WO2014042186A1 - Polymère sensible à la température et procédé de fabrication de celui-ci - Google Patents

Polymère sensible à la température et procédé de fabrication de celui-ci Download PDF

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Publication number
WO2014042186A1
WO2014042186A1 PCT/JP2013/074528 JP2013074528W WO2014042186A1 WO 2014042186 A1 WO2014042186 A1 WO 2014042186A1 JP 2013074528 W JP2013074528 W JP 2013074528W WO 2014042186 A1 WO2014042186 A1 WO 2014042186A1
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temperature
general formula
iii
formula
responsive polymer
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PCT/JP2013/074528
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English (en)
Japanese (ja)
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穣 山下
建 田保橋
木村　良晴
隆史 青木
嘉貢 西野
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味の素株式会社
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Publication of WO2014042186A1 publication Critical patent/WO2014042186A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
    • C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F220/52—Amides or imides
    • C08F220/54—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide
    • C08F220/60—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide containing nitrogen in addition to the carbonamido nitrogen
    • C08F220/603—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide containing nitrogen in addition to the carbonamido nitrogen and containing oxygen in addition to the carbonamido oxygen and nitrogen

Definitions

  • the present invention relates to a temperature-responsive polymer.
  • the present invention particularly relates to a temperature-responsive polymer including a copolymer of a zwitterionic monomer having a specific amino acid residue and a specific acrylic monomer.
  • a temperature-responsive polymer is a polymer that can reversibly change between a non-dissolved state (colloidal state) and a dissolved state in a solvent by changing the temperature.
  • the temperature-responsive polymer is a lower critical solution temperature (LCST) type temperature-responsive polymer that is solubilized when the temperature is lower than a certain temperature, and the upper critical solution temperature (Upper Critical solution temperature that is solubilized when the temperature is higher than a certain temperature).
  • Solution Temperature, UCST type temperature responsive polymer.
  • the UCST-type temperature-responsive polymer is solid at room temperature (25 ° C) and dissolves when entering the body, so it can be used as a sustained-release carrier for drugs and can be used in the field of drug delivery systems (DDS).
  • zwitterionic polymers represented by poly (2-methacryloyloxyethyl phosphoryl chlorin (MAC)) have an action of suppressing protein aggregation and adhesion of blood cells, etc. It has been used as an artificial organ material for a portion that comes into contact with blood such as a blood vessel or an artificial heart.
  • MAC 2-methacryloyloxyethyl phosphoryl chlorin
  • a polymer having both the characteristics of the temperature-responsive polymer and the characteristics of the zwitterionic polymer has been studied (see Non-Patent Documents 3 and 4).
  • a polymer showing zwitterionic properties has not been studied.
  • An object of the present invention is to provide an amino acid residue-containing polymer having properties of both a zwitterionic polymer and a temperature-responsive polymer, which has not been adopted in the prior art.
  • the present invention also provides a novel DDS that responds to changes in temperature while expressing appropriate biocompatibility by using an amino acid residue-containing polymer that has both the characteristics of the temperature-responsive polymer and the characteristics of the zwitterionic polymer.
  • the object is to provide a carrier.
  • the present invention further provides a protein aggregation suppressing action of an amino acid such as arginine and an action of solubilizing a drug that is hardly soluble in water by using a polymer having the amino acid residue. It aims at making it express effectively.
  • the present inventors have found that a specific copolymer containing a structural unit derived from a monomer having a zwitterionic amino acid residue and a structural unit derived from an acrylic monomer is good. It has been found that both temperature responsiveness and biocompatibility can be achieved, and the present invention has been completed. That is, the present invention can include the following contents.
  • a 1 is a group represented by the following general formula (II-1) or (II-2), and B 1 is a group represented by the following general formula (III-1) or (III -2) (wherein, in formula (III-1), R is -NH 2 , -NR 1 R 2 or -OR 3 , and R 1 to R 3 are each independently -H, C 1-10 An alkyl group or a C 2-10 alkenyl group, wherein R 4 is a C 1-10 alkylene group or a C 2-10 unsaturated alkylene group in formula (III-2).
  • Each of A 2 and B 2 is independently —H, —CH 3 or —C 2 H 5 , and the structural unit (a): structural unit (b) is in a molar ratio of 60:40 to 75:25, n is 20 to 500)
  • a temperature-responsive polymer represented by [2] The temperature-responsive polymer according to [1], wherein the molar ratio of the structural unit (a) to the structural unit (b) is 65:35 to 70:30.
  • [3] The temperature-responsive polymer according to [1] or [2], wherein A 1 is a group represented by the general formula (II-1), and A 2 is —H.
  • the B 1 is represented by the general formula (III-1) (in the formula (III-1), R is The temperature-responsive polymer according to any one of [1] to [3], wherein B 2 is —H.
  • R is The temperature-responsive polymer according to any one of [1] to [3], wherein B 2 is —H.
  • a temperature-responsive polymer composition comprising water and the temperature-responsive polymer according to any one of [1] to [4], having a pH of 3 to 9.
  • Each of A 2 and B 2 is independently —H, —CH 3 or —C 2 H 5 , and the structural unit (a): structural unit (b) is in a molar ratio of 60:40 to 75:25, n is 20 to 500)
  • the present invention provides a novel copolymer represented by the above general formula (I).
  • the novel copolymer of the present invention has a good upper limit solution temperature type temperature response.
  • the present invention is a copolymer containing a constitutional unit derived from a monomer having a zwitterionic amino acid residue such as an arginine residue, it is possible to use a drug that inhibits protein aggregation and is hardly soluble in water. It can be seen that it has a solubilizing action and biocompatibility.
  • the copolymer of this invention can be applied also as a surface modifier of the water treatment membrane used in order to desalinate seawater.
  • the copolymers of the present invention can be used as novel DDS carriers that are biocompatible and can respond to temperature changes.
  • Temperature-responsive polymer One aspect of the present invention is a temperature-responsive polymer represented by the following general formula (I). Hereafter, each functional group of general formula (I), each structural unit, etc. are demonstrated in detail.
  • a 1 is a group represented by the following general formula (II-1) or (II-2).
  • Formula (II-1) is a group containing an amino acid residue of arginine
  • Formula (II-2) is a group containing an amino acid residue of lysine. Since the functional group of each formula has both a carboxylic acid residue: —COO 2 — and an amino group: —NH 3 + , it can be a zwitterionic polymer.
  • a 1 is particularly preferably a functional group of the formula (II-1).
  • Each A 2 is independently —H, —CH 3 or —C 2 H 5 , preferably —H.
  • B 1 is a functional group represented by the following general formula (III-1) or (III-2).
  • R is —NH 2 , —NR 1 R 2 or —OR 3 .
  • R 1 to R 3 are each independently —H, a C 1-10 alkyl group or a C 2-10 alkenyl group, preferably —H, —CH 3 , —C 2 H 5 , —C 3 it is H 7.
  • -NH 2 (formula (III-1) is an acrylamide residue)
  • Formula (III-1) is an N, N-dimethylacrylamide residue
  • -OH formula (III-1) is an acrylic acid residue
  • R 4 is a C 1-10 alkylene group or a C 2-10 unsaturated alkylene group, preferably a C 1-5 alkylene group.
  • R 4 is particularly preferably —C 2 H 5 — (the formula (III-2) is a residue of 2-hydroxyethyl methacrylate (HEMA)).
  • B 2 is independently —H, —CH 3 or —C 2 H 5.
  • B is the formula (III-1)
  • —H is preferable
  • B is the formula (III-2). In some cases, -CH 3 is preferred.
  • the structural unit (a) represented by -CH 2 -C (-A 1 ) (-A 2 )-and -CH 2 -C (-B 1 ) (-B 2 )- And a structural unit (b).
  • the molar ratio of these structural units (a): structural units (b) contained in the copolymer of the present invention is, for example, 60:40 to 75:25, preferably 65:35 to 70:30, more preferably 66: 34-68: 32.
  • N in the general formula (I) is, for example, 20 to 500, preferably 20 to 300, more preferably 25 to 250.
  • the copolymer that can be represented by the general formula (I) may have any structure of a random copolymer, a block copolymer, and a graft copolymer composed of the structural units (a) and (b). .
  • the molecular weight of the copolymer is, for example, about 5000 to 50000, preferably about 7000 to 20000, and more preferably about 10,000 ⁇ 1000 to 2000.
  • the copolymer that can be represented by the above general formula (I) is a temperature-responsive polymer, more specifically, a temperature response of an upper critical solution temperature (Upper critical solution temperature, UCST) type that becomes soluble at a certain temperature or higher. It is a polymer.
  • the upper limit solution temperature can be measured using a known method.
  • the polymer to be measured is mixed with a solvent such as water or an organic solvent, and the solubility at a predetermined temperature is observed. Is determined by Examples of the organic solvent include methanol, ethanol, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), formaldehyde, ethylene glycol and the like.
  • the pH of the mixed solution of the solvent and the polymer is, for example, 1 to 11, preferably 2 to 10, and more preferably 3 to 9.
  • the upper limit solution temperature is usually 30 to 100 ° C., preferably 35 to 80 ° C., although it depends on the type of structural unit constituting the copolymer, the molecular weight, and the polymerization type (whether it is a random copolymer or a block copolymer). More preferably, it is in the range of 40 to 70 ° C.
  • the acrylamide derivative A represented by is prepared.
  • the acrylamide derivative A examples include acryloyl L-arginine, methacryloyl L-arginine, acryloyl L-lysine, and methacryloyl L-lysine. In addition to the L-form, it may be a D-form or a DL-form.
  • R 8 prepares a compound B represented by the general formula (III-1) or a group represented by the general formula (III-2).
  • compound B include acrylamide, N, N-dimethylacrylamide (DMAAm), acrylic acid, 2-hydroxyethyl methacrylate (HEMA), and the like.
  • the temperature-responsive polymer is obtained by polymerizing the acrylamide derivative A obtained in the step (1) and the compound B.
  • RAFT reversible addition-fragmentation chain
  • ATRP atom transfer radical
  • an azo initiator such as azobisisobutyronitrile (AIBN), benzoyl peroxide (BPO), or ammonium persulfate (APS) may be added as an initiator.
  • AIBN azobisisobutyronitrile
  • BPO benzoyl peroxide
  • APS ammonium persulfate
  • Temperature-responsive polymer composition Another embodiment of the present invention is a temperature-responsive polymer composition containing the above-described temperature-responsive polymer.
  • the temperature-responsive polymer composition may be in the form of an aqueous solution having a pH of, for example, 1 to 11, preferably 2 to 10, more preferably 3 to 9.
  • the temperature responsive polymer composition may preferably be a temperature responsive hydrogel.
  • the temperature-responsive hydrogel is obtained by forming a temperature-responsive polymer in the form of a polymer crosslinked body, and has a property of shrinking when the temperature is lower than the upper limit solution temperature and swelling when the temperature is higher than the upper limit solution temperature.
  • the temperature-responsive hydrogel having such characteristics can be used as a sustained-release carrier for drugs.
  • a known method for crosslinking a polymer can be used.
  • a temperature responsiveness is obtained by reacting in a solvent in the presence of a radical initiator and a crosslinking agent.
  • a polymer can be cross-linked to obtain a temperature-responsive hydrogel.
  • the solvent include dimethyl sulfoxide (DMSO) and dimethylformamide (DMF).
  • the radical initiator include azobisisobutyronitrile (AIBN).
  • the crosslinking agent include N-methylenebisacrylamide. .
  • acryloyl L-arginine (ALArg) As acrylamide derivative A, acryloyl L-arginine (ALArg) was prepared as follows. First, 8.7113 g (5.00 ⁇ 10 -2 mol) of L-arginine, 2.9737 g (5.30 ⁇ 10 -2 mol) of potassium hydroxide, 65 mL of water (H 2 O) and 65 mL of acetone are stirred in a 300 mL eggplant flask. did.
  • reaction solution was transferred to a separatory funnel, 130 mL of ethyl acetate was added, acrylic acid was extracted, and allowed to stand for 30 minutes. This operation with the separatory funnel was repeated three times. 15.0 mL of 3.0 mol / L KOH solution was added to the aqueous layer, and TLC measurement of the aqueous layer adjusted to pH 7 and the organic layer after repeating the operation with the above separating funnel for the third time was performed, and the product was extracted into the organic layer Confirmed that it was not done.
  • acetone in the aqueous layer (monomer aqueous solution) was distilled off using an evaporator, and 16.0 mL of a 3.0 mol / L HCl solution was added to adjust to pH 3.
  • This monomer aqueous solution was transferred to a separatory funnel, 50 mL of 1-butanol was added, extraction operation was performed, and the mixture was allowed to stand for 15 minutes.
  • the pH measurement of the obtained water layer and the TLC measurement of the water layer and the organic layer were performed. The extraction operation was repeated until no product spot was confirmed from the TLC result of the organic layer.
  • the organic layer (1-butanol solution) in which a monomer-only spot was confirmed by TLC measurement was placed in a 500 mL Erlenmeyer flask, and 30.0 mL of 1-butanol in which KOH was dissolved was further added to adjust to pH7.
  • Magnesium sulfate was added as a desiccant, stirred and allowed to stand overnight in the refrigerator. After standing, natural filtration was performed, and then 1-butanol was distilled off using an evaporator to obtain a concentrated monomer solution.
  • the concentrated monomer solution was added dropwise to 300 mL of ether and stirred for 1 hour to obtain a white solid.
  • the obtained white solid was suction filtered and dried under reduced pressure for 6 hours using a desiccator to obtain acryloyl L-arginine (ALArg) as acrylamide derivative A.
  • ALA-K (g): Amount of potassium salt of acryloyl L-arginine (g) DMAAm (g): N, N-dimethylacrylamide added amount (g) ALA-K: DMAAm (preparation ratio): molar ratio of added ALA-K and DMAAm M / I: total monomer (molar amount) / initiator (molar amount) APS: ammonium persulfate (as initiator) H 2 O (ml): amount of water added (ml)
  • FIGS. 1 to 3 show the 1 H-NMR spectra of the obtained Synthesis Examples 1 to 3, respectively.
  • the assignment of 1 H-NMR spectrum and the solvent used in each synthesis example are as follows.
  • dissolution test 2 Except for using various solvents instead of water as the solvent, dissolution test 2 was performed in the same manner as dissolution test 1, and the solubility of the copolymer was observed with the naked eye. The results are shown in Tables 7-9.
  • dissolution test 3 Except that the amount of poly (ALArg-co-DMAAm) in Synthesis Example 3 was 4.0 mg to 80.3 mg, dissolution test 3 was performed in the same manner as in dissolution test 1 for Synthesis Example 3, and the solubility of the copolymer was visually checked. Observed. The results are shown in Table 10. Moreover, the result of having measured the transmittance
  • the transmittance was measured by placing 4 cm 3 of an aqueous polymer solution in a quartz cell (optical path length: 1 mm) and changing the visible light transmittance of 500 nm while changing the temperature.
  • the heating rate was 0.5 ° C./min.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)

Abstract

L'invention concerne un polymère ionique amphotère, ledit polymère étant un polymère contenant un groupe résiduel acide aminé ayant également les propriétés d'un polymère sensible à la température. L'invention concerne de façon spécifique un polymère sensible à la température représenté par la formule générale (1). Dans la formule (1), A1 est un groupe représenté par la formule générale soit (II-1) soit (II-2) ci-dessous, B1 est un groupe fonctionnel représenté par la formule générale (III-1) ou (III-2) ci-dessous (dans la formule (III-1), R représente -NH2, -NR1R2 ou -OR3, R1 à R3 représentent, respectivement et indépendamment -H, des groupes alkyle en C1-10 ou des groupes alcényle en C2-10, et dans la formule (III-2), R4 représente un groupe alkylène en C1-10 ou un groupe alkylène insaturé en C2-10), A2 et B2 représentent, respectivement et indépendamment, -H, -CH3 ou -C2H５, et le rapport de unité de constituant (a) : unité de constituant (b) est, comme rapport molaire, 60:40 à 75:25, et n est de 20-500.
PCT/JP2013/074528 2012-09-11 2013-09-11 Polymère sensible à la température et procédé de fabrication de celui-ci WO2014042186A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107335127A (zh) * 2016-04-28 2017-11-10 美敦力心血管股份有限公司 医疗装置和用于覆盖医疗装置的可膨胀球囊的方法
CN110684150A (zh) * 2019-09-06 2020-01-14 南方医科大学 氨基酸纳米水凝胶及其制备方法和应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5891703A (ja) * 1981-11-19 1983-05-31 ソシエテ・デドウクスパンシオン・サイエンテイフイク「あ」エクスパンシア“ アミン活性化したアクリル共重合体および製法
JP2002145847A (ja) * 2000-11-01 2002-05-22 National Institute Of Advanced Industrial & Technology アミノ酸残基を有するアクリル酸誘導体
JP2004059540A (ja) * 2002-07-31 2004-02-26 Pola Chem Ind Inc 毛髪化粧料
JP2005002312A (ja) * 2003-08-21 2005-01-06 National Institute Of Advanced Industrial & Technology 熱応答性高分子材料

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5891703A (ja) * 1981-11-19 1983-05-31 ソシエテ・デドウクスパンシオン・サイエンテイフイク「あ」エクスパンシア“ アミン活性化したアクリル共重合体および製法
JP2002145847A (ja) * 2000-11-01 2002-05-22 National Institute Of Advanced Industrial & Technology アミノ酸残基を有するアクリル酸誘導体
JP2004059540A (ja) * 2002-07-31 2004-02-26 Pola Chem Ind Inc 毛髪化粧料
JP2005002312A (ja) * 2003-08-21 2005-01-06 National Institute Of Advanced Industrial & Technology 熱応答性高分子材料

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YAMEEN, BASIT ET AL.: "Single Conical Nanopores Displaying pH- Tunable Rectifying Characteristics. Manipulating Ionic Transport With Zwitterionic Polymer Brushes", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 131, no. 6, 2009, pages 2070 - 2071 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107335127A (zh) * 2016-04-28 2017-11-10 美敦力心血管股份有限公司 医疗装置和用于覆盖医疗装置的可膨胀球囊的方法
CN110684150A (zh) * 2019-09-06 2020-01-14 南方医科大学 氨基酸纳米水凝胶及其制备方法和应用
CN110684150B (zh) * 2019-09-06 2021-05-11 南方医科大学 氨基酸纳米水凝胶及其制备方法和应用

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