JPWO2019244875A1 - Lactic acid-glycolic acid copolymer and its production method - Google Patents
Lactic acid-glycolic acid copolymer and its production method Download PDFInfo
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- JPWO2019244875A1 JPWO2019244875A1 JP2020525741A JP2020525741A JPWO2019244875A1 JP WO2019244875 A1 JPWO2019244875 A1 JP WO2019244875A1 JP 2020525741 A JP2020525741 A JP 2020525741A JP 2020525741 A JP2020525741 A JP 2020525741A JP WO2019244875 A1 JPWO2019244875 A1 JP WO2019244875A1
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- Prior art keywords
- glycolic acid
- lactic acid
- acid copolymer
- glycolide
- copolymer according
- Prior art date
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- 229920001577 copolymer Polymers 0.000 title claims abstract description 80
- 238000004519 manufacturing process Methods 0.000 title claims description 15
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical group OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims abstract description 30
- 229910052751 metal Inorganic materials 0.000 claims abstract description 23
- 239000002184 metal Substances 0.000 claims abstract description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 105
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 69
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 claims description 52
- 238000006243 chemical reaction Methods 0.000 claims description 42
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 claims description 41
- 239000003054 catalyst Substances 0.000 claims description 22
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 19
- -1 N'-tert-butyl-N, N-dimethylform amidine diazabicycloundecene Chemical compound 0.000 claims description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- 150000001409 amidines Chemical class 0.000 claims description 10
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
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- 238000004581 coalescence Methods 0.000 claims 1
- KPADFPAILITQBG-UHFFFAOYSA-N non-4-ene Chemical compound CCCCC=CCCC KPADFPAILITQBG-UHFFFAOYSA-N 0.000 claims 1
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- 239000000243 solution Substances 0.000 description 69
- 229920000642 polymer Polymers 0.000 description 65
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
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- 238000000034 method Methods 0.000 description 31
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
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- 230000000052 comparative effect Effects 0.000 description 16
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 15
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- 239000000047 product Substances 0.000 description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 5
- 230000009477 glass transition Effects 0.000 description 5
- 239000004310 lactic acid Substances 0.000 description 5
- 235000014655 lactic acid Nutrition 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- XBBVURRQGJPTHH-UHFFFAOYSA-N 2-hydroxyacetic acid;2-hydroxypropanoic acid Chemical compound OCC(O)=O.CC(O)C(O)=O XBBVURRQGJPTHH-UHFFFAOYSA-N 0.000 description 4
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- 125000004432 carbon atom Chemical group C* 0.000 description 3
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
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- PHNRCFCIKPZSFS-UHFFFAOYSA-N n'-tert-butyl-n,n-dimethylmethanimidamide Chemical compound CN(C)C=NC(C)(C)C PHNRCFCIKPZSFS-UHFFFAOYSA-N 0.000 description 1
- RXOHFPCZGPKIRD-UHFFFAOYSA-N naphthalene-2,6-dicarboxylic acid Chemical compound C1=C(C(O)=O)C=CC2=CC(C(=O)O)=CC=C21 RXOHFPCZGPKIRD-UHFFFAOYSA-N 0.000 description 1
- SLCVBVWXLSEKPL-UHFFFAOYSA-N neopentyl glycol Chemical compound OCC(C)(C)CO SLCVBVWXLSEKPL-UHFFFAOYSA-N 0.000 description 1
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- 239000004745 nonwoven fabric Substances 0.000 description 1
- OEIJHBUUFURJLI-UHFFFAOYSA-N octane-1,8-diol Chemical compound OCCCCCCCCO OEIJHBUUFURJLI-UHFFFAOYSA-N 0.000 description 1
- XZZXKVYTWCYOQX-UHFFFAOYSA-J octanoate;tin(4+) Chemical compound [Sn+4].CCCCCCCC([O-])=O.CCCCCCCC([O-])=O.CCCCCCCC([O-])=O.CCCCCCCC([O-])=O XZZXKVYTWCYOQX-UHFFFAOYSA-J 0.000 description 1
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- 150000002989 phenols Chemical class 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000005015 poly(hydroxybutyrate) Substances 0.000 description 1
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- 229920001707 polybutylene terephthalate Polymers 0.000 description 1
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- 239000004632 polycaprolactone Substances 0.000 description 1
- 229920005668 polycarbonate resin Polymers 0.000 description 1
- 239000004431 polycarbonate resin Substances 0.000 description 1
- 238000006068 polycondensation reaction Methods 0.000 description 1
- 229920001225 polyester resin Polymers 0.000 description 1
- 239000004645 polyester resin Substances 0.000 description 1
- 229920006393 polyether sulfone Polymers 0.000 description 1
- 229920002523 polyethylene Glycol 1000 Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000139 polyethylene terephthalate Polymers 0.000 description 1
- 239000005020 polyethylene terephthalate Substances 0.000 description 1
- 239000002952 polymeric resin Substances 0.000 description 1
- 239000002685 polymerization catalyst Substances 0.000 description 1
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- 229920001155 polypropylene Polymers 0.000 description 1
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- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229960000380 propiolactone Drugs 0.000 description 1
- 229920005604 random copolymer Polymers 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
- C08G63/06—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids
- C08G63/08—Lactones or lactides
Abstract
本発明の乳酸−グリコール酸共重合体は、重量平均分子量が５０，０００〜３００，０００であり、金属成分を含まず、グリコール酸単位の平均連鎖長が４以下であり、有機溶媒への溶解性が高いことを特徴とする。The lactic acid-glycolic acid copolymer of the present invention has a weight average molecular weight of 50,000 to 300,000, does not contain a metal component, has an average chain length of glycolic acid unit of 4 or less, and is soluble in an organic solvent. It is characterized by high sex.
Description
本発明は、高分子量を有する乳酸−グリコール酸共重合体及びその製造方法に関するものである。 The present invention relates to a lactic acid-glycolic acid copolymer having a high molecular weight and a method for producing the same.
ポリ乳酸、ポリグリコール酸又はこれらの共重合体に代表される、ヒドロキシカルボン酸から製造される脂肪族ポリエステルは、生分解性の高分子として注目され、例えば、縫合糸等の医用材料、医薬、農薬、肥料等の徐放性材料等多方面に利用されている。 Aliphatic polyesters produced from hydroxycarboxylic acids, typified by polylactic acid, polyglycolic acid, or copolymers thereof, are attracting attention as biodegradable polymers, for example, medical materials such as sutures, pharmaceuticals, and the like. It is used in various fields such as sustained-release materials such as pesticides and fertilizers.
生体吸収性材料に用いることのできるポリヒドロキシカルボン酸の製造方法は既に幾例かが知られている。これらは一般的に、乳酸やグリコール酸等のヒドロキシカルボン酸を重縮合させる方法と、ラクチドやグリコリド等の環状エステルを開環重合させる方法とに分けられる。 Several methods are already known for producing polyhydroxycarboxylic acids that can be used as bioabsorbable materials. These are generally divided into a method of polycondensing a hydroxycarboxylic acid such as lactic acid and glycolic acid and a method of ring-opening polymerization of a cyclic ester such as lactide and glycolide.
重縮合による方法として、特許文献１には、ヒドロキシカルボン酸及びそのオリゴマ−からの直接脱水法によって、ポリヒドロキシカルボン酸を得る方法が開示されている。この方法は金属成分を使用しないが、直接脱水による重合法ではエステル化の際の生成水を系外へ速やかに除去することが高分子量ポリマーを得るために必要であり、そのため、高い減圧度でなおかつ１５０℃以上の高温の反応条件が必要となる。しかしながら、高温の条件では分解反応も促進されるため、高分子量のポリヒドロキシカルボン酸とするのに非常に長い処理時間を要し、実用的に有用な高分子量の製品を得ることが困難である。 As a method by polycondensation, Patent Document 1 discloses a method of obtaining a polyhydroxycarboxylic acid by a direct dehydration method from a hydroxycarboxylic acid and its oligomer. This method does not use metal components, but in the direct dehydration polymerization method, it is necessary to quickly remove the water produced during esterification to the outside of the system in order to obtain a high molecular weight polymer, and therefore, at a high degree of reduced pressure. Moreover, a high temperature reaction condition of 150 ° C. or higher is required. However, since the decomposition reaction is also promoted under high temperature conditions, it takes a very long treatment time to obtain a high molecular weight polyhydroxycarboxylic acid, and it is difficult to obtain a practically useful high molecular weight product. ..
また、特許文献２には、乳酸とグリコール酸の脱水縮合によって、乳酸−グリコール酸共重合体を得る方法が開示されているが、重量平均分子量は最大で３０，０００であるため、成形加工には不向きであり用途が限定される。 Further, Patent Document 2 discloses a method for obtaining a lactic acid-glycolic acid copolymer by dehydration condensation of lactic acid and glycolic acid, but since the weight average molecular weight is 30,000 at the maximum, it is suitable for molding. Is unsuitable and its use is limited.
一方、開環重合により生体吸収性材料に適したポリヒドロキシカルボン酸を得る方法としては、例えば無毒安定製剤としてアメリカ食品薬品局で認可されているオクチル酸スズを触媒とする方法が知られている（非特許文献１）。この方法は、高分子量のポリヒドロキシカルボン酸が比較的容易に得られるという長所があるが、触媒として特によく用いられているオクチル酸スズはその除去が困難であるため、最終的な製品に触媒は残存している。このような触媒の残存は、ポリヒドロキシカルボン酸の熱安定性に影響を及ぼす。 On the other hand, as a method for obtaining a polyhydroxycarboxylic acid suitable for a bioabsorbable material by ring-opening polymerization, for example, a method using tin octylate approved by the US Food and Drug Administration as a non-toxic stable preparation is known. (Non-Patent Document 1). This method has the advantage that a high molecular weight polyhydroxycarboxylic acid can be obtained relatively easily, but tin octylate, which is particularly often used as a catalyst, is difficult to remove, so that the catalyst is used in the final product. Remains. The residue of such a catalyst affects the thermal stability of the polyhydroxycarboxylic acid.
オクタン酸スズ等の金属触媒を用いずに環状エステルを開環重合させる方法として、アミジン系触媒を用いた手法が知られている（特許文献３）。この手法では、高分子量体のポリ乳酸やポリグリコール酸が得られることが開示されているが、乳酸−グリコール酸のランダム共重合体は開示されておらず、ＰＥＧ１０００によって機能化された乳酸−グリコール酸ジブロック共重合体が開示されているのみである。 As a method for ring-opening polymerization of a cyclic ester without using a metal catalyst such as tin octanate, a method using an amidine-based catalyst is known (Patent Document 3). It is disclosed that this method can obtain high molecular weight polylactic acid and polyglycolic acid, but does not disclose a random copolymer of lactic acid-glycolic acid, and lactic acid-glycol functionalized by PEG1000. Only acid diblock copolymers are disclosed.
本発明の目的は上記従来の問題を解消し、特定の条件により反応を制御することによって得られる、高分子量でありながら有機溶媒への溶解性が高い乳酸−グリコール酸共重合体を提供することにある。 An object of the present invention is to provide a lactic acid-glycolic acid copolymer having a high molecular weight and high solubility in an organic solvent, which is obtained by solving the above-mentioned conventional problems and controlling the reaction under specific conditions. It is in.
本発明者らは、鋭意研究を重ねた結果、乳酸−グリコール酸共重合体の反応において、ラクチドの重合反応を開始した直後からグリコリドを逐次添加することにより、グリコール酸単位の平均連鎖長が４以下になるよう反応制御することで、金属成分を含まない高分子量の乳酸−グリコール酸共重合体を得られることを見出し、本発明を完成するに至った。即ち、即ち、本発明は以下の発明を包含する。
［１］重量平均分子量が５０，０００〜３００，０００であり、金属成分を含まず、グリコール酸単位の平均連鎖長が４以下である、乳酸−グリコール酸共重合体。
［２］グリコール酸単位が、前記共重合体の繰り返し単位中の１〜５０ｍｏｌ％を占める、［１］に記載の乳酸−グリコール酸共重合体。
［３］前記重量平均分子量が７０，０００〜２５０，０００である、［２］に記載の乳酸−グリコール酸共重合体。
［４］前記重量平均分子量が１００，０００〜２５０，０００である、［３］に記載の乳酸−グリコール酸共重合体。
［５］グリコール酸単位が、前記共重合体の繰り返し単位中の１〜３５ｍｏｌ％を占める、［１］〜［４］のいずれかに記載の乳酸−グリコール酸共重合体。
［６］［１］〜［５］のいずれかに記載の乳酸−グリコール酸共重合体を含む樹脂組成物。
［７］［１］〜［５］のいずれかに記載の乳酸−グリコール酸共重合体、又は［６］に記載の樹脂組成物を含む成形品。
［８］［１］〜［５］のいずれかに記載の乳酸−グリコール酸共重合体、又は［６］に記載の樹脂組成物を含む医療材料。
［９］ラクチドを含む溶液に、アミジン系触媒及び重合開始剤を接触させて反応を開始する工程と、
反応開始直後から、グリコリドを含む溶液を反応溶液に逐次添加する工程とを含む、乳酸−グリコール酸共重合体の製造方法。
［１０］グリコリドを含む溶液を、反応開始直後から０．３〜１２ｇ／分で逐次添加する、［９］に記載の乳酸−グリコール酸共重合体の製造方法。
［１１］ラクチドを含む溶液の濃度が１０〜３５重量％であり、グリコリドを含む溶液の濃度が１５〜３５重量％である、［９］又は［１０］に記載の乳酸−グリコール酸共重合体の製造方法。
［１２］アミジン系触媒が、１，８−ジアザビシクロ［５，４，０］ウンデカ−７−エン、１，５−ジアザビシクロ［４，３，０］ノナ−５−エン、１,５,７−トリアザビシクロ[４,４,０]デカーエン又はＮ’−ｔｅｒｔ−ブチル−Ｎ，Ｎ−ジメチルホルムアミジンジアザビシクロウンデセンである、［９］〜［１１］のいずれかに記載の乳酸−グリコール酸共重合体の製造方法。
［１３］ラクチド又はグリコリドを含む溶液の溶媒が、ジクロロメタン、クロロホルム、ジクロロエタン、酢酸エチル、テトラヒドロフラン、アセトニトリル、Ｎ−メチルピロリドン、Ｎ，Ｎ’−ジメチルホルムアミド及びジメチルスルホキシドからなる群より選択される１種又はそれらの組み合わせである、［９］〜［１２］のいずれかに記載の乳酸−グリコール酸共重合体の製造方法。As a result of intensive studies, the present inventors have obtained an average chain length of 4 glycolic acid units by sequentially adding glycolide immediately after the start of the polymerization reaction of lactide in the reaction of the lactic acid-glycolic acid copolymer. We have found that a high-molecular-weight lactic acid-glycolic acid copolymer containing no metal component can be obtained by controlling the reaction as follows, and have completed the present invention. That is, the present invention includes the following inventions.
[1] A lactic acid-glycolic acid copolymer having a weight average molecular weight of 50,000 to 300,000, no metal component, and an average chain length of 4 or less in glycolic acid units.
[2] The lactic acid-glycolic acid copolymer according to [1], wherein the glycolic acid unit accounts for 1 to 50 mol% of the repeating unit of the copolymer.
[3] The lactic acid-glycolic acid copolymer according to [2], wherein the weight average molecular weight is 70,000 to 250,000.
[4] The lactic acid-glycolic acid copolymer according to [3], wherein the weight average molecular weight is 100,000 to 250,000.
[5] The lactic acid-glycolic acid copolymer according to any one of [1] to [4], wherein the glycolic acid unit accounts for 1 to 35 mol% of the repeating unit of the copolymer.
[6] A resin composition containing the lactic acid-glycolic acid copolymer according to any one of [1] to [5].
[7] A molded product containing the lactic acid-glycolic acid copolymer according to any one of [1] to [5] or the resin composition according to [6].
[8] A medical material containing the lactic acid-glycolic acid copolymer according to any one of [1] to [5] or the resin composition according to [6].
[9] A step of contacting a solution containing lactide with an amidine-based catalyst and a polymerization initiator to initiate a reaction, and
A method for producing a lactic acid-glycolic acid copolymer, which comprises a step of sequentially adding a solution containing glycolide to the reaction solution immediately after the start of the reaction.
[10] The method for producing a lactic acid-glycolic acid copolymer according to [9], wherein a solution containing glycolide is sequentially added at 0.3 to 12 g / min immediately after the start of the reaction.
[11] The lactic acid-glycolic acid copolymer according to [9] or [10], wherein the concentration of the solution containing lactide is 10 to 35% by weight, and the concentration of the solution containing glycolide is 15 to 35% by weight. Manufacturing method.
[12] Amidine-based catalysts are 1,8-diazabicyclo [5,4,0] undec-7-ene and 1,5-diazabicyclo [4,3,0] nona-5-ene, 1,5,7-. The lactate-glycol according to any one of [9] to [11], which is triazabicyclo [4,4,0] decaene or N'-tert-butyl-N, N-dimethylform amidinediazabicycloundecene. A method for producing an acid copolymer.
[13] One selected from the group consisting of dichloromethane, chloroform, dichloroethane, ethyl acetate, tetrahydrofuran, acetonitrile, N-methylpyrrolidone, N, N'-dimethylformamide and dimethyl sulfoxide as the solvent for the solution containing lactide or glycolide. The method for producing a lactic acid-glycolic acid copolymer according to any one of [9] to [12], which is a combination thereof.
一般的に、乳酸−グリコール酸共重合反応は、グリコリドやグリコール酸ポリマーが有機溶媒に対して溶解性が低く、また、ラクチドとグリコリドの開環重合速度が異なるため反応制御が難しい。本発明によれば、特定の条件下で反応を行うことで、ポリマーが析出することなく、重合反応が溶液中で均一に進行するため、高分子量であるにも関わらず有機溶媒への溶解性が高い乳酸−グリコール酸共重合体を得ることができる。そのため、成形品等への加工にも適している。 In general, in the lactic acid-glycolic acid copolymerization reaction, it is difficult to control the reaction because glycolide or glycolic acid polymer has low solubility in an organic solvent and the ring-opening polymerization rates of lactide and glycolide are different. According to the present invention, by carrying out the reaction under specific conditions, the polymerization reaction proceeds uniformly in the solution without precipitating the polymer, so that the solubility in an organic solvent is high despite the high molecular weight. A lactic acid-glycolic acid copolymer having a high content can be obtained. Therefore, it is also suitable for processing into molded products and the like.
以下、本発明を詳細に説明する。
[乳酸−グリコール酸共重合体]
本発明の乳酸−グリコール酸共重合体（以下「本発明の共重合体」とも称す）は乳酸単位とグリコール酸単位とからなり、乳酸単位とは、Ｌ−乳酸及び／又はＤ−乳酸を主成分とする重合体である。乳酸単位を構成する原料として用いられるラクチドの光学純度は、特に限定されるものではなく、Ｌーラクチド単体もしくはＤ−ラクチド単体又はそれらの混合物でもよい。Hereinafter, the present invention will be described in detail.
[Lactic acid-glycolic acid copolymer]
The lactic acid-glycolic acid copolymer of the present invention (hereinafter, also referred to as "copolymer of the present invention") is composed of a lactic acid unit and a glycolic acid unit, and the lactic acid unit is mainly L-lactic acid and / or D-lactic acid. It is a polymer as a component. The optical purity of lactide used as a raw material constituting the lactic acid unit is not particularly limited, and may be L-lactide alone, D-lactide alone, or a mixture thereof.
本発明の共重体は、後述するように有機触媒であり除去可能なアミジン系触媒を用いて製造されるため、触媒由来の金属成分を含まないという特徴がある。金属成分は、ポリマー樹脂の変色や安定性、生体中での安全性の点で含まない方がよく、この点から、本発明の共重合体は、医療材料に好適に適用することができる。本発明において「金属成分を含まず」又は「金属成分を含まない」とは、金属触媒由来の金属原子を含まないことを意味する。具体的には、ＩＣＰ発光分析法、原子吸光分析法あるいは比色法等の公知の分析手法で、ポリマー中の金属原子の検出を試みた場合に、検出限界以下であるときに金属触媒由来の金属原子を含まないと言える。金属触媒由来の金属原子としては、スズ、アルミ、チタン、ジルコニウム、アンチモン等が挙げられる。 Since the copolymer of the present invention is produced by using an amidine-based catalyst which is an organic catalyst and can be removed as described later, it is characterized in that it does not contain a metal component derived from the catalyst. The metal component should not be contained in terms of discoloration and stability of the polymer resin and safety in a living body, and from this point of view, the copolymer of the present invention can be suitably applied to medical materials. In the present invention, "without metal component" or "without metal component" means that the metal atom derived from the metal catalyst is not contained. Specifically, when an attempt is made to detect a metal atom in a polymer by a known analytical method such as ICP emission spectrometry, atomic absorption spectrometry, or colorimetric analysis, the metal catalyst is derived when it is below the detection limit. It can be said that it does not contain metal atoms. Examples of the metal atom derived from the metal catalyst include tin, aluminum, titanium, zirconium, antimony and the like.
本発明の共重合体において、重量平均分子量は所望される物性や用途に応じて選択すればよく、下限としては、５０，０００以上、６０，０００以上、７０，０００以上、８０，０００以上、９０，０００以上、１００，０００以上、１１０，０００以上又は１２０，０００以上を採用することができる。上限としては、３００，０００以下、２５０，０００以下、２００，０００以下、１８０，０００以下又は１６０，０００以下を採用することができる。機械物性や耐加水分解性の観点からは、１０万以上の範囲であると加工用途が広がる。なお、重量平均分子量とは、溶媒としてクロロホルムを用いたゲルパーミエーションクロマトグラフィー（ＧＰＣ）測定による標準ポリスチレン換算の重量平均分子量の値である。 In the copolymer of the present invention, the weight average molecular weight may be selected according to desired physical properties and applications, and the lower limit is 50,000 or more, 60,000 or more, 70,000 or more, 80,000 or more. 90,000 or more, 100,000 or more, 110,000 or more or 120,000 or more can be adopted. As the upper limit, 300,000 or less, 250,000 or less, 200,000 or less, 180,000 or less, or 160,000 or less can be adopted. From the viewpoint of mechanical properties and hydrolysis resistance, processing applications will expand if the range is 100,000 or more. The weight average molecular weight is a value of the weight average molecular weight in terms of standard polystyrene measured by gel permeation chromatography (GPC) using chloroform as a solvent.
本発明の共重合体は、グリコール酸単位の平均連鎖長が４以下であることが重要であり、４を超えると反応が均一に進行しないため高分子量の重合体が得られなくなる。より好ましい平均連鎖長は３．５以下である。下限は特に限定されないが、通常１以上であり、反応制御の点からは２以上であってもよい。 In the copolymer of the present invention, it is important that the average chain length of the glycolic acid unit is 4 or less, and if it exceeds 4, the reaction does not proceed uniformly, so that a high molecular weight polymer cannot be obtained. A more preferable average chain length is 3.5 or less. The lower limit is not particularly limited, but is usually 1 or more, and may be 2 or more from the viewpoint of reaction control.
本発明の共重合体は、機械物性に優れるという点で、分子量分布が１以上４以下であることが好ましく、ポリマー物性が均一となる点からは、１以上３以下がより好ましい。分子量分布が４を超える場合、ポリマー物性にばらつきが生じるため好ましくない。分子量分布が１未満である場合、溶融粘度が低く、成形加工性に劣るため好ましくない。なお、分子量分布とは、溶媒としてクロロホルムを用いたゲルパーミエーションクロマトグラフィー（ＧＰＣ）測定による標準ポリスチレン換算の数平均分子量に対する重量平均分子量の比である。 The copolymer of the present invention preferably has a molecular weight distribution of 1 or more and 4 or less in terms of excellent mechanical properties, and more preferably 1 or more and 3 or less in terms of uniform polymer physical properties. If the molecular weight distribution exceeds 4, it is not preferable because the physical properties of the polymer vary. When the molecular weight distribution is less than 1, the melt viscosity is low and the molding processability is inferior, which is not preferable. The molecular weight distribution is the ratio of the weight average molecular weight to the number average molecular weight in terms of standard polystyrene measured by gel permeation chromatography (GPC) using chloroform as a solvent.
本発明の共重合体は、乳酸単位（ｘ）とグリコール酸単位（ｙ）の構成比がｘ／ｙ＝９９／１〜１／９９（モル比）である。高分子量及び溶解性に優れる共重合体を効率的に得ることができるという点で、グリコール酸単位が、共重合体の繰り返し単位中で１〜５０モル％含むことが好ましく、より好ましくは１〜４０モル％含み、更に好ましくは１〜３５モル％含む。 In the copolymer of the present invention, the composition ratio of the lactic acid unit (x) and the glycolic acid unit (y) is x / y = 99/1 to 1/99 (molar ratio). The glycolic acid unit is preferably contained in an amount of 1 to 50 mol%, more preferably 1 to 50 mol% in the repeating unit of the copolymer, in that a copolymer having an excellent high molecular weight and excellent solubility can be efficiently obtained. It contains 40 mol%, more preferably 1 to 35 mol%.
本発明の共重合体は、より均一な特性が得られる点から、ランダム構造を有することが好ましい。ブロック共重合体である場合、グリコール酸単位の特性が溶解性に影響するため好ましくない。 The copolymer of the present invention preferably has a random structure from the viewpoint of obtaining more uniform characteristics. When it is a block copolymer, it is not preferable because the properties of the glycolic acid unit affect the solubility.
本発明の共重合体において、ガラス転移温度は４０〜６５℃であることが好ましい。６５℃以上の場合、乳酸−グリコール酸共重合体のポリ乳酸セグメントが大きく、溶解性の点で好ましくない。なお、ガラス転移温度とは、Ｔ・Ａ・インスツルメント社製示差走査型熱量計（Ｑ２０）により試料１０ｍｇを窒素雰囲気下中、３０℃から速度２０℃／分で２５０℃まで昇温、２５０℃で３分間保持、２５０℃から速度２０℃／分で３０℃まで降温、３０℃で１分間保持した後、３０℃から速度２０℃／分で２５０℃まで昇温することによって測定される温度である。 In the copolymer of the present invention, the glass transition temperature is preferably 40 to 65 ° C. When the temperature is 65 ° C. or higher, the polylactic acid segment of the lactic acid-glycolic acid copolymer is large, which is not preferable in terms of solubility. The glass transition temperature is defined as the temperature of 10 mg of a sample from 30 ° C. to 250 ° C. at a rate of 20 ° C./min in a nitrogen atmosphere using a differential scanning calorimeter (Q20) manufactured by TA Instruments. Temperature measured by holding at ° C for 3 minutes, lowering the temperature from 250 ° C to 30 ° C at a rate of 20 ° C / min, holding at 30 ° C for 1 minute, and then raising the temperature from 30 ° C to 250 ° C at a rate of 20 ° C / min. Is.
本発明において、乳酸−グリコール酸共重合体の性能を損なわない範囲で、他の共重合成分単位を含んでいてもよく、例えば、多価カルボン酸、多価アルコール、ヒドロキシカルボン酸、ラクトン等が挙げられ、具体的には、コハク酸、アジピン酸、セバシン酸、フマル酸、テレフタル酸、イソフタル酸、２，６−ナフタレンジカルボン酸、５−ナトリウムスルホイソフタル酸、５−テトラブチルホスホニウムスルホイソフタル酸等の多価カルボン酸類又はそれらの誘導体、エチレングリコール、プロピレングリコール、ブタンジオール、ヘキサンジオール、オクタンジオール、ネオペンチルグリコール、グリセリン、トリメチロールプロパン、ペンタエリスリトール、トリメチロールプロパン又はペンタエリスリトールにエチレンオキシド又はプロピレンオキシドを付加した多価アルコール、ビスフェノールにエチレンオキシドを付加反応させた芳香族多価アルコール、ジエチレングリコール、トリエチレングリコール、ポリエチレングリコール、ポリプロピレングリコール等の多価アルコール類又はそれらの誘導体、グリコール酸、３−ヒドロキシ酪酸、４−ヒドロキシ酪酸、４−ヒドロキシ吉草酸、６−ヒドロキシカプロン酸等のヒドロキシカルボン酸類、及びグリコリド、ε−カプロラクトングリコリド、ε−カプロラクトン、β−プロピオラクトン、δ−ブチロラクトン、β−又はγ−ブチロラクトン、δ−バレロラクトン等のラクトン類等が挙げられる。 In the present invention, other copolymerization component units may be contained as long as the performance of the lactic acid-glycolic acid copolymer is not impaired, and for example, polyvalent carboxylic acid, polyhydric alcohol, hydroxycarboxylic acid, lactone and the like may be contained. Specific examples thereof include succinic acid, adipic acid, sebacic acid, fumaric acid, terephthalic acid, isophthalic acid, 2,6-naphthalenedicarboxylic acid, 5-sodium sulfoisophthalic acid, 5-tetrabutylphosphonium sulfoisophthalic acid and the like. Polyvalent carboxylic acids or derivatives thereof, ethylene glycol, propylene glycol, butanediol, hexanediol, octanediol, neopentyl glycol, glycerin, trimethylolpropane, pentaerythritol, trimethylolpropane or pentaerythritol with ethylene oxide or propylene oxide. Additive polyhydric alcohol, aromatic polyhydric alcohol obtained by addition reaction of ethylene oxide to bisphenol, polyhydric alcohols such as diethylene glycol, triethylene glycol, polyethylene glycol, polypropylene glycol or derivatives thereof, glycolic acid, 3-hydroxybutyric acid, Hydroxycarboxylic acids such as 4-hydroxybutyric acid, 4-hydroxyvaleric acid, 6-hydroxycaproic acid, and glycolide, ε-caprolactone glycolide, ε-caprolactone, β-propiolactone, δ-butyrolactone, β- or γ-butyrolactone. , Lactones such as δ-valerolactone and the like.
本発明の共重合体は、目的に応じてその他の物質を加えた組成物として用いることもできる。その他の物質としては、例えば樹脂（ポリマー）としては、ポリ乳酸、ポリグリコール酸、ポリカプロラクトン、乳酸とカプロラクトンの共重合体、ポリヒドロキシ酪酸、ポリヒドロキシブチレイト吉草酸、ポリリンゴ酸、ポリ−α−アミノ酸、ポリオルソエステル、セルロース、コラーゲン、ラミニン、ヘパラン硫酸、フィブロネクチン、ビトロネクチン、コンドロイチン硫酸、ヒアルロン酸、桂皮酸、桂皮酸誘導体等の生分解性樹脂、ポリエチレンテレフタレート、ポリブチレンテレフタレート、ポリ（エチレン−２，６−ナフタレート）等のポリエステル樹脂、ポリカーボネート樹脂、ポリメチルメタクリレート等のアクリル樹脂、ポリスチレン樹脂、ポリプロピレン樹脂、ポリアリレート樹脂、ポリエーテルスルホン樹脂、ＡＢＳ樹脂が挙げられ、その他、金属や金属塩等の無機化合物、酸化防止剤やその他の添加剤、有機溶媒等が挙げられる。 The copolymer of the present invention can also be used as a composition to which other substances are added depending on the intended purpose. Other substances include, for example, as a resin (polymer), polylactic acid, polyglycolic acid, polycaprolactone, copolymer of lactic acid and caprolactone, polyhydroxybutyric acid, polyhydroxybutyrate valeric acid, polyapple acid, poly-α-. Biodegradable resins such as amino acids, polyorthoesters, cellulose, collagen, laminin, heparan sulfate, fibronectin, vitronectin, chondroitin sulfate, hyaluronic acid, cinnamic acid, cinnamon acid derivatives, polyethylene terephthalate, polybutylene terephthalate, poly (ethylene-2) , 6-Naphthalate) and other polyester resins, polycarbonate resins, polymethylmethacrylate and other acrylic resins, polystyrene resins, polypropylene resins, polyarylate resins, polyether sulfone resins, ABS resins, and other metals and metal salts. Examples thereof include inorganic compounds, antioxidants and other additives, and organic solvents.
本発明の共重合体は高分子量であるため、様々に成形加工することができ、フィルム状、シート状、繊維状、テープ状、板状等の任意の形状に加工することができる。具体的な態様としては、不織布や織編物、フィルム、パッキング、ケース、ボトル、ディスポーザブル包装用材料等の日用品、地表被覆用フィルム、肥料用袋、徐放性農薬材料等の農林業材料、漁網、釣り糸等の漁業用材料、レジャーバッグ、釣り用品包装材料等のレジャー用品及びドラッグデリバリーシステム材料、医療材料等が挙げられる。これらのうち、本発明の共重合体は、金属成分を含まないため、特に医療材料に適している。医療材料としては、ステント、プラグ、ネジ又はピン等の体内埋込用（インプラント）基材、糸、クリップ、ステープル又は外科用ガーゼ等の外科用縫合基材、接合材や組織置換材料（骨接合剤、歯周病手術時等の組織再生材料）等が挙げられる。
[製造方法]
本発明の共重合体は、予めラクチドとグリコリドとを含む溶液を準備した後に反応を開始する方法でも製造できるが、ラクチドを含む溶液に触媒及び重合開始剤を添加して反応を開始した後に、グリコリドを逐次的に添加して重合することがより好ましい。後者の方法（以下「逐次添加」又は「逐次添加方法」とも称す）では、ポリマーが析出せずに均一に反応を進めることができ、また、所望する共重合体の乳酸及びグリコール酸のポリマー組成が、反応前に仕込んだラクチド及びグリコール酸の割合と大きく相違しないように製造することができるため優れている。Since the copolymer of the present invention has a high molecular weight, it can be molded in various ways, and can be processed into any shape such as a film shape, a sheet shape, a fibrous shape, a tape shape, and a plate shape. Specific embodiments include daily necessities such as non-woven fabrics, woven and knitted fabrics, films, packings, cases, bottles, and disposable packaging materials, surface coating films, fertilizer bags, agricultural and forestry materials such as sustained-release pesticide materials, and fishing nets. Examples thereof include fishery materials such as fishing threads, leisure bags, leisure products such as packaging materials for fishing products, drug delivery system materials, medical materials, and the like. Of these, the copolymer of the present invention does not contain a metal component, and is therefore particularly suitable for medical materials. Medical materials include implant base materials such as stents, plugs, screws or pins, surgical suture base materials such as threads, clips, staples or surgical gauze, and bonding materials and tissue replacement materials (osteobonding). Agents, tissue regeneration materials for periodontal disease surgery, etc.) and the like.
[Production method]
The copolymer of the present invention can also be produced by a method of initiating the reaction after preparing a solution containing lactide and glycolide in advance, but after initiating the reaction by adding a catalyst and a polymerization initiator to the solution containing lactide. It is more preferable to add glycolide sequentially to polymerize. In the latter method (hereinafter, also referred to as "sequential addition method" or "sequential addition method"), the reaction can proceed uniformly without precipitating the polymer, and the polymer composition of the desired copolymer of lactic acid and glycolic acid. However, it is excellent because it can be produced so as not to be significantly different from the ratio of lactide and glycolic acid charged before the reaction.
本発明において、ラクチドを出発原料とし、既知の重合触媒を用いる開環重合法では、原料であるラクチドは、特に純度など限定されることなく、工業的に入手できるものを使用する。純度は高いほうが好ましいが、若干の不純物が含まれているのが通常であり、これらが含まれていてもかまわない。 In the present invention, in the ring-opening polymerization method using lactide as a starting material and a known polymerization catalyst, the raw material lactide is not particularly limited in purity and is industrially available. Higher purity is preferable, but it usually contains some impurities, and these may be contained.
開環重合法としては、ポリ乳酸を製造するための従来公知の製造装置を用いればよく、例えば撹拌翼を備え、内部を不活性ガス雰囲気に置換することが出来る縦型反応容器を使用することができる。開環重合には、触媒としてアミジン系化合物と、重合開始剤としてヒドロキシ系化合物と、ラクチドやグリコリド等のモノマーとを溶解することが可能な有機溶媒が使用される。かかる有機溶媒に例としてはジクロロメタン、クロロホルム、ジクロロエタンのようなハロゲン化炭化水素、酢酸エチル、テトラヒドロフラン、アセトニトリル、Ｎ−メチルピロリドン、Ｎ，Ｎ’−ジメチルホルムアミド、ジメチルスルホキシドのような非プロトン性極性溶媒が好適に使用されるが、後処理の簡便性を考慮した場合ジクロロメタン、ジクロロエタンが最も好ましい。有機溶媒は脱水することで、重合反応がより進み、高分子量の共重合体が得られることから好ましい。有機溶媒の添加量はラクチド等の反応基質を完全に溶解させることができる量であれば良く、通常、ラクチドの重量に対して１倍〜１０倍が好ましい。 As the ring-opening polymerization method, a conventionally known production apparatus for producing polylactic acid may be used. For example, a vertical reaction vessel equipped with a stirring blade and capable of replacing the inside with an inert gas atmosphere may be used. Can be done. For ring-opening polymerization, an organic solvent capable of dissolving an amidine compound as a catalyst, a hydroxy compound as a polymerization initiator, and a monomer such as lactide or glycolide is used. Examples of such organic solvents include halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane, ethyl acetate, tetrahydrofuran, acetonitrile, N-methylpyrrolidone, N, N'-dimethylformamide and aprotic polar solvents such as dimethyl sulfoxide. Is preferably used, but dichloromethane and dichloroethane are most preferable in consideration of the convenience of post-treatment. Dehydration of the organic solvent is preferable because the polymerization reaction proceeds further and a high molecular weight copolymer can be obtained. The amount of the organic solvent added may be any amount as long as it can completely dissolve the reaction substrate such as lactide, and is usually preferably 1 to 10 times the weight of lactide.
開環重合温度に制限はないが、好ましくは０℃以上１５０℃未満、更に好ましくは２５℃以上１２０℃未満である。０℃未満で重合を行った場合は重合速度が極端に遅くなり、１５０℃以上で重合を行った場合にはアミジン系化合物自身が分解し、効率的な重合が進行しない。重合雰囲気は、高分子量のポリ乳酸組成物を得ようとする場合、水分が開始剤とならないよう、良く乾燥させた窒素やアルゴンの様な不活性ガス雰囲気下で行うことが好ましい。 The ring-opening polymerization temperature is not limited, but is preferably 0 ° C. or higher and lower than 150 ° C., and more preferably 25 ° C. or higher and lower than 120 ° C. When the polymerization is carried out at a temperature lower than 0 ° C., the polymerization rate becomes extremely slow, and when the polymerization is carried out at a temperature of 150 ° C. or higher, the amidine-based compound itself is decomposed and efficient polymerization does not proceed. When a high molecular weight polylactic acid composition is to be obtained, the polymerization atmosphere is preferably carried out in a well-dried inert gas atmosphere such as nitrogen or argon so that water does not act as an initiator.
アミジン系触媒としては、１，８−ジアザビシクロ［５，４，０］ウンデカ−７−エン（ジアザビシクロウンデセン）（以下、ＤＢＵ（登録商標）と略記することがある。）、１，５−ジアザビシクロ［４，３，０］ノナ−５−エン（ジアザビシクロノネン）（ＤＢＮ）、１,５,７−トリアザビシクロ[４,４,０]デカーエン、Ｎ’−ｔｅｒｔ−ブチル−Ｎ，Ｎ−ジメチルホルムアミジン等が例示でき、重合終了後の減圧操作で容易に除去されるためには、その沸点が１３３．３２Ｐａ（１．０ｍｍＨｇ）において１５０℃未満、更に好ましくは１００℃未満であることが好ましい。 Examples of the amidine-based catalyst include 1,8-diazabicyclo [5,4,0] undec-7-ene (diazabicycloundecene) (hereinafter, may be abbreviated as DBU®), 1,5. -Diazabicyclo [4,3,0] nona-5-ene (diazabicyclononen) (DBN), 1,5,7-triazabicyclo [4,4,0] decaene, N'-tert-butyl-N , N-dimethylformamidine and the like can be exemplified, and in order to be easily removed by a reduced pressure operation after the completion of polymerization, the boiling point is less than 150 ° C., more preferably less than 100 ° C. at 133.32 Pa (1.0 mmHg). It is preferable to have.
アミジン系触媒の添加量としては、ヒドロキシ系化合物に対するモル比で１〜１０、好ましくは２〜５である。添加量を上記範囲外にした場合、重合時間が長期化するか、低分子量化の原因になる。 The amount of the amidine-based catalyst added is 1 to 10, preferably 2 to 5, in terms of molar ratio to the hydroxy-based compound. If the addition amount is out of the above range, the polymerization time will be prolonged or the molecular weight will be reduced.
ヒドロキシ系化合物としては、通常、脂肪族一級アルコール又はフェノール系化合物が採用され、具体的には、炭素数１〜２０の脂肪族一級アルコール、炭素数２〜２０の脂肪族一級ジオール、フェノール、ｐ−クレゾール、ｐ−ｔｅｒｔ−ブチルフェノール、ヒドロキノン等が好ましい。立体障害や水酸基の酸性度を考慮すると、上記例中のなかでも炭素数１〜２０の脂肪族一級アルコール、フェノールが好ましい。 As the hydroxy compound, an aliphatic primary alcohol or a phenol compound is usually adopted, and specifically, an aliphatic primary alcohol having 1 to 20 carbon atoms, an aliphatic primary diol having 2 to 20 carbon atoms, a phenol, p. -Cresol, p-tert-butylphenol, hydroquinone and the like are preferred. Considering steric hindrance and acidity of hydroxyl groups, aliphatic primary alcohols and phenols having 1 to 20 carbon atoms are preferable among the above examples.
ヒドロキシ系化合物の添加量としては、ラクチドに対するモル比で５×１０−４〜０．０１、好ましくは７×１０−４〜０．００１である。添加量を上記範囲外にした場合、最終的に得られる共重合体の収率が低下するか、或いは得られる共重合体の分子量が低下する。The amount of the hydroxy compound added is 5 × 10 -4 to 0.01, preferably 7 × 10 -4 to 0.001, in terms of molar ratio to lactide. When the addition amount is out of the above range, the yield of the finally obtained copolymer is lowered, or the molecular weight of the obtained copolymer is lowered.
反応時間としては、１５分間〜３時間、好ましくは３０分〜２時間である。 The reaction time is 15 minutes to 3 hours, preferably 30 minutes to 2 hours.
添加の雰囲気は特に限定しないが、好ましくは窒素やアルゴンのような不活性ガス気流下で行う。 The atmosphere of addition is not particularly limited, but is preferably carried out under an inert gas stream such as nitrogen or argon.
このような方法を採ることによって、ポリ乳酸セグメントとポリグリコール酸セグメントがランダム構造に近い構造を採る、乳酸−グリコール酸共重合体が得られる。
［逐次添加方法］
本発明において、逐次添加により乳酸−グリコール酸共重合体を製造する方法は、（１）ラクチドを含む溶液に、アミジン系触媒及び重合開始剤を含む溶液を接触させて反応を開始する工程と、（２）反応開始直後から、ラクチド及びアミジン系触媒を含む溶液に、グリコリドを含む溶液を逐次添加する工程とを含む。By adopting such a method, a lactic acid-glycolic acid copolymer in which the polylactic acid segment and the polyglycolic acid segment have a structure close to a random structure can be obtained.
[Sequential addition method]
In the present invention, the method for producing a lactic acid-glycolic acid copolymer by sequential addition includes (1) a step of contacting a solution containing lactide with a solution containing an amidin-based catalyst and a polymerization initiator to initiate a reaction. (2) Immediately after the start of the reaction, the step of sequentially adding the solution containing glycolide to the solution containing lactide and the amidin-based catalyst is included.
本発明において「反応開始直後」とは、ラクチドを含む溶液にアミジン系触媒及び重合開始剤を含む溶液を接触させた直後、ハンドリングにもよるが約１〜３秒後程度の時間を意味する。「逐次添加」とは、グリコリドを含む溶液を一定量ずつ滴下することを意味し、滴下に際しては、通常の微量滴下ポンプ等を使用すればよい。 In the present invention, "immediately after the start of the reaction" means a time of about 1 to 3 seconds immediately after the solution containing the lactide is brought into contact with the solution containing the amidine catalyst and the polymerization initiator, although it depends on the handling. "Sequential addition" means dropping a solution containing glycolide in a fixed amount at a time, and a normal microdrop pump or the like may be used for dropping.
グリコリドの添加方法としては、紛体、溶液、懸濁が好ましい。反応性や撹拌効率を考慮すると、有機溶媒に溶解した状態による添加が最も好ましい。 As a method for adding glycolide, a powder, a solution, or a suspension is preferable. Considering the reactivity and stirring efficiency, it is most preferable to add the mixture in a state of being dissolved in an organic solvent.
ラクチドを含む溶液のラクチド濃度は、通常１０〜３５重量％であり、好ましくは１５〜３０重量％である。グリコリドを含む溶液は、通常１０〜３５重量％であり、好ましくは１５〜３０重量％である。反応が均一に進む範囲内で、モノマーの濃度を上げることで、より高分子量の共重合体が得られる。 The lactide concentration of the solution containing lactide is usually 10 to 35% by weight, preferably 15 to 30% by weight. The solution containing glycolide is usually 10 to 35% by weight, preferably 15 to 30% by weight. By increasing the concentration of the monomer within the range in which the reaction proceeds uniformly, a copolymer having a higher molecular weight can be obtained.
グリコリドを含む溶液を逐次添加する際の添加速度は、反応溶媒にもよるが、通常０．０５〜１６ｇ／分であり、好ましくは０．３〜１２ｇ／分である。特に、モノマー添加量のモル比が、ラクチド：グリコリド＝９０：１０の時は、０．３〜１２ｇ／分が好ましく、ラクチド：グリコリド＝８０：２０の時は０．５〜２．６ｇ／分が好ましく、ラクチド：グリコリド＝７０：３０の時は、１．５〜２．４ｇ／分が好ましく、ラクチド：グリコリド＝６０：４０の時は、２〜２．３ｇ／分が好ましい。より好ましくは、グリコリド添加モル比（仕込みモル比）（Ｘ）及びグリコリドの添加速度（ｇ／分）（Ｙ）が、直交座標系（Ｘ，Ｙ）において、以下の頂点：点Ａ＝（１，１６）、点Ｂ＝（１０，１２）、点Ｃ＝（２０，２．６）、点Ｄ＝（３０，２．４）、点Ｅ＝（４０，２．３）、点Ｆ＝（４０，２）、点Ｇ＝（３０，１．５）、点Ｈ＝（２０，０．５）、点Ｉ＝（１０，０．３）、点Ｊ＝（１，０．０５）、を有する多角形の線状及びその内部領域の値を有することができる。 The rate of addition when the solution containing glycolide is sequentially added depends on the reaction solvent, but is usually 0.05 to 16 g / min, preferably 0.3 to 12 g / min. In particular, when the molar ratio of the amount of monomer added is lactide: glycolide = 90:10, 0.3 to 12 g / min is preferable, and when lactide: glycolide = 80:20, 0.5 to 2.6 g / min. When lactide: glycolide = 70:30, 1.5 to 2.4 g / min is preferable, and when lactide: glycolide = 60:40, 2 to 2.3 g / min is preferable. More preferably, the glycolide addition molar ratio (charged molar ratio) (X) and the glycolide addition rate (g / min) (Y) have the following vertices: points A = (1) in the Cartesian coordinate system (X, Y). , 16), point B = (10,12), point C = (20,2.6), point D = (30,2.4), point E = (40,2.3), point F = ( 40,2), point G = (30,1.5), point H = (20,0.5), point I = (10,0.3), point J = (1,0.05). It can have the values of the polygonal line and its internal region.
以下、実施例及び比較例を挙げて本発明を具体的に説明するが、これにより本発明の範囲が限定されるものではない。
〈重量平均分子量、分子量分布〉
重量平均分子量、分子量分布は、ゲルパーミエーションクロマトグラフィー（ＧＰＣ）により測定した標準ポリスチレン換算の重量平均分子量、数平均分子量の値であり、分子量分布とは数平均分子量に対する重量平均分子量の比で表される値である。ＧＰＣの測定は、検出器にＷＡＴＥＲＳ社示差屈折計ＷＡＴＥＲＳ４１０を用い、ポンプにＭＯＤＥＬ５１０高速液体クロマトグラフィーを用い、カラムにＳｈｏｄｅｘ ＧＰＣ ＨＦＩＰ−８０６Ｌを２本直列に接続したものを用いて行った。測定条件は、流速１．０ｍＬ／ｍｉｎとし、溶媒にクロロホルムを用い、試料濃度０．２ｍｇ／ｍＬの溶液を０．１ｍＬ注入した。
〈ポリマー組成比〉
乳酸−グリコール酸共重合の組成比は、重クロロホルムとヘキサフルオロイソプロパノールの混合溶液中、日本電子製核磁気共鳴装置ＪＮＭ−ＥＣＡ６００スペクトルメーターを使用して、１Ｈ−ＮＭＲを測定し、得られたスペクトルから乳酸由来の四重線ピーク（５．１０〜５．２０ｐｐｍ）並びに、グリコール酸由来のピーク（４.７０〜４．８０ｐｐｍ）の面積比を用いて算出した。
〈平均連鎖長〉
平均連鎖長は、重クロロホルムとヘキサフルオロイソプロパノールの混合溶液中、日本電子製核磁気共鳴装置ＪＮＭ−ＥＸ２７０スペクトルメーターを使用して、１３Ｃ−ＮＭＲを測定し、得られたスペクトルから乳酸連鎖由来のピーク（１７１．５〜１７２．０ｐｐｍ）、グリコール酸連鎖由来のピーク（１６８．５〜１６９．０ｐｐｍ）、乳酸−グリコール酸連鎖由来のピーク（１７２．０〜１７２．５ｐｐｍ）、グリコール酸―乳酸連鎖由来のピーク（１６８．５ｐｐｍ）の面積比を用いて算出した。
〈ガラス転移温度〉
ガラス転移温度は、Ｔ・Ａ・インスツルメント社製示差走査型熱量計（Ｑ２０）により試料１０ｍｇを窒素雰囲気下中で、３０℃から速度２０℃／ｍｉｎで２５０℃まで昇温、２５０℃で３分間保持、２５０℃から速度２０℃／ｍｉｎで３０℃まで降温、３０℃で１分間保持した後、３０℃から速度２０℃／ｍｉｎで２５０℃まで昇温して測定した。
〈金属成分量〉
オクチル酸スズを用いた溶融重合の反応終了後、ポリマー１ｇに対し１０倍量のジクロロメタンで溶解し、ジクロロメタン量の２０倍量のメタノールに、ポリマーのジクロロメタン溶液を１回再沈殿し、乳酸−ポリグリコール酸共重合体の固体を得た。得られたポリマーの固体０．２ｇを硝酸８ｍｌで溶解し、Agilent-ICP-OES-5100にて金属分析を行った。
［実施例１］
プランジャーポンプを取り付けた反応装置内を３回窒素置換し、コービオン製Ｌ−ラクチド（光学純度１００％）５０ｇ、ジクロロメタン１３３ｇ、アセトニトリル１５ｇを添加しラクチドを２５℃にて溶解した。ここに１−オクタデカノール０．００１ｇ、ＤＢＵ０．０３ｇを加えて重合を開始した。その直後にグリコリド４ｇをアセトニトリル１２ｇに溶解したものを、反応容器に０．６ｇ／分の速度で追加した。ＤＢＵを加えてから６０分後に酢酸１ｇを入れて重合を停止した。得られたポリマー溶液は均一で透明であった。得られたポリマー溶液をメタノールに再沈殿して、乳酸−グリコール酸共重合体の白色固体を得た。得られた白色固体はジクロロメタンに可溶であった。
［実施例２］
グリコリドとアセトニトリルの混合物の滴下速度を９．０ｇ／分にした以外は実施例１と同様に実施した。得られたポリマー溶液は均一で透明であった。得られたポリマー溶液をメタノールに再沈殿して、乳酸−グリコール酸共重合体の白色固体を得た。得られた白色固体はジクロロメタンに可溶であった。
［実施例３］
プランジャーポンプを取り付けた反応装置内を３回窒素置換し、コービオン製Ｌ−ラクチド（光学純度１００％）５０ｇ、ジクロロメタン１３３ｇ、アセトニトリル１５ｇを添加しラクチドを２５℃にて溶解した。更に、グリコリド４ｇをアセトニトリル１２ｇに溶解したものを、反応容器に追加し、ここに１−オクタデカノール０．００１ｇ、ＤＢＵ０．０３ｇを加えて重合を開始した。ＤＢＵを加えてから６０分後に酢酸１ｇを入れて重合を停止した。得られたポリマー溶液は均一で透明であった。得られたポリマー溶液をメタノールに再沈殿して乳酸−グリコール酸共重合体の白色固体を得た。得られた白色固体はジクロロメタンに可溶であった。
［実施例４］
Ｌ−ラクチドを４２ｇ、ジクロロメタン１３３ｇ、アセトニトリル１５ｇを添加しラクチドを２５℃にて溶解した。ここに１−オクタデカノール０．００１ｇ、ＤＢＵ０．０３ｇを加えて重合を開始した。その直後にグリコリド８ｇをアセトニトリル２４ｇに溶解したものを、反応容器に０．６ｇ／分の速度で追加した。ＤＢＵを加えてから６０分後に酢酸１ｇを入れて重合を停止した。得られたポリマー溶液は均一で透明であった。得られたポリマー溶液をメタノールに再沈殿してポリ乳酸−グリコール酸共重合体の白色固体を得た。得られた白色固体はジクロロメタンに可溶であった。
［実施例５］
グリコリドとアセトニトリルの混合物の滴下速度を０．９ｇ／分にした以外は実施例４と同様に実施した。得られたポリマー溶液は均一で透明であった。得られたポリマー溶液をメタノールに再沈殿してポリ乳酸−グリコール酸共重合体の白色固体を得た。得られた白色固体はジクロロメタンに可溶であった。
[実施例６]
Ｌ−ラクチドを３７ｇ、ジクロロメタン１３３ｇ、アセトニトリル１５ｇを添加しラクチドを２５℃にて溶解した。ここに１−オクタデカノール０．００１ｇ、ＤＢＵ０．０３ｇを加えて重合を開始した。その直後にグリコリド１３ｇをアセトニトリル３９ｇに溶解したものを、反応容器に２．６ｇ／分の速度で追加した。ＤＢＵを加えてから６０分後に酢酸１ｇを入れて重合を停止した。得られたポリマー溶液は均一で透明であった。得られたポリマー溶液をメタノールに再沈殿して乳酸−グリコール酸共重合体の白色固体を得た。得られた白色固体はジクロロメタンに可溶であった。
[実施例７]
グリコリドとアセトニトリルの混合物の滴下速度を２．０ｇ／分にした以外は実施例６と同様に実施した。得られたポリマー溶液は均一で透明であった。得られたポリマー溶液をメタノールに再沈殿して乳酸−グリコール酸共重合体の白色固体を得た。得られた白色固体はジクロロメタンに可溶であった。
［実施例８］
ジクロロメタンを１６０ｇにする以外は実施例７と同様に実施した。得られたポリマー溶液は均一で透明であった。得られたポリマー溶液をメタノールに再沈殿して乳酸−グリコール酸共重合体の白色固体を得た。得られた白色固体はジクロロメタンに可溶であった。
［比較例１］
グリコリドの添加速度を９．０ｇ／分にした以外は実施例１と同様に実施した。得られたポリマー溶液は白濁しており固体が析出していた。得られたポリマー溶液をメタノール溶液に再沈殿して白色固体のポリマーを得たが、得られた白色固体のポリマーはジクロロメタンに不溶であった。
［比較例２］
Ｌ−ラクチドを４２ｇ、ジクロロメタン１３３ｇ、アセトニトリル１５ｇを添加しラクチドを２５℃にて溶解した。ここに１−オクタデカノール０．００１ｇ、ＤＢＵ０．０３ｇを加えて重合を開始した。その直後にグリコリド８ｇをアセトニトリル２４ｇに溶解したものを、反応容器に２．８ｇ／分の速度で追加した。ＤＢＵを加えてから６０分後に酢酸１ｇを入れて重合を停止した。得られたポリマー溶液は白濁しており固体が析出していた。得られたポリマー溶液をメタノール溶液に再沈殿して白色固体のポリマーを得たが、得られた白色固体のポリマーはジクロロメタンに不溶であった。
［比較例３］
Ｌ−ラクチド４２ｇ、ジクロロメタン１３３ｇ、アセトニトリル１５ｇを添加しラクチドを２５℃にて溶解した。更に、グリコリド８ｇをアセトニトリル２４ｇに溶解したものを、反応容器に追加し、ここに１−オクタデカノール０．００１ｇ、ＤＢＵ０．０３ｇを加えて重合を開始したが、反応開始後から反応溶液が白濁し始めた。ＤＢＵを加えてから６０分後に酢酸１ｇを入れて重合を停止した。得られたポリマー溶液は白濁しており固体が析出していた。得られたポリマー溶液をメタノール溶液に再沈殿して白色固体のポリマーを得たが、得られた白色固体のポリマーはジクロロメタンに不溶であった。
［比較例４］
Ｌラクチドを４２ｇ、グリコリド８ｇを反応容器に入れ、２００℃で加熱溶融し、１−オクタデカノール０．００１ｇとオクチル酸スズ０．００４ｇを入れ、２００℃で１２０分反応させた。得られたポリマーをメタノールに再沈殿し、白色固体を得た。得られた白色固体はジクロロメタンに可溶であった。
［比較例５］
グリコリドとアセトニトリルの混合物の滴下速度を４．３ｇ／分にした以外は実施例６と同様に実施した。得られたポリマー溶液は白濁しており固体が析出していた。得られたポリマー溶液をメタノール溶液に再沈殿して白色固体のポリマーを得たが、得られた白色固体のポリマーはジクロロメタンに不溶であった。
［比較例６］
グリコリドとアセトニトリルの混合物の滴下速度を１．３ｇ／分にした以外は実施例６と同様に実施した。得られたポリマー溶液は白濁しており固体が析出していた。得られたポリマー溶液をメタノール溶液に再沈殿して白色固体のポリマーを得たが、得られた白色固体のポリマーはジクロロメタンに不溶であった。
［比較例７］
Ｌ−ラクチド３７ｇ、ジクロロメタン１３３ｇ、アセトニトリル１５ｇを添加しラクチドを２５℃にて溶解した。更に、グリコリド１３ｇをアセトニトリル３９ｇに溶解したものを、反応容器に追加し、ここに１−オクタデカノール０．００１ｇ、ＤＢＵ０．０３ｇを加えて重合を開始したが、反応開始後から反応溶液が白濁し始めた。ＤＢＵを加えてから６０分後に酢酸１ｇを入れて重合を停止した。得られたポリマー溶液は白濁しており固体が析出していた。得られたポリマー溶液をメタノール溶液に再沈殿して白色固体のポリマーを得たが、得られた白色固体のポリマーはジクロロメタンに不溶であった。
［比較例８］
Ｌラクチドを３７ｇ、グリコリド１３ｇを反応容器に入れ、２００℃で加熱溶融し、１−オクタデカノール０．００１ｇとオクチル酸スズ０．００４ｇを入れ、２００℃で１２０分反応させた。得られたポリマー溶液をメタノールに再沈殿し、白色固体を得た。得られた白色固体はジクロロメタンに可溶であった。
［比較例９］
Ｌラクチドを３３ｇ、グリコリド１７ｇを反応容器に入れ、２００℃で加熱溶融し、１−オクタデカノール０．００１ｇとオクチル酸スズ０．００４ｇを入れ、２００℃で１２０分反応させた。得られたポリマー溶液をメタノールに再沈殿し、白色固体を得た。得られた白色固体のポリマーはジクロロメタンに不溶であった。
［比較例１０］
Ｌ−ラクチドを２８ｇ、ジクロロメタン１３３ｇ、アセトニトリル１５ｇ、グリコリド２２ｇを添加し、ラクチド、グリコリドを２５℃にて溶解した。ここに１−オクタデカノール０．００１ｇ、ＤＢＵ０．０３ｇを加えて重合を開始した。ＤＢＵを加えてから６０分後に酢酸１ｇを入れて重合を停止した。得られたポリマー溶液は白濁し固体が析出していた。得られたポリマー溶液をメタノールに再沈殿してポリ乳酸グリコール酸共重合体の白色固体を得たが、得られた白色固体のポリマーはジクロロメタンに不溶であった。
［比較例１１］
Ｌラクチドを２８ｇ、グリコリド２２ｇを反応容器に入れ、２００℃で加熱溶融し、１−オクタデカノール０．００１ｇとオクチル酸スズ０．００４ｇを入れ、２００℃で１２０分反応させた。得られたポリマーをメタノールに再沈殿し、白色固体を得たが、得られた白色固体のポリマーはジクロロメタンに不溶であった。Hereinafter, the present invention will be specifically described with reference to Examples and Comparative Examples, but the scope of the present invention is not limited thereto.
<Weight average molecular weight, molecular weight distribution>
The weight average molecular weight and the molecular weight distribution are the values of the weight average molecular weight and the number average molecular weight in terms of standard polystyrene measured by gel permeation chromatography (GPC), and the molecular weight distribution is the ratio of the weight average molecular weight to the number average molecular weight. Is the value to be. The GPC was measured using a WATERS differential refractometer WATERS410 as a detector, MODEL510 high performance liquid chromatography as a pump, and two Shodex GPC HFIP-806L connected in series as a column. The measurement conditions were a flow rate of 1.0 mL / min, chloroform was used as a solvent, and 0.1 mL of a solution having a sample concentration of 0.2 mg / mL was injected.
<Polymer composition ratio>
The composition ratio of lactic acid-glycolic acid copolymer was obtained by measuring 1 H-NMR in a mixed solution of deuterated chloroform and hexafluoroisopropanol using a nuclear magnetic resonance apparatus JNM-ECA600 spectrum meter manufactured by JEOL Ltd. It was calculated from the spectrum using the area ratio of the lactic acid-derived quadruple line peak (5.1 to 5.20 ppm) and the glycolic acid-derived peak (4.70 to 4.80 ppm).
<Average chain length>
The average chain length was derived from the lactic acid chain from the obtained spectrum obtained by measuring 13 C-NMR using a nuclear magnetic resonance apparatus JNM-EX270 spectrum meter manufactured by JEOL in a mixed solution of dichlorochloro and hexafluoroisopropanol. Peak (171.5 to 172.0 ppm), peak derived from glycolic acid chain (168.5 to 169.0 ppm), peak derived from lactic acid-glycolic acid chain (172.0 to 172.5 ppm), glycolic acid-lactic acid chain It was calculated using the area ratio of the derived peak (168.5 ppm).
<Glass-transition temperature>
The glass transition temperature was raised from 30 ° C. to 250 ° C. at a rate of 20 ° C./min in a nitrogen atmosphere with 10 mg of the sample by a differential scanning calorimeter (Q20) manufactured by TA Instruments, Inc. at 250 ° C. The sample was held for 3 minutes, lowered from 250 ° C. to 30 ° C. at a speed of 20 ° C./min, held at 30 ° C. for 1 minute, and then raised to 250 ° C. at a speed of 20 ° C./min from 30 ° C.
<Amount of metal component>
After completion of the reaction of melt polymerization using tin octylate, the polymer was dissolved in 1 g of the polymer with 10 times the amount of dichloromethane, and the dichloromethane solution of the polymer was reprecipitated once in 20 times the amount of dichloromethane to lactic acid-poly. A solid glycolic acid copolymer was obtained. 0.2 g of the obtained solid polymer was dissolved in 8 ml of nitric acid, and metal analysis was performed with Agilent-ICP-OES-5100.
[Example 1]
The inside of the reactor equipped with the plunger pump was replaced with nitrogen three times, and 50 g of Corbion L-lactide (100% optical purity), 133 g of dichloromethane, and 15 g of acetonitrile were added to dissolve the lactide at 25 ° C. To this, 0.001 g of 1-octadecanol and 0.03 g of DBU were added to initiate polymerization. Immediately after that, 4 g of glycolide dissolved in 12 g of acetonitrile was added to the reaction vessel at a rate of 0.6 g / min. 60 minutes after the addition of DBU, 1 g of acetic acid was added to terminate the polymerization. The resulting polymer solution was uniform and transparent. The obtained polymer solution was reprecipitated in methanol to obtain a white solid of a lactic acid-glycolic acid copolymer. The white solid obtained was soluble in dichloromethane.
[Example 2]
The same procedure as in Example 1 was carried out except that the dropping rate of the mixture of glycolide and acetonitrile was set to 9.0 g / min. The resulting polymer solution was uniform and transparent. The obtained polymer solution was reprecipitated in methanol to obtain a white solid of a lactic acid-glycolic acid copolymer. The white solid obtained was soluble in dichloromethane.
[Example 3]
The inside of the reactor equipped with the plunger pump was replaced with nitrogen three times, and 50 g of Corbion L-lactide (100% optical purity), 133 g of dichloromethane, and 15 g of acetonitrile were added to dissolve the lactide at 25 ° C. Further, 4 g of glycolide dissolved in 12 g of acetonitrile was added to the reaction vessel, and 0.001 g of 1-octadecanol and 0.03 g of DBU were added thereto to initiate polymerization. 60 minutes after the addition of DBU, 1 g of acetic acid was added to terminate the polymerization. The resulting polymer solution was uniform and transparent. The obtained polymer solution was reprecipitated in methanol to obtain a white solid of a lactic acid-glycolic acid copolymer. The white solid obtained was soluble in dichloromethane.
[Example 4]
42 g of L-lactide, 133 g of dichloromethane, and 15 g of acetonitrile were added to dissolve lactide at 25 ° C. To this, 0.001 g of 1-octadecanol and 0.03 g of DBU were added to initiate polymerization. Immediately after that, 8 g of glycolide dissolved in 24 g of acetonitrile was added to the reaction vessel at a rate of 0.6 g / min. 60 minutes after the addition of DBU, 1 g of acetic acid was added to terminate the polymerization. The resulting polymer solution was uniform and transparent. The obtained polymer solution was reprecipitated in methanol to obtain a white solid of polylactic acid-glycolic acid copolymer. The white solid obtained was soluble in dichloromethane.
[Example 5]
The same procedure as in Example 4 was carried out except that the dropping rate of the mixture of glycolide and acetonitrile was set to 0.9 g / min. The resulting polymer solution was uniform and transparent. The obtained polymer solution was reprecipitated in methanol to obtain a white solid of polylactic acid-glycolic acid copolymer. The white solid obtained was soluble in dichloromethane.
[Example 6]
37 g of L-lactide, 133 g of dichloromethane and 15 g of acetonitrile were added to dissolve lactide at 25 ° C. To this, 0.001 g of 1-octadecanol and 0.03 g of DBU were added to initiate polymerization. Immediately after that, 13 g of glycolide dissolved in 39 g of acetonitrile was added to the reaction vessel at a rate of 2.6 g / min. 60 minutes after the addition of DBU, 1 g of acetic acid was added to terminate the polymerization. The resulting polymer solution was uniform and transparent. The obtained polymer solution was reprecipitated in methanol to obtain a white solid of a lactic acid-glycolic acid copolymer. The white solid obtained was soluble in dichloromethane.
[Example 7]
The same procedure as in Example 6 was carried out except that the dropping rate of the mixture of glycolide and acetonitrile was set to 2.0 g / min. The resulting polymer solution was uniform and transparent. The obtained polymer solution was reprecipitated in methanol to obtain a white solid of a lactic acid-glycolic acid copolymer. The white solid obtained was soluble in dichloromethane.
[Example 8]
It was carried out in the same manner as in Example 7 except that the amount of dichloromethane was 160 g. The resulting polymer solution was uniform and transparent. The obtained polymer solution was reprecipitated in methanol to obtain a white solid of a lactic acid-glycolic acid copolymer. The white solid obtained was soluble in dichloromethane.
[Comparative Example 1]
The same procedure as in Example 1 was carried out except that the addition rate of glycolide was set to 9.0 g / min. The obtained polymer solution was cloudy and solids were precipitated. The obtained polymer solution was reprecipitated into a methanol solution to obtain a white solid polymer, but the obtained white solid polymer was insoluble in dichloromethane.
[Comparative Example 2]
42 g of L-lactide, 133 g of dichloromethane, and 15 g of acetonitrile were added to dissolve lactide at 25 ° C. To this, 0.001 g of 1-octadecanol and 0.03 g of DBU were added to initiate polymerization. Immediately after that, 8 g of glycolide dissolved in 24 g of acetonitrile was added to the reaction vessel at a rate of 2.8 g / min. 60 minutes after the addition of DBU, 1 g of acetic acid was added to terminate the polymerization. The obtained polymer solution was cloudy and solids were precipitated. The obtained polymer solution was reprecipitated into a methanol solution to obtain a white solid polymer, but the obtained white solid polymer was insoluble in dichloromethane.
[Comparative Example 3]
42 g of L-lactide, 133 g of dichloromethane, and 15 g of acetonitrile were added to dissolve lactide at 25 ° C. Further, 8 g of glycolide dissolved in 24 g of acetonitrile was added to the reaction vessel, 0.001 g of 1-octadecanol and 0.03 g of DBU were added thereto to start the polymerization, but the reaction solution became cloudy after the start of the reaction. I started to do it. 60 minutes after the addition of DBU, 1 g of acetic acid was added to terminate the polymerization. The obtained polymer solution was cloudy and solids were precipitated. The obtained polymer solution was reprecipitated into a methanol solution to obtain a white solid polymer, but the obtained white solid polymer was insoluble in dichloromethane.
[Comparative Example 4]
42 g of L-lactide and 8 g of glycolide were placed in a reaction vessel, heated and melted at 200 ° C., 0.001 g of 1-octadecanol and 0.004 g of tin octylate were added, and the mixture was reacted at 200 ° C. for 120 minutes. The obtained polymer was reprecipitated in methanol to give a white solid. The white solid obtained was soluble in dichloromethane.
[Comparative Example 5]
The same procedure as in Example 6 was carried out except that the dropping rate of the mixture of glycolide and acetonitrile was set to 4.3 g / min. The obtained polymer solution was cloudy and solids were precipitated. The obtained polymer solution was reprecipitated into a methanol solution to obtain a white solid polymer, but the obtained white solid polymer was insoluble in dichloromethane.
[Comparative Example 6]
The same procedure as in Example 6 was carried out except that the dropping rate of the mixture of glycolide and acetonitrile was set to 1.3 g / min. The obtained polymer solution was cloudy and solids were precipitated. The obtained polymer solution was reprecipitated into a methanol solution to obtain a white solid polymer, but the obtained white solid polymer was insoluble in dichloromethane.
[Comparative Example 7]
37 g of L-lactide, 133 g of dichloromethane, and 15 g of acetonitrile were added to dissolve lactide at 25 ° C. Further, 13 g of glycolide dissolved in 39 g of acetonitrile was added to the reaction vessel, 0.001 g of 1-octadecanol and 0.03 g of DBU were added thereto to start the polymerization, but the reaction solution became cloudy after the start of the reaction. I started to do it. 60 minutes after the addition of DBU, 1 g of acetic acid was added to terminate the polymerization. The obtained polymer solution was cloudy and solids were precipitated. The obtained polymer solution was reprecipitated into a methanol solution to obtain a white solid polymer, but the obtained white solid polymer was insoluble in dichloromethane.
[Comparative Example 8]
37 g of L-lactide and 13 g of glycolide were placed in a reaction vessel, heated and melted at 200 ° C., 0.001 g of 1-octadecanol and 0.004 g of tin octylate were added, and the mixture was reacted at 200 ° C. for 120 minutes. The obtained polymer solution was reprecipitated in methanol to give a white solid. The white solid obtained was soluble in dichloromethane.
[Comparative Example 9]
33 g of L-lactide and 17 g of glycolide were placed in a reaction vessel, heated and melted at 200 ° C., 0.001 g of 1-octadecanol and 0.004 g of tin octylate were added, and the mixture was reacted at 200 ° C. for 120 minutes. The obtained polymer solution was reprecipitated in methanol to give a white solid. The resulting white solid polymer was insoluble in dichloromethane.
[Comparative Example 10]
28 g of L-lactide, 133 g of dichloromethane, 15 g of acetonitrile and 22 g of glycolide were added, and lactide and glycolide were dissolved at 25 ° C. To this, 0.001 g of 1-octadecanol and 0.03 g of DBU were added to initiate polymerization. 60 minutes after the addition of DBU, 1 g of acetic acid was added to terminate the polymerization. The obtained polymer solution became cloudy and a solid was precipitated. The obtained polymer solution was reprecipitated in methanol to obtain a white solid of a polylactic acid glycolic acid copolymer, but the obtained white solid polymer was insoluble in dichloromethane.
[Comparative Example 11]
28 g of L-lactide and 22 g of glycolide were placed in a reaction vessel, heated and melted at 200 ° C., 0.001 g of 1-octadecanol and 0.004 g of tin octylate were added, and the mixture was reacted at 200 ° C. for 120 minutes. The obtained polymer was reprecipitated in methanol to give a white solid, but the obtained white solid polymer was insoluble in dichloromethane.
以上の実施例及び比較例で得られた乳酸−グリコール酸共重合体について、ポリマー組成、平均連鎖長、ガラス転移温度（Ｔｇ）、重量平均分子量、分子量分布を測定した結果を、以下の表１にまとめる。なお、比較例１〜３、比較例５〜７及び比較例９〜１１は、乳酸−グリコール酸共重合体の白色固体は得られたものの、ＧＰＣの測定溶媒であるクロロホルムには溶解しなかったため、重量平均分子量及び分子量分布は測定できなかった。表１中、「全モノマー濃度」とは、ラクチドを含む溶液とグリコリドを含む溶液を合わせた全溶液中のラクチドモノマー及びグリコリドモノマーの合計の濃度である。「ラクチド濃度」とは、上記逐次添加方法における、グリコリドを含む溶液を添加する前の、ラクチドを含む溶液中のラクチドモノマー濃度である。「グリコリド濃度」とは、同様に、上記逐次添加における、添加前のグリコリドを含む溶液中のグリコリドモノマー濃度である。「ｎ．ｄ．」とは、検出限界以下であったことを意味する。 The results of measuring the polymer composition, average chain length, glass transition temperature (Tg), weight average molecular weight, and molecular weight distribution of the lactic acid-glycolic acid copolymers obtained in the above Examples and Comparative Examples are shown in Table 1 below. Summarize in. In Comparative Examples 1 to 3, Comparative Examples 5 to 7, and Comparative Examples 9 to 11, white solids of the lactic acid-glycolic acid copolymer were obtained, but they were not dissolved in chloroform, which is a measurement solvent for GPC. , Weight average molecular weight and molecular weight distribution could not be measured. In Table 1, the "total monomer concentration" is the total concentration of the lactide monomer and the glycolide monomer in the total solution including the solution containing lactide and the solution containing glycolide. The "lactide concentration" is the concentration of the lactide monomer in the solution containing lactide before the solution containing glycolide is added in the above-mentioned sequential addition method. Similarly, the "glycolide concentration" is the concentration of the glycolide monomer in the solution containing the glycolide before the addition in the above-mentioned sequential addition. “Nd” means that it was below the detection limit.
本発明によれば、金属成分を含まない高分子量の乳酸−グリコール酸共重合体が得られ、医療材料等の成形品に利用できる。
According to the present invention, a high molecular weight lactic acid-glycolic acid copolymer containing no metal component can be obtained and can be used for molded products such as medical materials.
Claims (13)
反応開始直後から、グリコリドを含む溶液を反応溶液に逐次添加する工程とを含む、乳酸−グリコール酸共重合体の製造方法。A step of contacting a solution containing lactide with an amidine-based catalyst and a polymerization initiator to initiate a reaction, and
A method for producing a lactic acid-glycolic acid copolymer, which comprises a step of sequentially adding a solution containing glycolide to the reaction solution immediately after the start of the reaction.
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