KR100795214B1 - Thermogelling poly(ethylene glycol)/polycarbonate block copolymer and preparation method thereof - Google Patents

Thermogelling poly(ethylene glycol)/polycarbonate block copolymer and preparation method thereof Download PDF

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KR100795214B1
KR100795214B1 KR1020060079580A KR20060079580A KR100795214B1 KR 100795214 B1 KR100795214 B1 KR 100795214B1 KR 1020060079580 A KR1020060079580 A KR 1020060079580A KR 20060079580 A KR20060079580 A KR 20060079580A KR 100795214 B1 KR100795214 B1 KR 100795214B1
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ethylene glycol
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정병문
김소영
김현정
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이화여자대학교 산학협력단
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    • C08G2220/00—Compositions for preparing gels other than hydrogels, aerogels and xerogels

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Abstract

A thermogelling poly(ethylene glycol)/polycarbonate block copolymer is provided to be present in a hydrosol form at temperature lower than bodily temperature but be changed into hydrogel at temperature higher than bodily temperature. A poly(ethylene glycol)/polycarbonate block copolymer comprises poly(ethylene glycol) blocks having a molecular weight of 500-3000 dalton and hydrophobic polycarbonate blocks having a molecular weight of 300-10,000 dalton, and has a molecular weight ranging from 1,000 to 50,000, a poly(ethylene glycol) content of 12-25wt%, and a polycarbonate content of 75-88wt%. A method for preparing the poly(ethylene glycol)/polycarbonate block copolymer includes the steps of: (1) changing the terminal group of poly(ethylene glycol) into a carboxylic acid group; and (2) reacting the carboxylic acid group with polycarbonate having hydroxyl groups at both terminals thereof.

Description

온도 민감성 졸-젤 전이 폴리(에틸렌 글리콜)/폴리(카보네이트) 블록 공중합체 및 이의 제조 방법{THERMOGELLING POLY(ETHYLENE GLYCOL)/POLYCARBONATE BLOCK COPOLYMER AND PREPARATION METHOD THEREOF}Temperature sensitive sol-gel transition poly (ethylene glycol) / poly (carbonate) block copolymers and methods for preparing the same

도 1은 본 발명의 폴리(에틸렌 글리콜)/폴리(카보네이트) 이원 블록(diblock) 다중 블록(multiblock) 공중합체 수용액의 온도 및 농도에 따른 졸-젤 전이 거동을 보여주는 상전이 그래프이다.1 is a phase transition graph showing sol-gel transition behavior with temperature and concentration of poly (ethylene glycol) / poly (carbonate) diblock multiblock copolymer aqueous solutions of the present invention.

도 2는 35 중량% 농도의 PTC-PEG-PTC 삼원 공중합체 수용액 0.5 mL를 쥐의 피하(subcutaneous layer)에 주사하고, 1, 5, 10, 20일이 경과한 후에 수술하여 찍은 사진을 보여주는 것이다.FIG. 2 shows 0.5 mL of an aqueous solution of PTC-PEG-PTC terpolymer copolymer at a concentration of 35% by weight, injected into the subcutaneous layer of rats, and shows a photograph taken after 1, 5, 10 and 20 days. .

본 발명은 온도 민감성 폴리(에틸렌 글리콜)/폴리(카보네이트) 블록 공중합체 및 이의 제조 방법에 관한 것이다.The present invention relates to temperature sensitive poly (ethylene glycol) / poly (carbonate) block copolymers and processes for their preparation.

수용액 중에서 졸-젤 전이 반응을 나타내는 것으로 현재까지 보고된 고분자는 폴리(에틸렌 글리콜)-폴리(프로필렌 글리콜)-폴리(에틸렌 글리콜) (폴록사머), 폴리(N-이소프로필아크릴 아미드) 및 이의 공중합체, 폴리(에틸렌 글리콜)/폴리(락 타이드/글리콜라이드), 폴리(에틸렌 글리콜)/폴리프로필렌프말레이트, 키토산/글리세롤 인산염, 폴리포스파젠, 폴리(에틸렌 글리콜)/폴리카프로락톤 등이 있다. Polymers reported so far to exhibit sol-gel transition reactions in aqueous solutions are poly (ethylene glycol) -poly (propylene glycol) -poly (ethylene glycol) (poloxamer), poly (N-isopropylacrylamide) and its airborne Coalesce, poly (ethylene glycol) / poly (lactide / glycolide), poly (ethylene glycol) / polypropylenephmaleate, chitosan / glycerol phosphate, polyphosphazene, poly (ethylene glycol) / polycaprolactone and the like.

이들 고분자의 수용액은 상온 또는 그 이하의 온도에서는 용액 또는 졸 상태로 존재하지만, 체온 (37℃) 근처의 온도에서는 수화젤로 전이가 일어나므로, 이러한 고분자는 의약 전달 및 조직 공학 재료로 이용될 수 있을 것으로 유력시되고 있다. 즉, 졸 상태에서 의약 또는 세포와 혼합한 후에 피하 또는 근육 주사를 통하여 체내에 투입하여 원하는 부위에서 수화젤 (depot)이 순간적으로 만들어지도록 함으로써, 약물을 서서히 방출하거나 세포가 자라서 조직이 재생되도록 할 수 있다. 이런 생분해성 재료는 외과적 수술이 필요 없이 임플랜트(implant)를 만들고, 졸 상태에서 단순한 마이클로 필터를 통하여 살균이 가능하다.Aqueous solutions of these polymers exist in solution or sol at room temperature or below, but transition to hydrogels at temperatures near body temperature (37 ° C), so these polymers can be used as drug delivery and tissue engineering materials. It is likely to be. That is, after mixing with a medicine or cells in a sol state, it is injected into the body by subcutaneous or intramuscular injection to instantaneously make depot at a desired site, thereby slowly releasing the drug or allowing cells to grow and regenerate tissue. Can be. These biodegradable materials make implants without the need for surgery and can be sterilized through a simple Michael filter in a sol state.

그러나, 폴록사머, 폴리(N-이소프로필 아크릴아미드) 및 이의 공중합체는 생체 내에서 분해되지 않으며, 폴리(에틸렌 글리콜)-폴리(프로필렌 글리콜)-폴리(에틸렌 글리콜)의 경우 25 중량%의 수용액으로부터 만든 수화젤이라도 하루 이내에 용해되어 젤의 형태를 유지하지 못한다.However, poloxamer, poly (N-isopropyl acrylamide) and copolymers thereof do not decompose in vivo, and 25% by weight of aqueous solution for poly (ethylene glycol) -poly (propylene glycol) -poly (ethylene glycol) Even hydrogels made from these dissolve within one day and do not retain their gel form.

미국특허 제6,117,949호, 제6,201,072호, 제6,841,617호는 온도를 상승시킬 때 수용액에서 수화젤로 전이가 일어나는 폴리(에틸렌 글리콜)/폴리(락타이드/글리콜라이드) 및 이들의 의학적 응용을 기술하고 있다. 미국 특허 공개 공보 제 20060018949호는 온도를 상승시킬 때 수용액에서 수화젤로 전이가 일어나는 폴리(에틸렌 글리콜)/폴리프로필렌프말레이트 및 이들의 의학적 응용을 기술하고 있다. 그러나, 폴리(에틸렌 글리콜)/폴리(락타이드/글리콜라이드)와 폴리(에틸렌 글리 콜)/폴리(프로필렌 프말레이트)는 분해 시에 산이 발생하고, 녹이는 데에 오랜 시간이 소요되며, 또한 수용액 상태로 상온에서 보관하는 경우에는 불안정하여 쉽게 가수 분해된다. 또한, 졸-젤 전이가 일어나는 최소 농도가 10 중량% 이상으로 비교적 높다 는 단점이 있다. U.S. Pat.Nos. 6,117,949, 6,201,072, 6,841,617 describe poly (ethylene glycol) / poly (lactide / glycolide) and their medical applications in which the transition from aqueous solution to hydrogel occurs at elevated temperatures. . US Patent Publication No. 20060018949 describes poly (ethylene glycol) / polypropylenephmalate and their medical applications in which the transition from aqueous solution to hydrogel occurs when the temperature is raised. However, poly (ethylene glycol) / poly (lactide / glycolide) and poly (ethylene glycol) / poly (propylene frmlate) generate acid upon decomposition and take a long time to dissolve, and also in aqueous solution. When stored at room temperature, it is unstable and easily hydrolyzed. In addition, there is a disadvantage that the minimum concentration at which the sol-gel transition occurs is relatively high, such as 10% by weight or more.

미국 특허 공개 공보 제20050020808호는 온도를 상승시킬 때 수용액에서 수화젤로 전이가 일어나는 폴리포스파젠을, 미국특허 제6,344,488호는 키토산/글리세롤 인산염 및 이들의 의학적 응용을 기술하고 있다. 폴리(에틸렌 글리콜)/폴리(락타이드/글리콜라이드), 폴리(에틸렌 글리콜)/폴리(프로필렌 프말레이트), 폴리포스파젠 등은 엿 형상으로서, 용해시키는 데에 오랜 시간이 소요되는 단점이 있다.U.S. Patent Publication No. 20050020808 describes polyphosphazenes in which a transition from aqueous solution to hydrogel occurs when the temperature is raised, while U.S. Patent No. 6,344,488 describes chitosan / glycerol phosphate and their medical applications. Poly (ethylene glycol) / poly (lactide / glycolide), poly (ethylene glycol) / poly (propylene fmarlate), polyphosphazene and the like are malt-shaped and have a disadvantage in that it takes a long time to dissolve.

미국 특허 공개 공보 제20040077780호는 온도를 상승시킬 때 수용액에서 수화젤로 전이가 일어나는 폴리(에틸렌 글리콜)/폴리펩타이드 및 이들의 의학적 응용을 광범위하게 기술하고 있다.US Patent Publication No. 20040077780 describes a wide range of poly (ethylene glycol) / polypeptides and their medical applications in which the transition from aqueous solution to hydrogel occurs when the temperature is raised.

대한민국 특허 공개 공보 제2002-0023441호는 졸-겔 상전이를 일으키는 이소프로필아크릴아미드 공중합체 및 이를 이용한 혈관 폐색을 기술하고 있다. 그러나, 이들은 생체 내에서 분해되지 않으므로 의약 전달 또는 조직 공학용 재료로 응용하는 경우에 체내에서 제거하여야 한다는 한계가 있다. 또한, 아크릴아미드는 발암 물질로서, 잔류 단량체의 독성이 문제가 될 수 있다.Korean Patent Laid-Open Publication No. 2002-0023441 describes an isopropylacrylamide copolymer causing sol-gel phase transition and vascular occlusion using the same. However, since they are not degraded in vivo, there is a limitation that they should be removed in the body when applied as a material for drug delivery or tissue engineering. In addition, acrylamide is a carcinogen, and the toxicity of residual monomers may be a problem.

따라서 본 발명의 목적은 체온 (37℃) 이하의 온도에서는 수용액 (졸) 상태로 존재하나, 체온 이상의 온도에서 수화젤로 변하는 생분해성 폴리(에틸렌 글리 콜)/폴리(카보네이트) 블록 공중합체 및 이의 제조 방법을 제공하는 것이다. Accordingly, an object of the present invention is to present a biodegradable poly (ethylene glycol) / poly (carbonate) block copolymer which exists in an aqueous solution (sol) state at a temperature below the body temperature (37 ° C.) but turns into a hydrogel at a temperature above the body temperature. Providing a manufacturing method will be.

본 발명은 분자량 500 ~ 3000 달톤의 폴리(에틸렌 글리콜) (블록 A)과 분자량 300 ~ 2000 달톤의 소수성 폴리(카보네이트) (블록 B)로 이루어진 분자량 1,000 ~ 50,000의 폴리(에틸렌 글리콜)/폴리(카보네이트) 블록 공중합체 및 그 제조 방법에 관한 것이다. The present invention relates to a poly (ethylene glycol) / poly (carbonate) having a molecular weight of 1,000 to 50,000 consisting of a poly (ethylene glycol) having a molecular weight of 500 to 3000 daltons (block A) and a hydrophobic poly (carbonate) having a molecular weight of 300 to 2000 daltons (block B). ) Block copolymer and a method for producing the same.

폴리(에틸렌 글리콜)/폴리(카보네이트) 블록 공중합체의 분자량 범위가 1,000 ~ 50,000인 경우에 소수성과 친수성의 균형을 맞추기에 유리하다. 분자량이 10,000 이상인 폴리(에틸렌글리콜)은 주사 후에 체외로 배출되는 데에 한계가 있고, 분자량이 너무 크면 졸 상태에서의 점도가 너무 커서 주사하기에도 곤란하다. 따라서 본 발명에 있어서는 위와 같은 분자량 범위가 적당하다.It is advantageous to balance hydrophobicity and hydrophilicity when the molecular weight range of the poly (ethylene glycol) / poly (carbonate) block copolymer is 1,000 to 50,000. Poly (ethylene glycol) having a molecular weight of 10,000 or more has a limitation in being discharged out of the body after injection, and if the molecular weight is too large, the viscosity in the sol state is too large to be difficult to scan. Therefore, in the present invention, the above molecular weight range is suitable.

폴리(에틸렌 글리콜)/폴리(카보네이트) 블록 공중합체에 있어서, 상기 폴리(에틸렌 글리콜)의 함량은 10 ~ 45 중량%이고, 폴리(카보네이트)의 함량은 55 ~ 90 중량%인 것이 좋다. 폴리(에틸렌 글리콜)/폴리(카보네이트) 블록 공중합체가 이와 같은 조성을 갖는 경우에 소수성과 친수성의 균형으로 졸-젤 전이가 가능하게 된다. 폴리에틸렌글리콜의 함량이 너무 크면 물에 잘 용해되지만 졸-젤 전이가 관찰되지 않으며, 폴리(카보네이트)의 조성이 너무 크면 물에 용해되지 않는다.In the poly (ethylene glycol) / poly (carbonate) block copolymer, the content of the poly (ethylene glycol) is 10 to 45% by weight, the content of the poly (carbonate) is preferably 55 to 90% by weight. When the poly (ethylene glycol) / poly (carbonate) block copolymer has such a composition, a sol-gel transition is possible with a balance of hydrophobicity and hydrophilicity. If the content of polyethylene glycol is too large, it is well soluble in water, but no sol-gel transition is observed, and if the composition of poly (carbonate) is too large, it is insoluble in water.

상기 폴리(카보네이트)는 폴리(트리메틸렌 카보네이트) 또는 폴리(프로필렌 카보네이트)이거나, 이들 카보네이트 단량체를 50 중량% 이상 함유하는 락타이드, 카프로락톤, 글리콜라이드 등과의 공중합체일 수 있다. The poly (carbonate) may be poly (trimethylene carbonate) or poly (propylene carbonate) or a copolymer with lactide, caprolactone, glycolide, etc. containing 50 wt% or more of these carbonate monomers.

본 발명에 따른 폴리(에틸렌 글리콜)/폴리(카보네이트) 블록 공중합체의 수용액은 일정 농도 이상에서, 체온 (37℃) 이하의 온도에서는 수용액으로 존재하지만, 37℃ 이상의 온도에서는 수화젤로 전이가 일어나는 것을 특징으로 한다. 따라서 본 발명에 따른 블록 공중합체는 의약 전달 물질, 소수성 의약의 가용화제로 사용될 수 있으며, 세포 배양, 조직 공학 등, 의학적으로 응용될 가능성이 있다. The aqueous solution of the poly (ethylene glycol) / poly (carbonate) block copolymer according to the present invention exists as an aqueous solution at a temperature above a certain concentration and below a body temperature (37 ° C.), but at a temperature above 37 ° C., a transition to a hydrogel occurs. It is characterized by. Therefore, the block copolymer according to the present invention can be used as a drug delivery material, a solubilizing agent for a hydrophobic drug, and may have a medical application such as cell culture and tissue engineering.

또한, 상기 폴리(에틸렌 글리콜)/폴리(카보네이트) 블록 공중합체는 콘드로사이트, 배아 줄기 세포, 중간엽 줄기 세포, 간세포, 심장 줄기 세포, 심근 세포, 내피 세포 또는 섬유 아세포를 이용한 치료에 사용될 수도 있다.The poly (ethylene glycol) / poly (carbonate) block copolymers may also be used for treatment with chondrocytes, embryonic stem cells, mesenchymal stem cells, hepatocytes, heart stem cells, cardiomyocytes, endothelial cells or fibroblasts. have.

본 발명에 따른 폴리(에틸렌 글리콜)/폴리(카보네이트) 블록 공중합체는 폴리(에틸렌 글리콜)을 폴리(카보네이트)와 반응시켜 제조할 수 있다. 구체적으로는, 폴리에틸렌 글리콜을 무수숙신산 또는 2-브로모초산 (2-Bromoacetic acid)과 반응시켜 말단을 카르복실 산으로 변형시키고, 이를 히드록시기를 양 말단으로 갖는 폴리(카보네이트)와 디사이클로헥실 카보디이미드 또는 디에틸카보디이미드를 촉매로 사용하여 고분자 말단의 카르복실 산과 수산기를 연결시켜 다중 블록 공중합체를 제조한다. 연결 반응의 용매로는 메틸렌클롤라이드, 클로로포름 또는 테트라하이드로퓨란 등을 사용할 수 있고, 반응은 0 ~ 100℃에서 2 ~ 24시간 동안 진행시킨다. The poly (ethylene glycol) / poly (carbonate) block copolymers according to the invention can be prepared by reacting poly (ethylene glycol) with poly (carbonate). Specifically, polyethylene glycol is reacted with succinic anhydride or 2-bromoacetic acid to modify the ends to carboxylic acids, which are poly (carbonate) and dicyclohexyl carbodies having hydroxy groups at both ends. Using a mid or diethyl carbodiimide as a catalyst, a multiblock copolymer is prepared by connecting carboxylic acid and hydroxyl groups at the polymer terminal. Methylene chloride, chloroform or tetrahydrofuran may be used as a solvent for the coupling reaction, and the reaction is performed at 0 to 100 ° C. for 2 to 24 hours.

블록 공중합체는 이원 블록(diblock), 삼원 블록 (triblock), 다중 블록 (multiblock) 공중합체를 포함한다. 즉, 본 발명에 따른 폴리(에틸렌 글리콜)/폴리(카보네이트) 블록 공중합체는 AB, ABA, BAB 또는 (AB)n의 블록 구조를 가질 수 있다. 상기 n은 2~ 30의 정수이다.Block copolymers include diblock, triblock, multiblock copolymers. That is, the poly (ethylene glycol) / poly (carbonate) block copolymer according to the present invention may have a block structure of AB, ABA, BAB or (AB) n . N is an integer of 2 to 30.

이원 블록 공중합체는 모노메톡시 폴리(에틸렌글리콜)을 진공 또는 톨루엔 존재 하에 증류시켜 수분을 제거하고, 여기에 주석 옥토에스터(stannous otoate), 염산 등의 산/염기 촉매 하에 카보네이트를 넣고, 0 ~ 130℃에서 5 ~ 48시간 동안 반응시켜 얻을 수 있다. 삼원블록 공중합체는 모노메톡시 폴리(에틸렌글리콜) 대신에 폴리에틸렌글리콜을 이용하여 동일한 조건에서 반응시켜 얻을 수 있다. The binary block copolymer distills monomethoxy poly (ethyleneglycol) in the presence of vacuum or toluene to remove water, to which a carbonate is placed under an acid / base catalyst such as stannous otoate or hydrochloric acid. It can be obtained by reacting at 130 ℃ for 5 to 48 hours. Ternary block copolymers can be obtained by reaction under the same conditions using polyethylene glycol instead of monomethoxy poly (ethylene glycol).

본 발명에 따른 폴리(에틸렌 글리콜)/폴리(카보네이트) 블록 공중합체는 의약 전달 시스템 및 조직 공학에 응용될 수 있다. Poly (ethylene glycol) / poly (carbonate) block copolymers according to the present invention It can be applied to medical delivery systems and tissue engineering.

실시예Example

이하에서는 실시예를 통하여 본 발명을 더욱 상세히 설명한다. 그러나 실시예는 본 발명의 예시에 불과할 뿐, 본 발명의 범위가 이들 실시예에 의하여 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples. However, the examples are only illustrative of the present invention, and the scope of the present invention is not limited to these examples.

실시예에 있어서, 분자량 및 분자량 분포 분석은 젤투과 크로마토그래피(gel permeation chromatography: GPC)로 수행되었다. 수소의 핵자기 공명 스펙트럼은 Bruker DPX-250 NMR Spectrophotometer를, 적외선 흡수 스펙트럼은 Nicolet Impact 400 FT-IR Spectrophotometer를 각각 사용하여 측정하였다. In the examples, molecular weight and molecular weight distribution analysis were performed by gel permeation chromatography (GPC). Hydrogen nuclear magnetic resonance spectra were measured using a Bruker DPX-250 NMR Spectrophotometer and infrared absorption spectra using a Nicolet Impact 400 FT-IR Spectrophotometer.

졸-젤 전이 온도는 일정 온도에서 수용액이 든 시험관을 뒤집었을 때 30초간 흐르지 않으면 젤, 흐르면 졸로 정의하였다. The sol-gel transition temperature was defined as a gel when not flowing for 30 seconds when the test tube containing the aqueous solution was turned over at a predetermined temperature, and a sol when flowing.

실시예Example 1:  One: 폴리Poly (에틸렌 글리콜)-(Ethylene glycol) 폴리Poly (( 트리메틸렌Trimethylene 카보네이트Carbonate ) 이원 블록 공중합체의 합성Synthesis of Binary Block Copolymers

폴리(에틸렌 글리콜) (분자량: 550)(2.2 g)과 건조된 톨루엔 80 ml를 플라스크에 넣은 다음 질소 기류 하에서 증류하여, 최종 부피를 30 mL 내외로 만든다. 여기에 트리메틸렌 카보네이트 (8.8 g)와 주석 옥토에스터(stannous octoate) (13 ㎕)를 넣고, 120℃에서 24시간 동안 반응시킨다. 반응이 끝난 후, 반응 용액을 디에틸 에테르에 부어 침전시키고, 잔류 용매를 진공 펌프로 제거한다. 수율은 60~70% 이다. Poly (ethylene glycol) (molecular weight: 550) (2.2 g) and 80 ml of dried toluene are placed in a flask and then distilled under a stream of nitrogen to bring the final volume to around 30 mL. To this, trimethylene carbonate (8.8 g) and tin octoester (stannous octoate) (13 μl) were added and reacted at 120 ° C. for 24 hours. After the reaction is completed, the reaction solution is poured into diethyl ether to precipitate, and the residual solvent is removed by a vacuum pump. Yield is 60-70%.

1H-NMR (CDCl3): 2.1 (-OCOCH2 CH 2 CH2-), 3.6 (-O CH 2 CH 2 -), 4.2 (-OCO CH 2 CH2 CH 2 -), 4.3 (-OCH2 CH 2 OCOCH2CH2CH2-) 1 H-NMR (CDCl 3 ): 2.1 (-OCOCH 2 CH 2 CH 2- ), 3.6 (-O CH 2 CH 2- ), 4.2 (-OCO CH 2 CH 2 CH 2- ), 4.3 (-OCH 2 CH 2 OCOCH 2 CH 2 CH 2- )

FTIR (cm-1): 2969, 2908, 1745, 1462, 1407, 1361, 1332, 1247, 1104, 1035, 934, 792.FTIR (cm −1 ): 2969, 2908, 1745, 1462, 1407, 1361, 1332, 1247, 1104, 1035, 934, 792.

실시예Example 2:  2: 폴리(트리메틸렌 카보네이트)의Of poly (trimethylene carbonate) 합성 synthesis

1,6-핵산디올 (2.2 g)과 건조된 톨루엔 80 ml를 플라스크에 넣은 다음 질소 기류 하에서 증류하여, 최종 부피를 30 mL 내외로 만든다. 여기에 트리메틸렌 카보네이트 (2.2 g)와 주석 옥토에스터 (13 ㎕)를 넣은 후, 120℃에서 24시간 동안 반응시킨다. 반응이 끝난 후, 반응 용액을 디에틸 에테르에 부어 재침전시키고, 잔류 용매를 진공 펌프로 제거한다.1,6-Nuclear diol (2.2 g) and 80 ml of dried toluene are placed in a flask and then distilled under nitrogen stream to bring the final volume to around 30 mL. To this, trimethylene carbonate (2.2 g) and tin octoester (13 μl) were added, followed by reaction at 120 ° C. for 24 hours. After the reaction, the reaction solution Pour into diethyl ether to reprecipitate and remove residual solvent with a vacuum pump.

1H-NMR (CDCl3): 1.4 (-OCH2CH2 CH 2 CH 2 CH2CH2O-), 1.7 (-OCH2 CH 2 CH2CH2 CH 2 CH2O-), 2.1 (-OCOCH2 CH 2 CH2-), 4.1 (-O CH 2 CH2CH2CH2CH2 CH 2 O-), 4.2 (-OCO CH 2 CH2 CH 2 -) 1 H-NMR (CDCl 3 ): 1.4 (-OCH 2 CH 2 CH 2 CH 2 CH 2 CH 2 O-), 1.7 (-OCH 2 CH 2 CH 2 CH 2 CH 2 CH 2 O-), 2.1 (- OCOCH 2 CH 2 CH 2- ), 4.1 (-O CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 O-), 4.2 (-OCO CH 2 CH 2 CH 2- )

실시예 3: 폴리(에틸렌 글리콜)/폴리(트리메틸렌 카보네이트) 삼원 블록 공중합체의 합성Example 3: Synthesis of Poly (ethylene Glycol) / Poly (trimethylene carbonate) Ternary Block Copolymers

폴리(에틸렌 글리콜) (분자량: 1,000)(2.0 g)과 건조된 톨루엔 80 ml를 플라스크에 넣은 다음 질소 기류 하에서 증류하여, 최종 부피를 20 mL 내외로 만든다. 여기에 트리메틸렌 카보네이트 (4.4 g)와 주석 옥토에스터 (6.5 ㎕)를 넣은 후, 120℃에서 24시간 동안 반응시킨다. 반응이 끝난 후, 반응 용액을 디에틸 에테르에 부어 재침전시키고, 잔류 용매를 진공 펌프로 제거한다.Poly (ethylene glycol) (molecular weight: 1,000) (2.0 g) and 80 ml of dried toluene are placed in a flask and then distilled under a stream of nitrogen to bring the final volume to around 20 mL. Here, trimethylene carbonate (4.4 g) and tin octoester (6.5 μl) were added, followed by reaction at 120 ° C. for 24 hours. After the reaction was over, the reaction solution was poured in diethyl ether and reprecipitated to remove the remaining solvent with a vacuum pump.

1H-NMR (CDCl3): 1.4 (-OCH2CH2 CH 2 CH 2 CH2CH2O-), 1.7 (-OCH2 CH 2 CH2CH2 CH 2 CH2O-), 2.1 (-OCOCH2 CH 2 CH2-), 3.6 (-O CH 2 CH 2 -), 4.1 (-O CH 2 CH2CH2CH2CH2 CH 2 O-), 4.2 (-OCO CH 2 CH2 CH 2 -), 4.3 (-OCH2 CH 2 OCOCH2CH2CH2-) 1 H-NMR (CDCl 3 ): 1.4 (-OCH 2 CH 2 CH 2 CH 2 CH 2 CH 2 O-), 1.7 (-OCH 2 CH 2 CH 2 CH 2 CH 2 CH 2 O-), 2.1 (- OCOCH 2 CH 2 CH 2- ), 3.6 (-O CH 2 CH 2- ), 4.1 (-O CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 O-), 4.2 (-OCO CH 2 CH 2 CH 2 -), 4.3 (-OCH 2 CH 2 OCOCH 2 CH 2 CH 2- )

FTIR (cm-1): 2966, 2907, 2874, 1747, 1462, 1407, 1361, 1332, 1247, 1104, 1035, 937, 792.FTIR (cm −1 ): 2966, 2907, 2874, 1747, 1462, 1407, 1361, 1332, 1247, 1104, 1035, 937, 792.

실시예Example 4:  4: 폴리Poly (에틸렌 글리콜)/(Ethylene glycol) / 폴리Poly (( 트리메틸렌Trimethylene 카보네이트Carbonate ) 다중 블록 공중합체의 합성) Synthesis of Multiblock Copolymers

α,ω-디카르복시 폴리(에틸렌 글리콜) (분자량 600 달톤) (1.13 g)을 톨루엔 60 mL에 넣고, 톨루엔을 질소 기류 하에서 증류하여 제거한 후, 상온으로 식힌다. 여기에 메틸렌 클롤라이드 20 mL를 넣은 다음, 폴리(트리메틸렌 카보네이트)(분자량 570 달톤) (1.0 g), 디사이클로 카보디이미드 (0.91 g) 및 4-(디메틸아 미노)피리딘 (0.054 g)을 가하고, 상온에서 24시간 반응시킨다. 반응 용액을 디에틸에테르에 재침전시켜 폴리(에틸렌 글리콜)/폴리(트리메틸렌 카보네이트) 다중 공중합체를 정제한다. α, ω-dicarboxy poly (ethylene glycol) (molecular weight 600 Daltons) (1.13 g) is placed in 60 mL of toluene, toluene is distilled off under nitrogen stream, and cooled to room temperature. To this was added 20 mL of methylene chloride, followed by poly (trimethylene carbonate) (molecular weight 570 daltons) (1.0 g), dicyclo carbodiimide (0.91 g) and 4- (dimethylamino) pyridine (0.054 g). Add, and react at room temperature for 24 hours. The reaction solution is reprecipitated in diethyl ether to purify the poly (ethylene glycol) / poly (trimethylene carbonate) multicopolymer.

1H-NMR (CDCl3): 1.4 (-OCH2CH2 CH 2 CH 2 CH2CH2O-), 1.7 (-OCH2 CH 2 CH2CH2 CH 2 CH2O-), 2.1 (-OCOCH2 CH 2 CH2-), 3.6 (-O CH 2 CH 2 -), 4.1 (-O CH 2 CH2CH2CH2CH2 CH 2 O-), 4.2 (-OCO CH 2 CH2 CH 2 -), 4.3 (-OCH2 CH 2 OCOCH2CH2CH2-) 1 H-NMR (CDCl 3 ): 1.4 (-OCH 2 CH 2 CH 2 CH 2 CH 2 CH 2 O-), 1.7 (-OCH 2 CH 2 CH 2 CH 2 CH 2 CH 2 O-), 2.1 (- OCOCH 2 CH 2 CH 2- ), 3.6 (-O CH 2 CH 2- ), 4.1 (-O CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 O-), 4.2 (-OCO CH 2 CH 2 CH 2 -), 4.3 (-OCH 2 CH 2 OCOCH 2 CH 2 CH 2- )

FTIR (cm-1): 2869, 1747, 1459, 1406, 1361, 1330, 1248, 1114, 1035, 942, 792.FTIR (cm −1 ): 2869, 1747, 1459, 1406, 1361, 1330, 1248, 1114, 1035, 942, 792.

폴리(에틸렌 글리콜)을 표준 물질로 사용하여 젤투과 크로마토그래피로 분석한 결과, 실시예 4에서 합성된 폴리(에틸렌 글리콜)/폴리(트리메틸렌 카보네이트) 다중 블록 공중합체의 수평균 분자량은 13,600이고, 분포도 (polydispersity)는 1.7인 것으로 확인되었다.As a result of gel permeation chromatography using poly (ethylene glycol) as a standard material, the number average molecular weight of the poly (ethylene glycol) / poly (trimethylene carbonate) multiblock copolymer synthesized in Example 4 was 13,600, The polydispersity was found to be 1.7.

실시예 5: 졸-젤 전이 특성 분석 실험Example 5: Sol-Gel Transfer Characterization Experiments

시험관에 일정 농도의 수용액을 일정 온도의 욕조에 넣는다. 이때, 시험관을 뒤집어도 흐르지 않는 온도를 졸-젤 전이 온도로 정의한다. 온도를 1℃ 씩 상승시키면서 졸-젤 거동을 관찰한다. 이 절차에 따라 관찰된 상전이 결과는 도 1에 제시되어 있다. 본 발명의 졸-젤 전이가 일어나는 농도 범위는 10 ~ 50 중량% 수용액이며 젤의 존재 영역은 20 ~ 50℃이다. 주사 가능한 생체 재료로 이용하기 위해서 는 체온 근처 (32 ~ 42℃)에서 젤 상태로 존재하여야 한다. 따라서, 본 발명에 따른 폴리(에틸렌 글리콜)/폴리(카보네이트) 블록 공중합체는 의약 전달 시스템 및 조직 공학에 응용될 수 있을 것이다. In a test tube, a constant concentration of an aqueous solution is placed in a constant temperature bath. At this time, the temperature which does not flow even if the test tube is reversed is defined as the sol-gel transition temperature. Observe sol-gel behavior with increasing temperature in 1 ° C increments. The phase change results observed following this procedure are shown in FIG. 1. The concentration range in which the sol-gel transition of the present invention takes place is from 10 to 50% by weight in aqueous solution and the region in which the gel is present is from 20 to 50 ° C. To be used as an injectable biomaterial, it must be present in the gel near body temperature (32 to 42 ° C). Accordingly, the poly (ethylene glycol) / poly (carbonate) block copolymers according to the present invention may be applied to pharmaceutical delivery systems and tissue engineering.

실시예 6: 동물 실험 결과Example 6: Animal Experimental Results

0.5 mL의 PTC-PEG-PTC 삼원 공중합체 수용액 (35 중량%)을 쥐의 피하 (subcutaneous layer)에 주사하여 수화젤의 생성 및 분해 거동을 관찰하였다. 도 2는 주사 후에 1, 5, 10, 20일 후에 수술하여 찍은 사진으로서, 주사 후 20일 이상의 기간 동안 체내에서 젤 상태로 존재하는 것을 볼 수 있다. 따라서, 본 발명에 따른 폴리(에틸렌 글리콜)/폴리(카보네이트) 블록 공중합체를 이용하는 경우, 단순한 주사를 통하여 임플랜트를 만들 수 있다는 것이 검증되었다. 0.5 mL of an aqueous solution of PTC-PEG-PTC terpolymer (35 wt%) was injected into the subcutaneous layer of rats to observe the formation and degradation behavior of the hydrogel. 2 is a photograph taken after surgery 1, 5, 10, 20 days after the injection, it can be seen that the gel is present in the body for a period of 20 days or more after the injection. Thus, it has been verified that implants can be made by simple injection when using the poly (ethylene glycol) / poly (carbonate) block copolymers according to the invention.

본 발명에 따라 의약 전달 또는 조직 공학용으로 응용이 유망한 폴리(에틸렌 글리콜)/폴리(트리메틸렌 카보네이트) 블록 공중합체 및 이의 제조 방법이 제공되었다. 본 발명에 따른 폴리(에틸렌 글리콜)/폴리(트리메틸렌 카보네이트) 다중 블록 공중합체는 일정 농도 이상의 수용액에서 5℃ ~ 체온 (37℃)에서는 수용액으로 존재하나, 졸-젤 전이 온도 이상, 특히 체온 근처 (35 ~ 42℃) 에서는 고분자 수용액이 수화젤로 전이가 일어나므로, 의약 전달 물질 또는 조직 공학용 생체 재료 등으로 응용될 수 있을 것으로 기대된다.According to the present invention there is provided a promising poly (ethylene glycol) / poly (trimethylene carbonate) block copolymer and its preparation for medicinal delivery or tissue engineering. The poly (ethylene glycol) / poly (trimethylene carbonate) multiblock copolymers according to the invention are present as aqueous solutions at 5 ° C. to body temperature (37 ° C.) in aqueous solutions above a certain concentration, but above the sol-gel transition temperature, especially near body temperature. (35-42 ° C.) is expected to be applied as a drug delivery material or a biomaterial for tissue engineering since the polymer aqueous solution transitions to a hydrogel.

Claims (6)

분자량 500 ~ 3000 달톤의 폴리(에틸렌 글리콜) 블록과, 분자량 300 ~ 10,000 달톤의 소수성 폴리(카보네이트) 블록으로 이루어지고, It consists of a poly (ethylene glycol) block having a molecular weight of 500 to 3000 Daltons, and a hydrophobic poly (carbonate) block having a molecular weight of 300 to 10,000 Daltons, 분자량 범위가 1,000 ~ 50,000이며,The molecular weight ranges from 1,000 to 50,000, 폴리(에틸렌 글리콜)의 함량이 12 ~ 25 중량%이고, 폴리(카보네이트)의 함량이 75 ~ 88 중량%인 Poly (ethylene glycol) content of 12 to 25% by weight, poly (carbonate) content of 75 to 88% by weight 폴리(에틸렌 글리콜)/폴리(카보네이트) 블록 공중합체. Poly (ethylene glycol) / poly (carbonate) block copolymers. 제1항에 있어서, 폴리(에틸렌 글리콜)-폴리(카보네이트), 폴리(에틸렌 글리콜)-폴리(카보네이트)-폴리(에틸렌 글리콜), 폴리(카보네이트)-폴리(에틸렌 글리콜)-폴리(카보네이트) 또는 [폴리(에틸렌-글리콜)-폴리(카보네이트)]n의 블록 구조를 가지며, 상기 n은 2~3의 정수인 블록 공중합체. The method of claim 1 wherein the poly (ethylene glycol) -poly (carbonate), poly (ethylene glycol) -poly (carbonate) -poly (ethylene glycol), poly (carbonate) -poly (ethylene glycol) -poly (carbonate) or [poly (ethylene-glycol), poly (carbonate) having a block structure of n, wherein n is an integer block copolymers of two or three. 제1항에 있어서, 상기 폴리(카보네이트) 블록은 폴리(트리메틸렌 카보네이트) 또는 폴리(프로필렌 카보네이트)이거나, 상기 폴리(카보네이트) 단량체를 60 중량% 이상 함유하는 락타이드, 카프로락톤 또는 글리콜라이드와의 공중합체인 블록 공중합체.The method of claim 1, wherein the poly (carbonate) block is poly (trimethylene carbonate) or poly (propylene carbonate), or with lactide, caprolactone or glycolide containing 60% by weight or more of the poly (carbonate) monomer Block copolymers that are copolymers. 제1항에 있어서, 수용액 상태에서 10 ~ 체온 (37℃) 이하의 온도에서는 용액으로 존재하지만 졸-젤 전이 온도 이상의 온도에서는 수화젤로의 전이가 일어나는 것인 블록 공중합체.The block copolymer of claim 1, wherein the block copolymer exists as a solution at a temperature of 10 ° C. or less (37 ° C.) in an aqueous solution but occurs above a sol-gel transition temperature. 제1항에 있어서, 폴리(에틸렌 글리콜)의 함량이 14 ~ 20 중량%이고, 폴리(카보네이트)의 함량이 80 ~ 86 중량%인 블록 공중합체. The block copolymer according to claim 1, wherein the content of poly (ethylene glycol) is 14 to 20% by weight and the content of poly (carbonate) is 80 to 86% by weight. (1) 폴리에틸렌 글리콜의 말단을 카르복실산기로 변형시키는 단계와,(1) modifying the terminal of the polyethylene glycol to a carboxylic acid group, (2) 상기 카르복실산기를, 히드록시기를 양 말단으로 갖는 폴리(카보네이트)와 반응시키는 단계를 포함하는, (2) the carboxylic acid group, Reacting with a poly (carbonate) having a hydroxy group at both ends, 제1항에 따른 폴리(에틸렌 글리콜)/폴리(카보네이트) 블록 공중합체의 제조 방법.A process for producing a poly (ethylene glycol) / poly (carbonate) block copolymer according to claim 1.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015030535A1 (en) * 2013-08-29 2015-03-05 (주) 엘지화학 Terminal-modified polyoxyalkylene glycol and polycarbonate resin composition with improved optical properties, comprising same

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR19990067013A (en) * 1995-10-25 1999-08-16 젠터 게렌 엠. Thermosensitive Biodegradable Polymers Composed of Poly (ether-ester) Block Interpolymers
KR20040111466A (en) * 2002-05-03 2004-12-31 얀센 파마슈티카 엔.브이. Polymeric microemulsions
EP1555278A1 (en) 2004-01-15 2005-07-20 Innocore Technologies B.V. Biodegradable multi-block co-polymers

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR19990067013A (en) * 1995-10-25 1999-08-16 젠터 게렌 엠. Thermosensitive Biodegradable Polymers Composed of Poly (ether-ester) Block Interpolymers
KR20040111466A (en) * 2002-05-03 2004-12-31 얀센 파마슈티카 엔.브이. Polymeric microemulsions
EP1555278A1 (en) 2004-01-15 2005-07-20 Innocore Technologies B.V. Biodegradable multi-block co-polymers

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015030535A1 (en) * 2013-08-29 2015-03-05 (주) 엘지화학 Terminal-modified polyoxyalkylene glycol and polycarbonate resin composition with improved optical properties, comprising same
KR20150026965A (en) * 2013-08-29 2015-03-11 주식회사 엘지화학 Terminal-modified polyoxyalkylene glycol and optically improved polycarbonate resin composition containing the same
KR101602568B1 (en) 2013-08-29 2016-03-10 주식회사 엘지화학 Terminal-modified polyoxyalkylene glycol and optically improved polycarbonate resin composition containing the same
US9303121B2 (en) 2013-08-29 2016-04-05 Lg Chem, Ltd. Terminally modified polyoxyalkylene glycol and polycarbonate resin composition having improved optical characteristics comprising the same

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