JPS63289020A - Production of (co)polymer of lactic acid and/or glycolic acid - Google Patents
Production of (co)polymer of lactic acid and/or glycolic acidInfo
- Publication number
- JPS63289020A JPS63289020A JP28306586A JP28306586A JPS63289020A JP S63289020 A JPS63289020 A JP S63289020A JP 28306586 A JP28306586 A JP 28306586A JP 28306586 A JP28306586 A JP 28306586A JP S63289020 A JPS63289020 A JP S63289020A
- Authority
- JP
- Japan
- Prior art keywords
- polymerization reaction
- lactic acid
- glycolic acid
- polymer
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 title claims abstract description 74
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 title claims abstract description 66
- 235000014655 lactic acid Nutrition 0.000 title claims abstract description 33
- 239000004310 lactic acid Substances 0.000 title claims abstract description 33
- 229920001577 copolymer Polymers 0.000 title claims abstract description 21
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- 238000010438 heat treatment Methods 0.000 claims abstract description 25
- 230000000379 polymerizing effect Effects 0.000 claims abstract description 4
- 238000006116 polymerization reaction Methods 0.000 abstract description 45
- 239000003814 drug Substances 0.000 abstract description 10
- 230000006866 deterioration Effects 0.000 abstract description 6
- 238000000354 decomposition reaction Methods 0.000 abstract description 3
- 239000011521 glass Substances 0.000 abstract description 3
- 238000002845 discoloration Methods 0.000 abstract description 2
- 230000036425 denaturation Effects 0.000 abstract 1
- 238000004925 denaturation Methods 0.000 abstract 1
- 238000000034 method Methods 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 239000002954 polymerization reaction product Substances 0.000 description 14
- 230000005587 bubbling Effects 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 229910001873 dinitrogen Inorganic materials 0.000 description 10
- 229940079593 drug Drugs 0.000 description 9
- 239000003054 catalyst Substances 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- 238000009826 distribution Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000004737 colorimetric analysis Methods 0.000 description 3
- 239000000178 monomer Substances 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 241001550224 Apha Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- PWATWSYOIIXYMA-UHFFFAOYSA-N Pentylbenzene Chemical compound CCCCCC1=CC=CC=C1 PWATWSYOIIXYMA-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- ADCOVFLJGNWWNZ-UHFFFAOYSA-N antimony trioxide Chemical compound O=[Sb]O[Sb]=O ADCOVFLJGNWWNZ-UHFFFAOYSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 238000013269 sustained drug release Methods 0.000 description 2
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 229930182843 D-Lactic acid Natural products 0.000 description 1
- JVTAAEKCZFNVCJ-UWTATZPHSA-N D-lactic acid Chemical compound C[C@@H](O)C(O)=O JVTAAEKCZFNVCJ-UWTATZPHSA-N 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 229940022769 d- lactic acid Drugs 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- HQWPLXHWEZZGKY-UHFFFAOYSA-N diethylzinc Chemical compound CC[Zn]CC HQWPLXHWEZZGKY-UHFFFAOYSA-N 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012567 medical material Substances 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 229940094933 n-dodecane Drugs 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000006068 polycondensation reaction Methods 0.000 description 1
- 235000008476 powdered milk Nutrition 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- -1 racemic D Chemical compound 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007151 ring opening polymerisation reaction Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 229920003051 synthetic elastomer Polymers 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000002747 voluntary effect Effects 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Polyesters Or Polycarbonates (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、乳酸および／またはグリコール酸の（共）重
合体の製造方法に関するものである。DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a method for producing a (co)polymer of lactic acid and/or glycolic acid.
近年、慢性疾患やガンと称される悪性新生物の治療を目
的として、薬剤運搬システム（Ｄ、口、Ｓ、）が注目を
浴びてきている。このシステムのうち、特に薬剤を含有
する担体を患者の体内に注入しあるいは埋め込んで当該
薬剤を長期間に亘って徐放させるシステムは、薬剤を患
部に集中投与することができ、不連続投与の場合のよう
に患者にショックを与えることがなく、しがも在宅療養
が可能である、などの利点を有することがら、その重要
性が増大している。In recent years, drug delivery systems (D, S,) have been attracting attention for the purpose of treating chronic diseases and malignant neoplasms called cancer. Among these systems, systems in which a carrier containing a drug is injected or implanted into the patient's body to release the drug in a sustained manner over a long period of time are capable of administering the drug centrally to the affected area, and are capable of discontinuous administration. Its importance is increasing because it has the advantage of not causing shock to the patient as in cases where it occurs, and it allows patients to receive treatment at home.
斯かる薬剤徐放システムに用いられる担体は、直接体内
に注入あるいは埋め込まれるものであるため、当然のこ
とながら生体に無害のものであることが不可欠であり、
同時に、薬剤の徐放と共に体内において安全に分解され
吸収される性質のものであることが好ましい、現在にお
いて、乳酸およびグリコール酸は、生体内における代謝
の経路が解明されており、従ってこれらの−（共）重合
体は、それが例えば１ 、０００〜４０．０００程度の
分子量を有するものであれば、上記のような目的のため
に好適に使用し得るものとして期待されている。Since the carriers used in such sustained drug release systems are directly injected or implanted into the body, it is essential that they are harmless to living organisms.
At the same time, it is preferable that lactic acid and glycolic acid have properties that allow them to be safely degraded and absorbed in the body while allowing for sustained release of the drug.Currently, the metabolic pathways of lactic acid and glycolic acid in the body have been elucidated, and therefore these - (Co)polymers having a molecular weight of, for example, about 1,000 to 40,000 are expected to be suitably used for the above purposes.
従来、乳酸および／またはグリコール酸の（共）重合体
を製造するための方法としては、大別して、２つの方法
が知られている。第１の方法は、先ず、乳酸および／ま
たはグリコール酸を脱水縮合して分子量が数百の（共）
重合体を得、次にこれを三酸化アンチモンなどの触媒の
存在下において解重合させて環状二量体であるラクチド
類を得、更にこの二量体を、オクチル酸スズ、ジエチル
亜鉛などの触媒の存在下において開環重合させて目的と
する（共）重合体を製造する方法である。BACKGROUND ART Conventionally, methods for producing (co)polymers of lactic acid and/or glycolic acid are broadly classified into two known methods. The first method involves first dehydrating and condensing lactic acid and/or glycolic acid to obtain a (co-)acetate with a molecular weight of several hundred.
A polymer is obtained, which is then depolymerized in the presence of a catalyst such as antimony trioxide to obtain lactides, which are cyclic dimers, and this dimer is further depolymerized in the presence of a catalyst such as tin octylate or diethylzinc. In this method, the desired (co)polymer is produced by ring-opening polymerization in the presence of.
第２の方法は、乳酸および／またはグリコール酸を１０
０℃以上の温度に加熱することによって重縮合させて直
接的に目的とする（共）重合体を製造する方法である。The second method involves adding lactic acid and/or glycolic acid to 10
This is a method of directly producing the desired (co)polymer by polycondensation by heating to a temperature of 0° C. or higher.
しかしながら、上記第１の方法は、薬剤徐放担体として
有用な範囲の分子量を有する（共）重合体が比較的容易
に得られる点において好ましいものであるが、重合反応
において触媒を用いるため、最終生成物中に当該触媒に
由来する重金属などの不純物が残存するという問題点が
ある。このような不純物が含有されることは、当然のこ
とながら医療用薬剤の担体として致命的な欠陥である。However, although the first method described above is preferable in that a (co)polymer having a molecular weight within a range useful as a drug sustained release carrier can be obtained relatively easily, it uses a catalyst in the polymerization reaction, so the final There is a problem that impurities such as heavy metals derived from the catalyst remain in the product. The inclusion of such impurities is, of course, a fatal defect as a carrier for medical drugs.
第２の方法は、分子量が数千以上の（共）重合体を製造
するためには、重合反応を相当長時間に亘って継続する
ことが必要であって工業上きわめて不利である。１ｉ合
反応時間を短縮するためには、特開昭５９−９６１２３
号公報に見られるように、重合反応温度を２２０〜２６
０℃とする手段も提案されているが、このように加熱温
度を高くする場合には、重合反応の進行と同時に、一旦
生成した（共）重合体が熱劣化して変質したり分解が生
ずるようになるため、製造される生成物が着色したもの
となり、また均一なものを得ることができない。The second method is extremely disadvantageous industrially since it is necessary to continue the polymerization reaction for a considerably long time in order to produce a (co)polymer having a molecular weight of several thousand or more. In order to shorten the 1i reaction time, Japanese Patent Application Laid-Open No. 59-96123
As seen in the publication, the polymerization reaction temperature was set at 220-26
A method of lowering the heating temperature to 0°C has also been proposed, but when the heating temperature is raised in this way, the (co)polymer once formed will undergo thermal deterioration, change in quality, or decompose as the polymerization reaction progresses. As a result, the product produced is colored and cannot be uniform.
本発明は、上記のような欠点を解決し、触媒を用いずに
、分子量が数千以上の乳酸および／またはグリコール酸
の（共）重合体を容易に製造することのできる方法を提
供することを目的とする。The present invention solves the above-mentioned drawbacks and provides a method by which a (co)polymer of lactic acid and/or glycolic acid having a molecular weight of several thousand or more can be easily produced without using a catalyst. With the goal.
Ｃ問題点を解決するための手段〕
本発明においては、乳酸および／またはグリコール酸を
誘電加熱により重合させることを特徴とする方法により
、乳酸および／またはグリコール酸の（共）重合体を製
造する。Means for Solving Problem C] In the present invention, a (co)polymer of lactic acid and/or glycolic acid is produced by a method characterized by polymerizing lactic acid and/or glycolic acid by dielectric heating. .
本発明において原料として用いられる乳酸またはグリコ
ール酸は、具体的にはＬ−乳酸、Ｄ−乳酸、ラセミ体で
ある Ｄ、Ｌ−乳酸およびグリコール酸から選ばれるも
のである。これらは、単独で用いてもよいし、複数のも
のを任意の比率で混合して用いることもでき、また、水
溶液の状態のものであってもよい、しかし、水溶液の濃
度が５０重量％以下の場合のように無用に水分量の多い
原料を使用すると、重合反応の初期において生成する水
を除去するための工程に長時間を要することとなるため
、工業的には不利である。Lactic acid or glycolic acid used as a raw material in the present invention is specifically selected from L-lactic acid, D-lactic acid, racemic D, L-lactic acid, and glycolic acid. These may be used alone, or a plurality of them may be mixed in any ratio, and may be in the form of an aqueous solution, but the concentration of the aqueous solution is 50% by weight or less. If a raw material with an unnecessarily high water content is used as in the case of , the process for removing the water produced at the beginning of the polymerization reaction will take a long time, which is industrially disadvantageous.
重合反応容器としては、内部に収容された乳酸および／
またはグリコール酸が有効に誘電加熱されることを妨害
しない材質および形状のものであれば特に限定されるこ
とはないが、通常、小スケールの場合にはガラス製のセ
パラブルフラスコが好適に使用され、大スケールの場合
には、誘電加熱のための電磁波が直接反応容器内に導入
することができるように設計された反応容器が使用され
る。斯かる重合反応容器には、必要に応じて攪拌機、窒
素ガスなどの不活性ガス導入管、生成水分離管、冷却管
、減圧ポンプなどの装置が接続されスー
次に、重合反応容器内に原料である乳酸および／または
グリコール酸を仕込み、この重合反応容器を外部から誘
電加熱処理の可能な装置内にセットし、容器壁を介して
誘電加熱するか、または重合反応容器内に電磁波発振機
を導入して直接誘電加熱することにより、乳酸および／
またはグリコール酸の重合反応が遂行される０重合反応
容器には、原料である乳酸および／またはグリコール酸
に加え、重合反応液の粘度を低減させる目的あるいは脱
水の促進を図る目的で、重合反応に対して不活性な有機
溶剤を添加することも可能であるこれらの重合反応に対
して不活性な有機溶剤としては、デカリン、テトラリン
、１，４−ジオキサン、１．２−ジブトキシエタン、ア
セトニルアセトン、ペンチルベンゼン、ジクロロベンゼ
ン、ベンジルエーテル、ｎ−ドデカン、ｎ−デカン、ｎ
−ノナンなどを挙げることができる。As a polymerization reaction vessel, the lactic acid and/or
The material and shape are not particularly limited as long as they do not interfere with the effective dielectric heating of glycolic acid, but usually, a separable flask made of glass is preferably used for small scale applications. , in large scale cases, a reaction vessel is used that is designed so that electromagnetic waves for dielectric heating can be introduced directly into the reaction vessel. Devices such as a stirrer, an inert gas introduction pipe such as nitrogen gas, a produced water separation pipe, a cooling pipe, and a pressure reduction pump are connected to the polymerization reaction vessel as necessary, and then the raw materials are introduced into the polymerization reaction vessel. lactic acid and/or glycolic acid are charged, and the polymerization reaction vessel is placed in a device capable of dielectric heating from the outside, and dielectric heating is performed through the vessel wall, or an electromagnetic wave oscillator is installed inside the polymerization reaction vessel. By introducing and direct dielectric heating, lactic acid and/or
Or, in the polymerization reaction vessel where the polymerization reaction of glycolic acid is carried out, in addition to the raw materials lactic acid and/or glycolic acid, there is a It is also possible to add an inert organic solvent to these polymerization reactions. Acetone, pentylbenzene, dichlorobenzene, benzyl ether, n-dodecane, n-decane, n
- Examples include nonane.
本発明において、誘電加熱とは被加熱物である誘電体が
電磁波中に置かれるとき、当該透電体が誘電損失によっ
て発熱する現象を利用することである。In the present invention, dielectric heating refers to the use of the phenomenon that when a dielectric object to be heated is placed in electromagnetic waves, the electrically conductive object generates heat due to dielectric loss.
誘電加熱を実行するために使用する周波数帯としては、
低周波、高周波、マイクロ波などが挙げられ、使用周波
数は一般的に５０ＭＨｚ〜３００Ｇｌｌｚである。The frequency band used to perform dielectric heating is
Examples include low frequency, high frequency, microwave, etc., and the frequency used is generally 50 MHz to 300 Gllz.
本発明においては特にマイクロ波を使用することが好ま
しい。In the present invention, it is particularly preferable to use microwaves.
本発明において使用されるマイクロ波は、通常「サブミ
リメートル波」、「ミリメートル波」、「センチメート
ル波」、「デシメートル波」および「メートル波」と称
される電磁波をいい、その周波数の領域は３００ＭＨｚ
〜３００Ｇ）Ｉｚの範囲、好ましくは５００ＭＨｚ ＝
１０ＧＨｚの範囲とされる。The microwave used in the present invention refers to electromagnetic waves usually referred to as "submillimeter waves,""millimeterwaves,""centimeterwaves,""decimeterwaves," and "meter waves," and the frequency range thereof is is 300MHz
~300G) Iz range, preferably 500MHz =
The range is 10 GHz.
使用する電磁波の出力は、特に制限されるものではない
が、通常、モノマー１ｇ当たり１ｍＷ〜ＩＩＭＷであり
、モノマー１ｇ当たりＩＭＷを越えると、通常、重合反
応液の温度が過度に上昇してしまうため生成物が熱劣化
するおそれがあり、また出力がモノマー１ｇ当たり１ｍ
Ｗ未満では、目的とする所要の分子量を存する生成物を
短時間のうちに製造することが困難となり、効率が低下
する点で不利である。The output of the electromagnetic waves used is not particularly limited, but is usually 1 mW to IIMW per gram of monomer; if it exceeds IMW per gram of monomer, the temperature of the polymerization reaction solution will normally rise excessively. There is a risk of thermal deterioration of the product, and the output is 1 m per 1 g of monomer.
If it is less than W, it becomes difficult to produce a product having the desired molecular weight in a short period of time, which is disadvantageous in that efficiency decreases.
使用する電磁波の出力は、重合反応の間一定に維持して
もよいが、重合反応温度を厳密に制御するために出力可
変型の電磁波照射装置を用いることが好ましい。Although the output of the electromagnetic waves used may be kept constant during the polymerization reaction, it is preferable to use a variable output electromagnetic wave irradiation device in order to strictly control the polymerization reaction temperature.
本発明によれば、乳酸および／またはグリコール酸を誘
電加熱することによって当該乳酸および／またはグリコ
ール酸の温度が上昇し、これによってその重合反応が進
行するので、他の加熱は通常不要であるが、別途設けた
ヒーターなどにより補助的に加熱を行うこともできる。According to the present invention, by dielectrically heating the lactic acid and/or glycolic acid, the temperature of the lactic acid and/or glycolic acid increases, and thereby the polymerization reaction proceeds, so that other heating is usually not necessary. , auxiliary heating can be performed using a separately provided heater.
本発明において、重合反応温度は、好ましくは８０〜２
２０℃、特に好ましくは１００〜２１５℃であり、反応
容器内の圧力は、通常７６０ ｍ＋ｍｔ１ｇ以下、好ま
しくは３Ｑ＋ｍ＊Ｉ１ｇ以下、特に好ましくは５ ｍｍ
Ｈｇ以下である。In the present invention, the polymerization reaction temperature is preferably 80 to 2
The temperature is 20°C, particularly preferably 100 to 215°C, and the pressure inside the reaction vessel is usually 760 m+mt1g or less, preferably 3Q+m*I1g or less, particularly preferably 5 mm.
Hg or less.
上記のようにして誘電加熱が開始されると、乳酸および
／またはグリコール酸を含む重合反応液の温度の上昇と
共に水が留出する。この水は水分離管により適宜除去さ
れる０重合反応を高い効率で実行するために、系を減圧
状態とすることおよび／または乾燥した窒素ガスのよう
な不活性ガスを反応系内に導入することがを効である。When dielectric heating is started as described above, water is distilled out as the temperature of the polymerization reaction solution containing lactic acid and/or glycolic acid increases. This water is appropriately removed by a water separation tube.In order to carry out the polymerization reaction with high efficiency, the system is kept under reduced pressure and/or an inert gas such as dry nitrogen gas is introduced into the reaction system. That is effective.
本発明の方法によれば、数千以上、好ましくは１．００
０〜４０．０００という好適な範囲の数平均分子量を有
し、しかも着色のない均質で良質の乳酸および／または
グリコール酸の（共）重合体を、高い効率でかつ短時間
のうちに製造することができる。According to the method of the invention, more than a few thousand, preferably 1.00
To produce a homogeneous and high quality (co)polymer of lactic acid and/or glycolic acid having a number average molecular weight in a suitable range of 0 to 40,000 and without coloring, with high efficiency and in a short time. be able to.
なお、通常、本発明により得られる乳酸および／または
グリコール酸の（共）重合体はＪＩＳに１５５７−１９
７０に記載されている比色法による＾ＰＩＩＡ Ｎｏ、
で３０以下である。また重合反応に触媒を使用しないた
め、製造される（共）重合体に不純物が含有されること
もない。従って、得られた乳酸および／またはグリコー
ル酸の（共）重合体は、医療用薬剤の担体、特に薬剤徐
放担体その他の医用材料としてきわめて好適に使用する
ことのできるものとなる。Note that the (co)polymer of lactic acid and/or glycolic acid obtained by the present invention is generally specified in JIS 1557-19.
According to the colorimetric method described in 70 ^PIIA No.
It is 30 or less. Furthermore, since no catalyst is used in the polymerization reaction, the produced (co)polymer does not contain impurities. Therefore, the obtained (co)polymer of lactic acid and/or glycolic acid can be very suitably used as a carrier for medical drugs, especially as a drug sustained release carrier and other medical materials.
このような優れた効果が奏される理由は、乳酸および／
またはグリコール酸を誘電加熱することによって当該乳
酸および／またはグリコール酸を重合させるからであり
、重合反応液の全体において均一に温度の上昇および維
持が達成されるからであると推定される。The reason for such excellent effects is lactic acid and/or
Alternatively, it is presumed that this is because the lactic acid and/or glycolic acid is polymerized by dielectrically heating the glycolic acid, and the temperature can be raised and maintained uniformly throughout the polymerization reaction solution.
以下本発明の実施例について説明するが、本発明はこれ
らによって限定されるものではない。Examples of the present invention will be described below, but the present invention is not limited thereto.
実施例１
一窒素ガス導入管および攪拌機を備えた実容量２１のガ
ラス製セパラブルフラスコ内に、濃度９０重量％のし一
乳酸水溶液１，５２０ｇを仕込み、これを誘電加熱用オ
ーブン内にセットした。このセパラブルフラスコは、当
該オープンの外部に伸びる冷却管および水分離管が接続
され、また減圧ポンプが接続されたものである。そして
窒素ガス導入管を介して窒素ガスを徐々に導入しながら
、フラスコ内の減圧および重合反応液の攪拌を同時に開
始し、次いで周波数２．４５ Ｇ１１ｚのマイクロ波の
照射を開始して次第にその出力を高めた。１９分間を経
過した後に重合反応液の温度は１０３℃、圧力は３５＋
ｕ＋Ｈｇに達し、重合反応液は激しいバブリング状態と
なった。このバブリング状態となった時のマイクロ波の
出力は１８０Ｗであった。Example 1 1,520 g of a monolactic acid aqueous solution with a concentration of 90% by weight was placed in a separable glass flask with an actual capacity of 21, equipped with a nitrogen gas introduction tube and a stirrer, and this was placed in a dielectric heating oven. . This separable flask is connected to a cooling pipe and a water separation pipe extending outside the open part, and is also connected to a vacuum pump. Then, while gradually introducing nitrogen gas through the nitrogen gas inlet tube, we simultaneously started reducing the pressure in the flask and stirring the polymerization reaction solution. Next, we started irradiating microwaves with a frequency of 2.45 G11z and gradually increased the output. increased. After 19 minutes, the temperature of the polymerization reaction solution was 103°C, and the pressure was 35+.
The temperature reached u+Hg, and the polymerization reaction solution entered a state of intense bubbling. The output of the microwave at this bubbling state was 180W.
このバブリング状態を５０分間維持し、留出してきた水
は水分離管を介して除去した。その後バブリング状態が
穏やかになったところでマイクロ波の出力を６００Ｗま
で上昇させ、同時に減圧の程度を高めて圧力を３ ｍｍ
Ｈｇとした。マイクロ波の出力が６００Ｗ、圧力を３請
−〇、としてから更にマイクロ波の出力を上昇させなが
ら１時間を経過した後、重合反応液の温度は１８０℃で
あり、マイクロ波の出力は約８００Ｗであった。更にこ
の状態を８時間維持して重合反応を続けた結果、重合反
応液は粘稠なものとなった。その後マイクロ波の照射を
停止し、系の温度を６０℃に降下させて固体状の重合反
応生成物９９２ｇを得た。This bubbling state was maintained for 50 minutes, and the distilled water was removed through a water separation tube. After that, when the bubbling condition became calm, the microwave output was increased to 600 W, and at the same time, the degree of decompression was increased to reduce the pressure to 3 mm.
It was set as Hg. After setting the microwave output to 600 W and the pressure for 3 times, and increasing the microwave output for 1 hour, the temperature of the polymerization reaction solution was 180°C, and the microwave output was about 800 W. Met. This state was further maintained for 8 hours to continue the polymerization reaction, and as a result, the polymerization reaction liquid became viscous. Thereafter, the microwave irradiation was stopped and the temperature of the system was lowered to 60° C. to obtain 992 g of a solid polymerization reaction product.
このようにして得られた重合反応生成物は、着色がなく
、熱劣化による変質や分解のないものであり、ポリマー
末端のカルボキシル基を非水系溶媒を用いて電導度滴定
により定量し、ポリマー重量で割って数平均分子量を算
出する方法である末端基定量法によって求めた数平均分
子ＮＭｎの値は６，９５０、またゲルバーミエーション
クロマトグラフィーによって分子量分布を測定して得ら
れた数平均分子量Ｍｎに対する重量平均分子量Ｍ−の比
Ｍｗ／Ｍｎの値は１．７８であった。また、この重合反
応生成物のＪＩＳ Ｋ１５５７−１９７０に記載の比色
法によるＡＰＨＡ Ｎｏ、は２０であった。The polymerization reaction product obtained in this way is free from coloration, deterioration and decomposition due to thermal deterioration, and the carboxyl group at the end of the polymer is determined by conductivity titration using a non-aqueous solvent. The value of the number average molecular weight NMn determined by the terminal group determination method, which is a method of calculating the number average molecular weight by dividing by The value of the ratio Mw/Mn of the weight average molecular weight M- to the weight average molecular weight M- was 1.78. Further, the APHA No. of this polymerization reaction product was 20 according to the colorimetric method described in JIS K1557-1970.
実施例２
実施例１におけると同様のセパラブルフラスコを用い、
予め乾燥した乳Ｍ８１０ｇとグリコール酸８１０ ｇと
をセパラブルフラスコ内に仕込んだ、そして窒素ガスを
徐々に導入しながら、フラスコ内の減圧と攪拌を開始し
、同時に周波数５．０ ＧＨｚ、３００ Ｗのマイクロ
波の照射を開始してその出力を徐々に高め８００Ｗとし
た。出力が８００Ｗとなってから更に約３２分間を経過
した後に重合反応液の温度は１７５℃、圧力は２ ｍｍ
１ｇに達し、重合反応液は適度なバブリング状態を保っ
た。この状態を１０時間維持した後、系を冷却して固体
状の重合反応生成物１，１３５ｇを得た。この重合反応
生成物の分子量および分子量分布を実施例１と同様にし
て測定したところ、数平均分子量は８．２１０、Ｍｗ／
Ｍｎの値は１．８３であった。Example 2 Using the same separable flask as in Example 1,
810 g of pre-dried milk M and 810 g of glycolic acid were placed in a separable flask, and while nitrogen gas was gradually introduced, vacuuming and stirring were started inside the flask, and at the same time, the air was heated at a frequency of 5.0 GHz and 300 W. Microwave irradiation was started and the output was gradually increased to 800W. After approximately 32 minutes had passed since the output reached 800 W, the temperature of the polymerization reaction solution was 175°C and the pressure was 2 mm.
The amount reached 1 g, and the polymerization reaction solution maintained a moderate bubbling state. After maintaining this state for 10 hours, the system was cooled to obtain 1,135 g of a solid polymerization reaction product. The molecular weight and molecular weight distribution of this polymerization reaction product were measured in the same manner as in Example 1, and the number average molecular weight was 8.210, Mw/
The Mn value was 1.83.
実施例３
実施例１におけると同様のセパラブルフラスコを用い、
グリコール酸（結晶） １，６９０ ｇをセパラブルフ
ラスコ内に仕込んだ、そして窒素ガスを導入しながら、
オイルバスを用い、温度１００℃にて２時間加熱しグリ
コール酸の溶融を行った。グリコール酸が溶融した後オ
イルバスを除去し、フラスコ内の減圧と攪拌を開始し、
同時に周波数２．４５Ｇｌｌｚ 、 ２３０ Ｗのマイ
クロ波の照射を開始して１００℃の温度を保ちながら圧
力を３（１＋＋ｍＨｇとし、重合反応液をバブリング状
態とした。Example 3 Using the same separable flask as in Example 1,
1,690 g of glycolic acid (crystals) was placed in a separable flask, and while nitrogen gas was introduced,
The glycolic acid was melted by heating at 100° C. for 2 hours using an oil bath. After the glycolic acid has melted, remove the oil bath, reduce the pressure inside the flask and start stirring.
At the same time, microwave irradiation with a frequency of 2.45 Gllz and 230 W was started, and the pressure was set to 3 (1++ mHg) while maintaining the temperature at 100° C., and the polymerization reaction solution was brought into a bubbling state.
このバブリング状態を１時間維持し、留出してきた水は
水分離管を介して除去した。その後マイクロ波の出力を
上昇させ、同時に減圧の程度を高めて圧力を２＋ｕａｉ
１ｇとした。マイクロ波の出力上昇を開始してから１時
間を経過した後の重合反応液の温度は１７６℃であり、
またマイクロ波の出力は約６５０Ｗであった。更にこの
状態を１２時間維持して重合反応を続けた結果、重合反
応液は粘稠なものとなった。その後マイクロ波の照射を
停止し、系の温度を室温に降下させて固体状の重合反応
生成物１．１３９ｇを得た。この重合反応生成物の分子
量および分子量分布を実施例１と同様にして測定したと
ころ、数平均分子量は６，８９３、Ｍｗ／ＭｎＯ値は２
．０３であった。This bubbling state was maintained for 1 hour, and the distilled water was removed through a water separation tube. After that, increase the microwave output and at the same time increase the degree of decompression to raise the pressure to 2+uai.
It was set as 1g. The temperature of the polymerization reaction solution 1 hour after starting to increase the microwave output was 176°C,
Further, the output of the microwave was approximately 650W. This state was further maintained for 12 hours to continue the polymerization reaction, and as a result, the polymerization reaction solution became viscous. Thereafter, the microwave irradiation was stopped and the temperature of the system was lowered to room temperature to obtain 1.139 g of a solid polymerization reaction product. The molecular weight and molecular weight distribution of this polymerization reaction product were measured in the same manner as in Example 1, and the number average molecular weight was 6,893, and the Mw/MnO value was 2.
．． It was 03.
実施例４
実施例１におけると同様のセパラブルフラスコを用い、
予め乾燥した乳酸９００ ｇとグリコール酸６８０ｇと
をセパラブルフラスコ内に仕込んだ。そして窒素ガスを
徐々に導入しながら、フラスコ内の減圧と攪拌を開始し
、同時に周波数３．５ ＧＨｚ、２８０Ｗのマイクロ波
の照射を開始してその出力を徐々に８００Ｗまで高めた
。出力が８００Ｗとなってから更に約２８分間を経過し
た後に重合反応液の温度は１８２℃、圧力は３＋ｎ＋ｎ
Ｈｇに達し、重合反応液は適度なバブリング状態を保っ
た。この状態を８時間維持した後、系を冷却して固体状
の重合反応生成物１．１０３ｇを得た。この重合反応生
成物の分子量および分子量分布を実施例１と同様にして
測定したところ、数平均分子量は５，８４０、Ｍｗ／Ｍ
ｎの値は２．１５であった。Example 4 Using the same separable flask as in Example 1,
900 g of lactic acid and 680 g of glycolic acid, which had been dried in advance, were charged into a separable flask. Then, while gradually introducing nitrogen gas, the pressure inside the flask was reduced and stirring was started, and at the same time, microwave irradiation with a frequency of 3.5 GHz and 280 W was started, and the output was gradually increased to 800 W. After about 28 minutes have passed since the output reached 800W, the temperature of the polymerization reaction liquid was 182℃, and the pressure was 3+n+n.
Hg was reached, and the polymerization reaction solution maintained a moderate bubbling state. After maintaining this state for 8 hours, the system was cooled to obtain 1.103 g of a solid polymerization reaction product. The molecular weight and molecular weight distribution of this polymerization reaction product were measured in the same manner as in Example 1, and the number average molecular weight was 5,840, Mw/M
The value of n was 2.15.
比較例１
実施例１におけると同様のセパラブルフラスコ内に濃度
９０重量％のし一乳酸水溶液１ 、５３０ ｇを仕込み
、これをマイクロ波照射用オープンの代わりにオイルバ
ス上にセットし、攪拌しながら窒素ガスを流し始めると
同時に反応容器内の温度を９０℃まで徐々に上昇させた
。これと並行して、セパラブルフラスコ内を圧力が３Ｑ
ｓ＋ｍＨｇとなるよう減圧状態にした。この状態を５５
分間維持して重合反応を行い、重合反応液のバブリング
状態が穏やかになった時点で留出水を水分離管を介して
除去した。Comparative Example 1 In a separable flask similar to that in Example 1, 530 g of a 90% by weight aqueous lactic acid solution was placed on an oil bath instead of the microwave irradiation open, and stirred. At the same time as starting to flow nitrogen gas, the temperature inside the reaction vessel was gradually raised to 90°C. At the same time, the pressure inside the separable flask increases to 3Q.
The pressure was reduced to s+mHg. This state is 55
The polymerization reaction was carried out for a minute, and when the bubbling state of the polymerization reaction liquid became calm, distilled water was removed through a water separation tube.
そしてセパラブルフラスコ内の温度を１８５℃、圧力を
３ ｍ＋ｓＨｇとして８時間重合反応を続行した。冷却
後、重合反応生成物を取り出したところ、８９３ｇであ
った。また、この重合反応生成物の分子量および分子量
分布を実施例１と同様にして測定したところ、数平均分
子量は２．１００と小さく、またＭ ｗ ／ Ｍ ｎの
値は３．７５であった。Then, the temperature inside the separable flask was set to 185° C., the pressure was set to 3 m+sHg, and the polymerization reaction was continued for 8 hours. After cooling, the polymerization reaction product was taken out and weighed 893 g. Furthermore, when the molecular weight and molecular weight distribution of this polymerization reaction product were measured in the same manner as in Example 1, the number average molecular weight was as small as 2.100, and the value of M w /M n was 3.75.
比較例２
実施例１におけると同様のセパラブルフラスコ内に濃度
９０重量％のし一乳酸水溶液１．４５０ｇを仕込み、こ
れをマイクロ波照射用オーブンの代わりにオイルバス上
にセットし、攪拌しながら窒素ガスを流し始めると同時
に反応容器内の温度を１００℃まで徐々に上昇させた。Comparative Example 2 1.450 g of a 90% by weight aqueous monolactic acid solution was placed in a separable flask similar to that in Example 1, placed on an oil bath instead of a microwave irradiation oven, and heated while stirring. At the same time as starting to flow nitrogen gas, the temperature inside the reaction vessel was gradually raised to 100°C.
これと並行して、セパラブルフラスコ内を圧力が３０ｍ
麟Ｈ，となるよう減圧状態にした。この状態を１時間維
持して重合反応を行い、重合反応液のバブリング状態が
穏やかになった時点で留出水を水分離管を介して除去し
た。In parallel with this, the pressure inside the separable flask was increased to 30 m.
The pressure was reduced to Rin H. This state was maintained for 1 hour to carry out the polymerization reaction, and when the bubbling state of the polymerization reaction liquid became calm, the distilled water was removed through the water separation tube.
そしてセパラブルフラスコ内の温度を２３０ ℃、圧力
を５ 謄ｍＨｇとして９時間重合反応を続行した。冷却
後、重合反応生成物を取り出したところ、８６９ｇであ
った。また、この重合反応生成物の分子量および分子量
分布を実施例１と同様にして測定したところ、数平均分
子量は１ 、０３０と小さく、またＭｗ／ＭｎＯ値は３
．８１であった。また、この重合反応生成物のＪＩＳ
Ｋ１５５７−１９７０に記載の比色法によるＡＰＨＡ
Ｎｏ、は１００以上であった。Then, the temperature inside the separable flask was set at 230° C., the pressure was set at 5 mHg, and the polymerization reaction was continued for 9 hours. After cooling, the polymerization reaction product was taken out and weighed 869 g. Furthermore, when the molecular weight and molecular weight distribution of this polymerization reaction product were measured in the same manner as in Example 1, the number average molecular weight was as small as 1.030, and the Mw/MnO value was 3.
．． It was 81. In addition, the JIS of this polymerization reaction product
APHA by the colorimetric method described in K1557-1970
No. was 100 or more.
本発明により得られた乳酸および／またはグリコール酸
の（共）重合体は、誘電加熱により重合されるため、変
色がなく、熱劣化による変質や分解もないものである。Since the (co)polymer of lactic acid and/or glycolic acid obtained by the present invention is polymerized by dielectric heating, there is no discoloration, and there is no alteration or decomposition due to thermal deterioration.
また、本発明によれば、分子量が数千以上のものも短時
間で製造することができる。さらに、本発明により得ら
れた乳酸および／またはグリコール酸の（共）重合体は
、重合時に触媒を必要としないので不純物を含むことも
なく、医療用薬剤の担体、特に薬剤徐放担体として好適
に用いることができる。Further, according to the present invention, products having a molecular weight of several thousand or more can be produced in a short time. Furthermore, the (co)polymer of lactic acid and/or glycolic acid obtained by the present invention does not require a catalyst during polymerization and therefore does not contain any impurities, making it suitable as a carrier for medical drugs, especially as a sustained drug release carrier. It can be used for.
手続補正書（自発）
昭和６２年７月７７日
特許庁長官 小 川 邦 夫 殿
１、事件の表示
特願昭６１−２８３０６５号
２、発明の名称
乳酸および／またはグリコール酸の
（共）重合体の製造方法
３、補正をする者
事件との関係 特許出願人
住 所 東京都中央区築地二丁目１１番２４号名 称
（４１７）日本合成ゴム株式会社４、代理人
５、補正の対象
６、補正の内容
（１）明細書第６頁第５行を下記のように訂正する。Procedural amendment (voluntary) July 77, 1985 Director General of the Patent Office Kunio Ogawa 1, Indication of the case Patent Application No. 1983-283065 2, Name of the invention (co)polymer of lactic acid and/or glycolic acid Manufacturing method 3, relationship with the case of the person making the amendment Patent applicant address 2-11-24 Tsukiji, Chuo-ku, Tokyo Name (417) Japan Synthetic Rubber Co., Ltd. 4, agent 5, subject of amendment 6, Contents of amendment (1) Line 5 of page 6 of the specification is corrected as follows.
「合反応容器内に電磁波を導入して直接誘電」（２）同
第９頁第１２行中「３０」をｒｌｏＯＪと訂正する。"Direct induction of electromagnetic waves by introducing electromagnetic waves into the reaction vessel" (2) Correct "30" in line 12 of page 9 to rloOJ.
（３）同第１２頁第８行中「２０Ｊを「５０」と訂正す
る。(3) "20J" in line 8 of page 12 is corrected to "50".
（４）同第１３頁第１６行から第１７行までの間を下記
のように訂正する。(4) The section between lines 16 and 17 on page 13 should be corrected as follows.
「このバブリング状態を１時間維持し、その後マイ」
（５）同第１７頁第３行中ｒｌｏＯＪをｒ ５００ Ｊ
と訂正する。"Maintain this bubbling state for 1 hour, then move on" (5) rloOJ in the 3rd line of page 17 of the same page as r 500 J
I am corrected.
Claims (1)
重合させることを特徴とする乳酸および／またはグリコ
ール酸の（共）重合体の製造方法。1) A method for producing a (co)polymer of lactic acid and/or glycolic acid, which comprises polymerizing lactic acid and/or glycolic acid by dielectric heating.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28306586A JPS63289020A (en) | 1986-11-29 | 1986-11-29 | Production of (co)polymer of lactic acid and/or glycolic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28306586A JPS63289020A (en) | 1986-11-29 | 1986-11-29 | Production of (co)polymer of lactic acid and/or glycolic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS63289020A true JPS63289020A (en) | 1988-11-25 |
Family
ID=17660747
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP28306586A Pending JPS63289020A (en) | 1986-11-29 | 1986-11-29 | Production of (co)polymer of lactic acid and/or glycolic acid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63289020A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2858616A1 (en) * | 2003-08-07 | 2005-02-11 | Aldivia Sa | METHOD OF ESTOLIDATION BY DIELECTRIC HEATING |
| JP2007002087A (en) * | 2005-06-23 | 2007-01-11 | Sumitomo Chemical Co Ltd | Polyester and method for producing the same |
| WO2007049707A1 (en) * | 2005-10-26 | 2007-05-03 | Mitsui Chemicals, Inc. | Process for producing glycolic acid |
| US7659322B1 (en) | 2004-12-16 | 2010-02-09 | Iowa State University Research Foundation, Inc. | Synthesis of anhydride containing polymers by microwave radiation |
| JP5229917B2 (en) * | 2007-05-16 | 2013-07-03 | 独立行政法人産業技術総合研究所 | Lactic acid oligomer and method for producing the same |
| JP2014504654A (en) * | 2010-12-30 | 2014-02-24 | クラリアント・ファイナンス・（ビーブイアイ）・リミテッド | Hydroxyl group and ester group-supported polymer and method for producing the same |
-
1986
- 1986-11-29 JP JP28306586A patent/JPS63289020A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2858616A1 (en) * | 2003-08-07 | 2005-02-11 | Aldivia Sa | METHOD OF ESTOLIDATION BY DIELECTRIC HEATING |
| WO2005014518A1 (en) * | 2003-08-07 | 2005-02-17 | Aldivia S.A. | Estoliding method using dielectric heating |
| US7659322B1 (en) | 2004-12-16 | 2010-02-09 | Iowa State University Research Foundation, Inc. | Synthesis of anhydride containing polymers by microwave radiation |
| JP2007002087A (en) * | 2005-06-23 | 2007-01-11 | Sumitomo Chemical Co Ltd | Polyester and method for producing the same |
| WO2007049707A1 (en) * | 2005-10-26 | 2007-05-03 | Mitsui Chemicals, Inc. | Process for producing glycolic acid |
| JPWO2007049707A1 (en) * | 2005-10-26 | 2009-04-30 | 三井化学株式会社 | Method for producing glycolic acid |
| US8519185B2 (en) | 2005-10-26 | 2013-08-27 | Mitsui Chemicals, Inc. | Process for producing glycolic acid |
| JP5229917B2 (en) * | 2007-05-16 | 2013-07-03 | 独立行政法人産業技術総合研究所 | Lactic acid oligomer and method for producing the same |
| JP2014504654A (en) * | 2010-12-30 | 2014-02-24 | クラリアント・ファイナンス・（ビーブイアイ）・リミテッド | Hydroxyl group and ester group-supported polymer and method for producing the same |
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