longitudinal direction at 50 ° C. Then under tension, 60
After annealing at ℃ for several seconds, heat treatment is further performed at 110 ℃ under reduced pressure for 3 hours, and the thickness is 0.2.
mm mm monofilament suture was produced. The linear tensile strength, Young's modulus, and residual rate of strength after hydrolysis of the obtained suture were measured by the above-mentioned methods and judged by the following judgment criteria. The results are shown in Table 2 (Table 2).

Linear tensile strength A: 400 MPa or more B: 300 MPa or more and less than 400 MPa C: 250 MPa or more and less than 300 MPa D: 200 MPa or more but less than 250 MPa F: less than 200 MPa Young's modulus A: 1.3 GPa or less B: more than 1.3 GPa -2.1 GPa or less C: 2.1 GPa or more to 3.0 GPa or less F: 3.0 GPa or more Strength residual rate after hydrolysis A: 30% or more to 70% or less B: 20% or more to less than 30% or 70% More than 80% or less C: 10% or more and less than 20% or more than 80% to 90% F: less than 10% or more than 90%

Examples 2 to 9 and Comparative Examples 1 to 6 PLA having the molecular weights shown in Table 1 (Table 1) and Table 3 (Table 3) is part by weight shown in Table 1 (Table 1) and Table 3 (Table 3). A copolymer was produced in the same manner as in Example 1 except that CL and GLD were used in the amounts shown in Table 1 (Table 1) and Table 3 (Table 3). Each characteristic value of the obtained copolymer was measured in the same manner as in Example 1, and the results are shown in Table 1 (Table 1) and Table 3.
It is shown in (Table 3). A monofilament suture was produced in the same manner as in Example 1 except that the spinning temperature, the drawing temperature, the draw ratio and the annealing temperature were set to the conditions shown in Table 2 (Table 2) and Table 4 (Table 4). The characteristics of the obtained suture were measured in the same manner as in Example 1, and the results are shown in Table 2 (Table 2) and Table 4 (Table 4).

[0072]

[Table 1]

[0073]

[Table 2]

[0074]

[Table 3]

[0075]

[Table 4]

Comparative Example 7 In the presence of 100 parts by weight of PLA powder having an Mw of 86,000, 100 parts by weight of GLD was first subjected to ring-opening polymerization (the amount of tin octanoate used was 0.015% by weight based on GLD). Polymerization was carried out at 220 ° C., but the viscosity of the polymer in the reactor became too high, making stirring difficult, and the reaction internal temperature was 235.
Since the temperature exceeded 0 ° C, the external temperature set temperature of the reactor was set to 235 ° C. After 1 hour, the conversion rate of GLD reached 97% by weight. 100 parts by weight of CL was continuously added to the reactor over about 10 minutes.
Did not mix well and remained uneven. After 3 hours, the melt finally became almost uniform, but it was a dark brown colored and low-viscosity melt. The conversion rate of CL was 89%. The pressure inside the reactor was gradually reduced to remove unreacted residual monomers. Table 5 (Table 5) shows the molecular weight of the PLA used, the composition of the charge, and the charge sequence for the reaction system. Further, the characteristics of the obtained copolymer composition and the like were measured in the same manner as in Example 1, and the results are shown in Table 5 (Table 5). An attempt was made to spin the resulting dark brown copolymer, but an unusual odor was generated, and a low-viscosity melt was discharged from the extruder, but no filament was obtained.

Comparative Example 8 100 parts by weight of LTD was first subjected to ring-opening polymerization at 220 ° C. in the presence of 100 parts by weight of PCL pellets having an Mw of 150,000 (the amount of tin octanoate used was 0.01 with respect to LTD).
5% by weight). After 1 hour, the conversion rate of LTD is about 90% by weight.
Reached. The polymerization time was extended by 2 hours, but LT
The conversion of D did not increase. G heated and melted there
100 parts by weight of LD was continuously added into the reactor over about 10 minutes and vigorously stirred for 5 minutes. Thereafter, the reaction temperature was raised to 235 ° C. with gentle stirring, and the state was maintained for about 1 hour. The conversion rate of GLD to the copolymer was about 99% by weight. The pressure inside the reactor was gradually reduced to remove unreacted residual monomers. Table 5 shows the molecular weight of PCA used, the composition of the charge, and the charge sequence for the reaction system.
It shows in (Table 5). Further, the characteristics of the obtained copolymer composition and the like were measured in the same manner as in Example 1, and the results are shown in Table 5 (Table 5). Example 1 except that the spinning temperature, the drawing temperature, the draw ratio and the annealing temperature were set to the conditions shown in Table 6 (Table 6).
A monofilament-like suture having a thickness of 0.2 mm was manufactured in the same manner as in. The characteristics of the obtained suture were measured in the same manner as in Example 1, and the results are shown in Table 6 (Table 6).

Comparative Example 9 In the presence of 100 parts by weight of PCL pellets having an Mw of 150,000, 100 parts by weight of GLD was first subjected to ring-opening polymerization at 220 ° C. (the amount of tin octanoate used was 0.01 based on LTD.
5% by weight). The polymerization was initially carried out at 220 ° C., but the polymer viscosity in the reactor became too high, stirring became difficult, and the internal temperature of the reaction exceeded 235 ° C., so the external temperature setting temperature of the reactor was set to 235 ° C. . After 1 hour, the conversion rate of GLD reached 98% by weight. 100 parts by weight of LTD was continuously added into the reactor over about 10 minutes, but the polymer melt and LTD in the reactor were not well mixed and remained non-uniform. After 2 hours, the melt finally became almost uniform, but it was a viscous, low-viscosity melt colored deeply brown. The conversion rate of LTD was 86%. The pressure inside the reactor was gradually reduced to remove unreacted residual monomers. Table 5 (Table 5) shows the molecular weight of PCL used, the composition of the charge, and the charge sequence for the reaction system. Further, the characteristics of the obtained copolymer composition and the like were measured in the same manner as in Example 1, and the results are shown in Table 5 (Table 5). A monofilament suture having a thickness of 0.2 mm was produced in the same manner as in Example 1 except that the spinning temperature, the stretching temperature, the stretching ratio, and the annealing temperature were set to the conditions shown in Table 6 (Table 6). The characteristics of the obtained suture were measured in the same manner as in Example 1, and the results are shown in Table 6 (Table 6).
Shown in

Comparative Example 10 Mw 89,000 polyglycolic acid pellets (hereinafter referred to as
CL10 in the presence of 100 parts by weight of PGA).
0 part by weight of ring-opening polymerization was tried (the amount of tin octanoate used is 0.015% by weight based on CL). Polymerization initially 220 ℃
However, the reaction temperature was set to 235 ° C. because PGA did not melt and the reaction system was heterogeneous. After 2 hours, the reaction system slightly thickened. Upon sampling, it was found that black PGA particles were dispersed nonuniformly in places of a yellowish brown polymer. The conversion rate of CL was 70%. LTD
100 parts by weight were continuously added into the reactor over about 10 minutes. After 4 hours, the conversion rate of LTD was 86%.
The pressure inside the reactor was gradually reduced to remove unreacted residual monomers. The molecular weight of PGA used, the composition of the charge, and the sequence of charge to the reaction system are shown in 5. The characteristics of the obtained copolymer composition and the like were measured in the same manner as in Example 1,
The results are shown in Table 5 (Table 5). An attempt was made to spin the obtained dark brown copolymer, but an unusual odor was generated,
No filament was obtained, only the low viscosity melt was discharged from the extruder.

Comparative Example 11 In the presence of 100 parts by weight of PGA having an Mw of 89,000, 100 parts by weight of LTD was first tried to undergo ring-opening polymerization (the amount of tin octanoate used is 0.015% by weight based on LTD). The polymerization was initially carried out at 220 ° C, but the reaction temperature was set to 235 ° C because PGA did not melt and the reaction system was heterogeneous. 2
After a while, the reaction system thickened, so when sampling,
The product was a tan polymer. The conversion rate of LTD was 85%. Approximately 10 parts by weight of CL in the reactor
It was added continuously over a period of minutes. After 3 hours, the conversion rate of CL was 86%. The pressure inside the reactor was gradually reduced to remove unreacted residual monomers. Molecular weight of PGA used,
Table 5 (Table 5) shows the charging composition and the charging sequence for the reaction system. Further, the characteristics of the obtained copolymer composition and the like were measured in the same manner as in Example 1, and the results are shown in Table 5 (Table 5). An attempt was made to spin the resulting dark brown copolymer, but an unusual odor was generated, and a low-viscosity melt was discharged from the extruder, but no filament was obtained.

[0081]

[Table 5]

[0082]

[Table 6]

<Evaluation of ligation stability> The monofilament sutures obtained in Examples 1 to 9 were evaluated for ligation stability by the above method. All monofilaments were evaluated as A, and the stability was stable for 3 days. Hold the knot.

[0084]

The bioabsorbable polymer of the present invention has excellent mechanical strength and flexibility. Therefore, a medical molded article such as a monofilament suture having excellent mechanical strength and flexibility can be produced from the bioabsorbable polymer. The monofilament suture obtained from the bioabsorbable polymer of the present invention has a pH of 7.27 and a temperature of 50.
After being immersed in a phosphate buffer solution at a temperature of 6 ° C. for 6 days, the residual ratio of tensile strength is about 10 to 90%, and it has appropriate hydrolyzability. Moreover, it has excellent ligation stability. for that reason,
The monofilament suture formed from the bioabsorbable polymer of the present invention is particularly useful as a surgical suture in which the period from the surgical operation to the thread removal is about 1 week to 10 days. The bioabsorbable polymer having such characteristics can be obtained only by adopting the method of the present invention, and is a very useful method as a method for producing a polymer for a material of a medical molded article.

Claims (13)

[Claims] 1. In the presence of 100 parts by weight of polylactic acid having a hydroxyl group at a terminal and having a weight average molecular weight of 2000 or more and 500,000 or less, first, ε-caprolactone 20-
1,200 parts by weight of ring-opening polymerization, and then glycolide 15-
A polylactic acid segment, a poly (ε-caprolactone) segment, and a polyglycolic acid segment, which are obtained by ring-opening polymerization with addition of 1200 parts by weight, have a weight average molecular weight of 10,000 to 1,000,000.
A terpolymer block copolymer of 0. 2. ε-caprolactone 2 relative to 100 parts by weight of polylactic acid having a weight average molecular weight of 10,000 or more.
The ternary block copolymer according to claim 1, wherein 0 to 300 parts by weight and 25 to 1200 parts by weight of glycolide are used. 3. A weight average molecular weight of 50,000 to 40.
The ternary block copolymer according to claim 1, wherein the terpolymer is 30,000. 4. The amount of ε-caprolactone used is one of the total amount of polylactic acid, ε-caprolactone and glycolide.
It is 5% or more, and the total amount of polylactic acid and ε-caprolactone used is 30% or more and 90% or less of the total amount of polylactic acid, ε-caprolactone and glycolide. Coalescing. 5. Formula 1 (Formula 1) (In the formula, x, y and z represent positive numbers, and x: y: z =
100: a: b, a is 13 to 810, and b is 20 to 1593. Further, P is a hydrogen atom, or an alkyl group or a carboxyalkylene group having 1 to 18 carbon atoms, and Q is a hydrogen atom or a monovalent or polyvalent metal atom), the polylactic acid segment (A) An ABC type ternary block copolymer comprising a polycaprolactone segment (B) and a polyglycolic acid segment (C). 6. The ε-caprolactone 20-
1,200 parts by weight of ring-opening polymerization, and then glycolide 15-
1,200 parts by weight is added to carry out ring-opening polymerization,
A polylactic acid segment, a poly (ε-caprolactone) segment, and a polyglycolic acid segment having a weight average molecular weight of 10,000 to 1,000,000 3
Method for producing original block copolymer. 7. Epsilon-caprolactone 2 relative to 100 parts by weight of polylactic acid having a weight average molecular weight of 10,000 or more.
The method for producing a ternary block copolymer according to claim 6, wherein 0 to 300 parts by weight and 25 to 1200 parts by weight of glycolide are used. 8. The amount of ε-caprolactone used is one of the total amount of polylactic acid, ε-caprolactone and glycolide.
It is 5% or more, and the total amount of polylactic acid and ε-caprolactone used is 30% or more and 90% or less of the total amount of polylactic acid, ε-caprolactone and glycolide. Manufacturing method of coalescence. 9. The method for producing a ternary block copolymer according to claim 8, wherein the addition of glycolide is started when the conversion of ε-caprolactone reaches at least 70% by weight. 10. The amount of glycolide added per minute is
The method for producing a terpolymer block copolymer according to claim 9, wherein glycolide is continuously or intermittently added so that the amount thereof does not exceed 20% of the total amount of polylactic acid and ε-caprolactone used. . 11. The method for producing a ternary block copolymer according to claim 10, wherein ring-opening polymerization of glycolide is carried out until the conversion rate of glycolide becomes at least 95% by weight or more. 12. The method according to claim 1,
A bioabsorbable medical composition made from the original block copolymer. 13. The bioabsorbable medical molded article according to claim 12, wherein the bioabsorbable medical molded article is a monofilament suture.