JP2005065771A - Manufacturing method of bioabsorbable polymer - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide the manufacturing method of a bioabsorbable polymer for performing polymerization in practical time and suppressing a residual metal catalyst amount regarding the manufacturing method of the bioabsorbable polymer for performing the polymerization by using a metallic catalyst. <P>SOLUTION: After polymerizing the bioabsorbable polymer by using the metallic catalyst, it is dissolved in an acidic solvent or an alkaline solvent. Then, by adding a poor solvent for the bioabsorbable polymer to it, the bioabsorbable polymer is settled and refined, and the residual metallic catalyst amount is reduced. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a method for producing a bioabsorbable polymer used as a material such as a suture thread or an osteosynthesis material that is used by being embedded in a living body, and particularly suppresses the residual amount of a catalyst used for the polymerization. Regarding technology.

  In recent years, bioresorbable polymers are used for sutures, bone bonding materials, and the like that are used by being embedded in a living body in the medical field. This is because the bioabsorbable polymer is decomposed and absorbed in the living body after embedding, and therefore has the advantage of reducing the burden on the patient by reducing the number of re-operations such as thread removal.

  As such bioabsorbable polymers, diol / carboxylic acid resins such as polyvinyl alcohol and polybutylene succinate, and polyester resins such as polyglycolic acid, polylactic acid, polycaprolactone, and p-dioxanone are known. Yes.

  However, since such a bioabsorbable polymer is usually produced by adding a metal catalyst that is harmful to the living body during the polymerization, the bioabsorbable polymer can be embedded in the living body. It is desired to reduce the amount of metal catalyst.

  As a method for removing the catalyst from the polymer compound, a method of dissolving the polymer in an organic solvent and precipitating (reprecipitation method) is generally known, but the removal efficiency of the catalyst is low and it is not practical.

On the other hand, as a technique for suppressing the amount of residual catalyst, a polymerization method for suppressing the amount of catalyst used for polymerization has been proposed (see Patent Document 1). According to this method, since the amount of catalyst used is small, the bioabsorbability is high. The amount of residual catalyst in the molecule can be suppressed.
JP 2000-191753 A

  However, if the amount of the catalyst added is suppressed as in the above polymerization method, a very long polymerization time of 10 to 40 days is required, and it is considered impractical as an industrial production method.

  An object of this invention is to provide the manufacturing method of the bioabsorbable polymer which can be manufactured in practical manufacturing time and can suppress the amount of residual catalysts in view of the said subject.

  In order to solve the above problems, a method for producing a bioabsorbable polymer according to the present invention includes a polymerization step of polymerizing a bioabsorbable polymer using a metal catalyst, and an acidic solvent obtained by polymerizing the polymer polymerized in the polymerization step. Alternatively, a solution preparation step in which a polymer solution is prepared by dissolving in an alkaline solvent, and a bioabsorbable polymer in the solution is precipitated by adding a poor solvent for the bioabsorbable polymer to the solution prepared in the solution preparation step And a precipitation step for purification.

  By using an acidic solvent or an alkaline solvent instead of an organic solvent in the solution preparation step, a part of the molecular chain of the bioabsorbable polymer is broken in the prepared solution, compared to the case of using an organic solvent. It is believed that the catalyst will be able to diffuse into the solvent. Therefore, more catalyst is dispersed in the solution, and it is considered that the amount of residual catalyst is reduced in the bioabsorbable polymer by precipitation purification in the precipitation step.

  A specific acidic solvent is a solvent selected from the group consisting of hydrochloric acid and acetic acid, and a solvent selected from the group consisting of sodium hydroxide, ammonia and potassium hydroxide can be used as the alkaline solvent.

  Here, in the precipitation step, if the cyclodextrin that includes the metal catalyst is added before the poor solvent is added, the catalyst in the solution is included, so that the residual catalyst amount can be further reduced.

  Moreover, it is thought that the same effect can be acquired even if it adds the chelating agent coordinated to a metal catalyst instead of a cyclodextrin.

  As a specific composition of the bioabsorbable polymer, a lactic acid-ε-caprolactone copolymer can be used.

  In order to solve the above problems, a method for producing a bioabsorbable polymer according to the present invention comprises a polymerization step of polymerizing a bioabsorbable polymer using a metal catalyst, and a polymer polymerized in the polymerization step. Extract the metal catalyst by adding a poor solvent for the bioabsorbable polymer to the solvent contact process that changes the properties of the polymer by contacting with an acidic or alkaline solvent, and the polymer that has been contacted with the solvent in the solvent contact process. And an extraction step.

  Here, in the solvent contact step, by bringing the acidic solvent or alkaline solvent into contact, the polymer is partially decomposed or swelled, or the polymer is completely dissolved.

  According to the method for producing a bioabsorbable polymer as described above, the amount of the residual metal catalyst can be reduced to 60 ppm or less.

  As described above, according to the present invention, even when the bioabsorbable polymer is polymerized using the amount of catalyst normally used, the bioabsorbable polymer is dissolved in an acidic solvent or an alkaline solvent in the solution preparation process. Since the solution is prepared and the bioabsorbable polymer is purified from the solution in the precipitation step, polymerization can be performed in a practical production time, and the amount of residual catalyst in the bioabsorbable polymer is suppressed. be able to.

  In addition, according to the present invention, since there is a solvent contact step in which an acidic solvent or an alkaline solvent is contacted, the properties of the polymer can be changed, for example, by lowering the molecular weight of the polymer. As a result, the metal catalyst incorporated between the molecules becomes easy to be removed in the extraction process, so that the amount of the residual metal catalyst can be suppressed in the manufactured bioabsorbable polymer.

  According to such a method for producing a bioabsorbable polymer, the amount of residual metal catalyst can be reduced to 60 ppm or less.

  Hereinafter, an embodiment of a method for producing a bioabsorbable polymer according to the present invention will be described.

  Since the present invention does not unnecessarily increase the polymerization time as in the prior art, it is characterized in that the bioabsorbable polymer is polymerized with a generally used catalyst amount and a part of the catalyst is removed therefrom. doing. That is, since the present invention is polymerized without reducing the catalyst amount as in Patent Document 1, the polymerization time does not take long, and the amount of catalyst after polymerization is reduced, so that the residual catalyst amount can be suppressed. A bioabsorbable polymer can be produced within a practical time.

  In general, a bioabsorbable polymer is prepared by adding a monomer of the polymer to a gas-tight container and a catalyst of 100 to 500 ppm with respect to the monomer, and under reduced pressure at a temperature of 80 to 170 ° C. for 5 to 168 hours. It is obtained by performing bulk polymerization.

  Since the bioabsorbable polymer produced in this way still contains the catalyst, a process for removing it is added in the present embodiment.

  FIG. 1 is a diagram showing an outline of a method for producing a bioabsorbable polymer according to the present invention. Hereinafter, a description will be given with reference to FIG.

  As a method for removing the catalyst, first, a polymer 1 comprising the bioabsorbable polymer 11 obtained in the above-described polymerization process shown in FIG. A solution is prepared by dissolving in an acidic solvent 21 such as hydrochloric acid or acetic acid in the container 2 or a mixture thereof, or an alkaline solvent 21 such as sodium hydroxide, ammonia and potassium hydroxide, or a mixture thereof. Thereby, the catalyst 12 dispersed inside the polymer 1 can be dispersed in the solution. In particular, the use of the acidic solvent 21 or the alkaline solvent 21 is considered to increase the effect of dispersing the catalyst 12 compared to the case of using an organic solvent. This is not because the acidic solvent 21 or the alkaline solvent 21 partially cuts the molecules 11 of the bioabsorbable polymer so that the catalyst 12 trapped between the molecules can be dispersed in the solvent. It is thought.

  Next, the bioabsorbable polymer 4 is precipitated as shown in FIG. 1 (d) by adding a precipitant 31 such as ethanol or methanol which is a poor solvent to the bioabsorbable polymer. As a result, the bioabsorbable polymer 4 is precipitated and purified while a part of the catalyst 12 is dispersed in the solution. Therefore, the amount of catalyst contained in the precipitated bioabsorbable polymer 4 is reduced. Specifically, the amount can be reduced to about 60 ppm or less.

  According to the production method of the present invention, at the time of polymerization, the catalyst is removed from the bioabsorbable polymer in the subsequent solution preparation step and precipitation step without reducing the amount of the catalyst as in Patent Document 1 and contained catalyst. The amount can be reduced. Therefore, a bioabsorbable polymer with a short polymerization time and a small amount of catalyst can be produced, and a practical method for producing a bioabsorbable polymer can be provided.

  In the above embodiment, the bioabsorbable polymer is dissolved in an acidic solvent or an alkaline solvent and then precipitated. However, after the bioabsorbable polymer is dissolved, the catalyst is further deactivated. You may make it precipitate after adding a chelating agent.

  Since the catalyst dispersed in the solution forms a complex with the chelating agent by adding the chelating agent before the precipitation in this way, when the bioabsorbable polymer is precipitated, it becomes difficult for the catalyst to be taken into the inside. Conceivable.

  Such chelating agents include organic chelating agents and inorganic chelating agents.

  Examples of organic chelating agents include, but are not limited to, amino acids, phenols, hydroxycarboxylic acids, diketones, amines, oximes, phenanthrolines, pyridine compounds, dithio compounds, N-containing phenols as coordination atoms, coordination atoms N-containing carboxylic acids, diazo compounds, thiols, porphyrins and the like. They form a complex with the metal ion of the catalyst contained in the hydroxycarboxylic acid-based polyester composition and lose the catalytic activity.

  Examples of inorganic chelating agents include phosphoric acids such as phosphoric acid, phosphorous acid, pyrophosphoric acid, and polyphosphoric acid.

  Alternatively, cyclodextrin may be mixed in place of the chelating agent and the catalyst may be included to make it difficult for the catalyst to be taken inside when the bioabsorbable polymer is precipitated.

  In the above embodiment, the bioabsorbable polymer is dissolved in an acidic or alkaline solvent and then precipitated. However, as a method for reducing the amount of residual catalyst, a massive bioabsorbable polymer is used. The catalyst may be extracted by dropping the chelating agent as described above after increasing the area where the catalyst is exposed without being dissolved in an acidic or alkaline solution.

In the above embodiment, the bioabsorbable polymer is completely dissolved in an acidic or alkaline solvent, but the bioabsorbable polymer is modified by bringing the solvent into contact with the bioabsorbable polymer. Also good. The term “denaturation” as used herein refers to the case where the structure is changed, for example, by cutting the molecule of the bioabsorbable polymer to reduce the molecular weight, and the catalyst trapped between the molecules is extracted by the cleavage of the molecule. It will be easier. Therefore, it is not always necessary to completely dissolve the bioabsorbable polymer in the solvent, and even when the bioabsorbable polymer is swollen by contacting the solvent, the molecule is cut and the structure is changed. Therefore, it is considered that the catalyst is easily detached. Then, if an extraction process is provided and a metal catalyst is extracted using the poor solvent with respect to a bioabsorbable polymer, the amount of residual catalysts can be reduced.
[Example 1]

  168 g of L-lactide (manufactured by Pulac) and 132 g of ε-caprolactone (manufactured by Wako Pure Chemical Industries, Ltd.) are mixed in a 500 ml polymerization tube, and tin octylate (manufactured by Sigma) as a catalyst is used as the monomer. It added so that it might become 0.05 mass% with respect to it. Furthermore, lauryl alcohol (manufactured by Sigma-Aldrich Japan Co., Ltd.) was added so as to be 0.1% by mass with respect to the monomer.

  The polymerization tube to which these compounds were added was sealed under vacuum and immersed in an oil bath at 130 ° C. for polymerization for 16 hours.

  The polymer mass of the lactic acid-ε-caprolactone copolymer thus obtained was dissolved in acetic acid, and the copolymer was purified by mixing ethanol with the solution and precipitating.

  The polymerization average molecular weight of the obtained lactic acid-ε-caprolactone copolymer was 200000 as a result of measurement by GPC.

The amount of residual catalyst was 10 ppm as a result of measurement by high-frequency plasma emission spectrometry.
[Comparative Example 1]

  A lactic acid-ε-caprolactone copolymer having a polymerization average molecular weight of 200,000 was prepared using a method similar to the above polymerization method.

  The polymer polymer mass was dissolved in chloroform, which is an organic solvent, and then precipitated using ethanol.

The copolymer obtained was measured for the amount of residual catalyst by high-frequency plasma emission spectrometry as in Example 1. As a result, it was 446 ppm, and it was found that most of the added catalyst remained. That is, it was found that when the solvent for dissolving the polymer mass was an organic solvent, the amount of residual catalyst could not be reduced as in the present embodiment.
[Comparative Example 2]

  Except that tin octylate (manufactured by Sigma) as a catalyst was added to 0.005% by mass (addition of 1/10 of Example 1) with respect to the monomer, the same as Example 1 Polymerization was carried out by mixing the raw materials in a 500 mL polymerization tube.

  Here, as in Example 1, it was immersed in an oil bath at 130 ° C. and polymerized for 16 hours, but the viscosity of the liquid in the polymerization tube was not increased, and it was determined that the polymerization did not proceed. Polymerization was carried out for 13 days until the temperature increased.

  The copolymer thus obtained was dissolved in chloroform and then precipitated using ethanol to purify the copolymer.

  The result of measuring the weight average molecular weight of the copolymer was 360000, and the residual catalyst was 38 ppm. Thus, it can be seen that in Comparative Example 2, the amount of residual catalyst remained about four times that of Example 1 although the amount of catalyst used for polymerization was one tenth of Example 1.

(Comparison of mechanical properties)
The copolymer samples obtained in Example 1 and Comparative Example 2 were thermoformed into a film shape, and the mechanical properties (breaking strength, elastic modulus, breaking elongation, elastic modulus at 300% elongation) of the film were measured. . In addition, the dumbbell piece based on JIS3 was used for the test piece, and it measured based on the measuring method of JISK6301.

  Table 1 shows the measurement results.

この測定結果からも分かるように、実施例１は、比較例２に比べて重量平均分子量が小さいにも関らず略同程度かつ実用上十分な物性を有していることが分かった。

As can be seen from the measurement results, it was found that Example 1 had substantially the same and practically sufficient physical properties although the weight average molecular weight was smaller than that of Comparative Example 2.

  The method for producing a bioabsorbable polymer according to the present invention is particularly effective in the field of medical devices that require a small amount of residual catalyst.

It is the schematic which shows the manufacturing process of the bioabsorbable polymer which concerns on this invention.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Polymer 2 Container 11 Bioabsorbable polymer 12 Catalyst 21 Solvent 31 Precipitant

Claims (9)

A polymerization step of polymerizing the bioabsorbable polymer using a metal catalyst;
A solution preparation step of preparing a polymer solution by dissolving the polymerized polymer in the polymerization step in an acidic solvent or an alkaline solvent;
A bioresorbability comprising a precipitation step of precipitating and purifying the bioabsorbable polymer in the solution by adding a poor solvent for the bioabsorbable polymer to the solution prepared in the solution preparation step. Polymer production method.   The acidic solvent is a solvent selected from the group consisting of hydrochloric acid and acetic acid, and the alkaline solvent is a solvent selected from the group consisting of sodium hydroxide, ammonia and potassium hydroxide. 2. A method for producing a bioabsorbable polymer according to 1.   The method for producing a bioabsorbable polymer according to claim 1 or 2, wherein in the precipitation step, a cyclodextrin that includes a metal catalyst is added before the poor solvent is added.   The method for producing a bioabsorbable polymer according to claim 1 or 2, wherein a chelating agent that coordinates to the metal catalyst is added to the precipitation step before the poor solvent is added.   The method for producing a bioabsorbable polymer according to any one of claims 1 to 4, wherein the bioabsorbable polymer is a lactic acid-ε-caprolactone copolymer. A polymerization step of polymerizing the bioabsorbable polymer using a metal catalyst;
A solvent contacting step of changing the properties of the polymer by bringing the polymerized in the polymerization step into contact with an acidic solvent or an alkaline solvent;
A method for producing a bioabsorbable polymer, comprising: an extraction step of extracting a metal catalyst by adding a poor solvent for the bioabsorbable polymer to the polymer contacted with the solvent in the solvent contacting step.   The method for producing a bioabsorbable polymer according to claim 6, wherein, in the solvent contacting step, the polymer is partially decomposed or swollen by contacting the acidic solvent or the alkaline solvent.   The method for producing a bioabsorbable polymer according to claim 6, wherein, in the solvent contacting step, the polymer is completely dissolved by contacting the acidic solvent or the alkaline solvent. A bioabsorbable polymer produced by the method for producing a bioabsorbable polymer according to claim 1, wherein the amount of residual metal catalyst is 60 ppm or less.

Images