JP2566786B2 - Process for producing molded article for medical use composed of copolymer of lactic acid and ε-caprolactone - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing a biodegradable medical molded article comprising a copolymer of lactic acid and ε-caprolactone.

[Conventional technology]

Polylactic acid (polylactide), which is a polymer of lactic acid, and a copolymer obtained by copolymerizing lactic acid with other components have a property that when they are left in the living body, they are hydrolyzed by water existing in the living body and eventually disappear. However, utilization of this property for various biomaterials has been studied, and some of them have been put to practical use.

For example, Japanese Patent Publication No. 41-2734 discloses a suture made of polylactic acid, and Japanese Patent Publication No. 45-31696 discloses a suture thread.
A suture made of a copolymer mainly composed of lactic acid is disclosed. A copolymer obtained by copolymerizing a small amount of lactic acid and a large amount of glycolic acid is also known, and is actually widely used as a suture. As these sutures, those in which a large number of thin filaments are braided and made flexible are generally used, because the reason is that monofilaments become hard and impractical. is there. Further, Japanese Patent Publication No. 60-501217 discloses an artificial ligament formed by combining a carbon fiber with a copolymer of a small amount of lactic acid and a large amount of ε-caprolactone.

In these prior arts, a melt molding method is generally adopted for molding a polymer. That is, fibers or films are produced by extruding a polymer heated in a molten state at a melting temperature or higher into a molten state through a nozzle or a die, or molding the molten polymer by injecting it into a mold. There have been methods such as making. In addition, a method of casting a solution of a polymer dissolved in a solvent, coating the solution, and then evaporating the solvent to obtain a molded article is also performed on a laboratory scale.

[Problems to be solved by the invention]

Since the braided suture is made by braiding a large number of filaments, the manufacturing process is complicated and the manufacturing efficiency is poor.
Therefore, the manufacturing cost becomes high and it is not preferable in terms of economy. In addition, there are some applications that cannot be used depending on the purpose because the decomposition rate in vivo becomes relatively high.
One of the objects of the present invention is to provide a preferable method for molding a lactic acid-based polymer which is flexible and can be used in a living body in the form of a monofilament or a film. That is, when a lactic acid-based polymer is molded by a melt molding method, thermal stability at the time of melting the polymer is not good, which causes considerable thermal deterioration at the time of molding, so use a polymer with a high degree of polymerization as a raw material. However, the degree of polymerization of the obtained molded product was low, and it was difficult to produce a molded product having sufficient strength. In addition, a method of dissolving the polymer in a solvent and then evaporating the solvent can provide a molded product having no problem in strength, but since the evaporation of the solvent takes time, the molding should be performed efficiently. Can not be done, it is not practical. An object of the present invention is to provide a molding method which does not have such problems.

[Means for solving problems]

The present inventors have conducted various studies on various polymers in order to achieve the above object, and as a result, it is shown that a polymer obtained by copolymerizing lactic acid with a small amount of ε-caprolactone can achieve the above object. I found it.

Then, as a result of investigating a method for efficiently producing this polymer without using a melt molding method, the method in which the polymer is dissolved in a solvent and brought into contact with a lower alcohol solution to coagulate the polymer does not have the above-mentioned problems. It has been found to be an excellent method. That is, the second invention of the present invention is that the lactic acid unit
95-65 mol%, ε-caprolactone unit 5-35 mol%
A medical composition comprising a copolymer of lactic acid and ε-caprolactone, characterized in that the copolymer containing is dissolved in a solvent to prepare a polymer solution, and then the solution is contacted with a lower alcohol solution to coagulate. It is a method of manufacturing a molded product.

[Action]

According to the present invention, a flexible monofilament suture can be obtained, and a preferable film can be obtained.

In addition, since the polymer is not heated during molding of the copolymer, thermal deterioration does not occur. As a result, a molded product made of a polymer having a high degree of polymerization is obtained. Also, the polymer solution will solidify immediately upon contact with the lower alcohol solution,
Since the solvent is eluted in the lower alcohol solution, a molded product can be obtained with good efficiency. Furthermore, since water is not used as the coagulation liquid, the obtained molded product is not hydrolyzed.

〔Example〕

The molded product composed of a copolymer of lactic acid and ε-caprolactone used in the present invention has a lactic acid unit of 95 to 65 mol%, ε-caprolactone.
It contains a caprolactone unit in the range of 5 to 35 mol%. When the content of ε-caprolactone unit is more than 35 mol%, the crystallinity of the polymer is deteriorated and a fiber or film having practically sufficient strength cannot be obtained. Further, if the ε-caprolactone unit is less than 5 mol%, the flexibility becomes insufficient, which is not preferable. Further, a small amount of other copolymerization component may be contained as long as the gist of the present invention is not impaired.

The copolymer of lactic acid and ε-caprolactone can be obtained by a known method. That is, it can be produced by heating lactide, which is a cyclic dimer of lactic acid, and ε-caprolactone in the presence of a catalyst to carry out ring-opening polymerization. Since the copolymerization ratio has a correlation with the charging ratio of raw materials, a polymer having an arbitrary copolymerization composition can be obtained by adjusting the charging ratio. As the catalyst, tin or zinc compounds of carboxylic acid are preferable, and tin octylate, zinc octylate and the like can be exemplified as suitable catalysts. The reaction is preferably carried out under reduced pressure or in an inert gas stream, and the reaction temperature is preferably in the range of 140 to 220 ° C. The obtained copolymer is preferably further purified by a method such as a recrystallization method or a vacuum distillation method before being used.

Next, a method for molding the copolymer thus obtained will be described. First, as a solvent used for dissolving the copolymer at the time of molding, chloroform, tetrahydrofuran, methylene chloride, trichloroethylene, dioxane, benzene, toluene and the like can be mentioned as preferred examples. These may be used alone or in combination of two or more. Solution concentration is 5-40%
Is suitable, and a range of 10 to 30% is particularly preferable.

The greatest feature of the molding method of the present invention is that a lower alcohol solution is used as a coagulating liquid for coagulating the copolymer solution. That is, although methods similar to those of the present invention have been conventionally used in the production of synthetic fibers and semipermeable membranes, all of them use water or an aqueous solution containing a small amount of other components as a coagulating liquid. . In the present invention, water cannot be used as the coagulating liquid because the polymer is a substance that is susceptible to hydrolysis. As a result of various studies, it was found that good results can be obtained by using a lower alcohol solution. As the lower alcohol, those having a relatively low boiling point such as methyl alcohol, ethyl alcohol and isopropyl alcohol are preferable because they can be easily removed later, and ethyl alcohol is particularly preferable. These are used alone or as a mixture. Further, these solutions may contain water as long as the amount is small, and may further contain other organic substances or inorganic substances.

In order to produce a molded product such as a fiber or a film from the polymer solution, the polymer solution is shaped into a fiber or film, and this is dipped in a coagulating liquid consisting of a lower alcohol solution to coagulate. That is, in the case of producing fibers, the polymer solution is extruded from the spinning nozzle into the coagulation liquid, but the polymer solution may be extruded directly into the coagulation liquid, or once extruded into the air and then extruded into the coagulation liquid. May be. In the case of producing a film, the polymer solution may be cast in a film form and immersed in the coagulating liquid, or the polymer solution may be extruded into the coagulating liquid into a film form through a T-die or the like. Good. The obtained molded product is thoroughly washed with a coagulating liquid to remove the solvent, and then the lower alcohol is removed in an air flow or an inert gas flow or under reduced pressure. Then, if necessary, heat treatment or the like is performed.

Since the molded product thus obtained is flexible and supple, it is useful as a biomaterial, and is suitable for medical applications such as sutures, anti-adhesion materials, wound dressing materials and hemostatic materials. Especially, the suture made of monofilament
The decomposition rate is lower than that of braided multifilaments, and it can be used for applications that could not be used in the past.

Example 1 80 parts by weight of L-lactide, 20 parts by weight of ε-caprolactone, 0.03 part by weight of tin octylate and 0.
In the presence of 01 parts by weight, a polymerization reaction was carried out at 180 ° C. for 5 hours under a reduced pressure of 10 ⁻³ mmHg to produce a copolymer of lactic acid and ε-caprolactone.

Next, the obtained copolymer was purified by a recrystallization method and then dissolved in chloroform to prepare a solution having a concentration of 20%. Then, it was cast on a glass plate to a thickness of 50 μm, immersed in ethyl alcohol and solidified to obtain a film.
The obtained film was supple and had high strength.

Example 2 90 parts by weight of L-lactide, 10 parts by weight of ε-caprolactone, 0.03 part by weight of tin octylate and 0.
Polymerization was carried out in the same manner as in Example 1 in the presence of 01 parts by weight,
A copolymer was obtained. Then, it was purified by a recrystallization method and then dissolved in chloroform to prepare a solution having a concentration of 15%, which was used as a spinning stock solution.

A stock solution for spinning prepared at 30 ° C. was continuously extruded through a spinneret into ethyl alcohol to produce a fiber, which was drawn and heat-treated to obtain a monofilament fiber having a thickness of about 0.2 mm. The obtained fiber was flexible and supple, and had a tensile strength of 1.5 kg / f or more, and was suitable as a monofilament suture.

〔The invention's effect〕

According to the present invention, a soft and flexible biodegradable and absorbable fiber or film can be obtained. Therefore, even if it comes into direct contact with the living body, it does not damage the living body and is suitable for medical use. In particular, a monofilament suture having excellent properties can be obtained.

Further, according to the method for molding a copolymer according to the present invention, since the copolymer is not exposed to a high temperature during molding, it is possible to obtain a molded product composed of a polymer having a high degree of polymerization without causing thermal deterioration. it can. Therefore, a molded product excellent in strength can be obtained. Since a lower alcohol solution is used as the coagulating liquid, hydrolysis is not promoted by the coagulating liquid, and decomposition and absorption do not occur rapidly when used in a living body. Furthermore, it is preferable to use ethyl alcohol as the coagulation liquid because it is completely safe for the living body even if the coagulation liquid remains in the molded product.

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Claims (3)

(57) [Claims] 1. A copolymer containing 95 to 65 mol% of lactic acid units and 5 to 35 mol% of ε-caprolactone units is dissolved in a solvent to prepare a polymer solution, which is then used as a lower alcohol solution. Lactic acid and ε characterized by contacting and solidifying
A method for producing a molded article for medical use, which comprises a copolymer with caprolactone. 2. The method according to claim 1, wherein the alcohol is ethyl alcohol. 3. The method according to claim 1, wherein the medical molded product is a monofilament suture.