JPH08143631A - Temperature-sensitive polymer material and its production - Google Patents

Abstract

PURPOSE: To obtain the subject material comprising a copolymer of N-vinylic acid amides, sharp in the transition response speed, and capable of arbitrarily widely controlling the transition temperature. CONSTITUTION: This material comprises a copolymer containing (A) repeating units of formula I (R<1> is a 2-8C aliphatic hydrocarbon, a 4-8C alicyclic or aromatic hydrocarbon) (preferably containing isobutyric acid amide groups) and (B) repeating units of formula II (R<2> is H, methyl, ethyl, etc.,) (preferably containing acetoamide groups) in a weight ratio of 95:5 to 40:60 as main constituents. The material is synthesized by copolymerizing N-vinyl acid amides of formulas CH2 =CH-NH-CO-R<1> and CH2 =CH-NH-CO-R<2> , and is useful for uses such as gels for controlling the release of medicines and those for chromatographic separation and culture beds for cell culture.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a temperature-responsive polymer material and a method for producing the same.

[0002]

2. Description of the Related Art Recently, the development of stimuli-responsive materials has been actively pursued. Regarding temperature-responsive materials, N-isopropylacrylamide (NIPAAM),
Polymers synthesized from vinyl methyl ether and the like are being studied. The latter has poor polymerizability and little research has been done, whereas the former has been studied in detail because the reaction proceeds by ordinary radical polymerization and the copolymerization is easy. The aqueous solution of the NIPAAM homopolymer has a transition temperature in the vicinity of 32 ° C. and is dissolved on the lower temperature side, but precipitates on the higher temperature side.
Utilizing this fact, a cross-linking agent and a copolymer with other monomer are synthesized, and the control of drug release, separation gel for chromatography, development to cell culture bed and the like are being studied. However, the drawbacks of this NIPAM-based polymer include the toxicity of the monomer NIPAAM and the narrow control range of the transition temperature. The former toxicity problem may be able to remove the residual monomer by thoroughly washing the synthesized polymer, but the latter narrow temperature range is an essential problem and cannot be avoided. Generally, the transition point is moved to a low temperature side by copolymerizing a hydrophobic monomer such as butyl methacrylate, and conversely, the transition point is changed by copolymerizing a hydrophilic monomer such as N, N-dimethylacrylamide. Move to high temperature side. However, the range of movement is at most ± 10 ° C, and the response is slow (Proceedings of the Polymer Society of Japan, vol. 42, P. 311).
7, 1993, vol. 42, P.I. 3180,199
3 years). On the other hand, it has been recently reported that a homopolymer of N-vinylbutyric acid amide exhibits temperature response (Proceedings of the Polymer Society of Japan, vol. 42, P. 2742, 1993, v
ol. 43, P.I. 843, 1994) only discloses that this aqueous solution has a transition temperature around 25 ° C.

[0003]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a material having a sharp transition response speed and capable of arbitrarily controlling the transition temperature, and a method for producing the same.

[0004]

The inventors of the present invention have made extensive studies in view of such a situation. As a result, a material obtained by copolymerizing N-vinyl amide having a specific chemical structure has an extremely sensitive temperature response. The present inventors have found that the material can control the transition temperature in a wide range while maintaining That is, the present invention is achieved by the following.

(1) A temperature-responsive polymer material comprising a copolymer having repeating units (A) and (B) represented by the following structural formulas as main constituent components.

[0006]

Embedded image

[0007]

[Chemical 4]

In the formula, R ¹ represents a linear or branched aliphatic hydrocarbon group having 2 to 8 carbon atoms, or an alicyclic or aromatic hydrocarbon group having 4 to 8 carbon atoms, and R ² represents hydrogen. Group, methyl group,
Represents an ethyl group.

(2) The temperature-responsive polymer material according to (1), wherein the acid amide group (-NHCOR ¹ ) of the repeating unit (A) is an isobutyric acid amide group.

(3) The temperature-responsive polymer material according to (1) or (2), wherein the acid amide group (-NHCOR ² ) of the repeating unit (B) is an acetamide group.

(4) The weight composition ratio of the repeating unit (A) and the repeating unit (B) is 95: 5 to 40:60, and the temperature response is high as described in (1) to (3). Molecular material.

(5) The temperature-responsive polymer described in (1) to (4), which is synthesized by copolymerization of N-vinyl amides represented by the following chemical formulas (C) and (D). Material manufacturing method. _{CH 2 = CH-NH-CO} -R 1 (C) CH 2 = CH-NH-CO-R 2 (D) Incidentally, wherein R ¹ is a linear or branched aliphatic hydrocarbon having 2 to 8 carbon atoms Represents a group or an alicyclic or aromatic hydrocarbon group having 4 to 8 carbon atoms, and R ² represents a hydrogen group, a methyl group or an ethyl group.

(6) The method for producing a temperature-responsive polymer material described in (1) to (4), which is synthesized by acid amidation of polyvinylamine in a polymer reaction.

The temperature-responsive polymer material of the present invention is characterized by being a copolymer comprising both the repeating unit (A) and the repeating unit (B) in order to change the transition temperature of the polymer material in a wide range. Is.

In the repeating unit (A) constituting the copolymer of the present invention, the substituent R ¹ is ethyl group, propyl group, isopropyl group, isobutyl group, n-butyl group, hexyl group, 2-ethylhexyl group, etc. A linear or branched hydrocarbon group having 2 to 8 carbon atoms, or a cyclobutyl group,
Examples thereof include alicyclic or aromatic hydrocarbon groups having 4 to 8 carbon atoms such as cyclopentyl group, cyclohexyl group, phenyl group and toluyl group. Among them, those in which R ¹ is an isopropyl group, that is, one of the repeating units is isobutyric acid amidoethylene are particularly preferable in view of easiness of monomer synthesis or polymer reaction.

Further, in the repeating unit (B) constituting the copolymer of the present invention, the substituent R ² may be a hydrogen group, a methyl group or an ethyl group, but it is easy to carry out monomer synthesis or polymer reaction. Particularly preferred is the methyl group, ie where one of the repeating units is acetamidoethylene.

Further, the repeating unit (A) mainly has a function of expressing temperature responsiveness, and the repeating unit (B) mainly has a function of controlling transition temperature. When the substituent R ¹ or R ² is an ethyl group, that is, when the repeating unit is propionamidoethylene, it has both the function of expressing the temperature dependence and the function of controlling the transition temperature.

Therefore, in the temperature-responsive polymer material of the present invention, the transition temperature can be arbitrarily controlled by the composition ratio of the repeating units (A) and (B). That is, the transition point rises as the proportion of the repeating unit (B) increases. This temperature rising range cannot be limited because it depends on the chemical structures shown in the repeating units (A) and (B), but the repeating unit (A) is isobutyric acid amide ethylene type and the repeating unit (B) is acetamide ethylene type. In the case of, the composition ratio (A) / (B) is in the range of 95/5 to 30/70, preferably 95/5 to 40/60, and the transition temperature of the polymer material is from around room temperature to around 100 ° C. Change.

As the method for producing the temperature-responsive material in the present invention, a method via a vinyl monomer corresponding to each repeating unit (A) or (B) or an amide group is introduced by a polymer reaction based on polyvinylamine There is a way to do it.

As the former specific method, N-vinyl amide represented by the following chemical formula (C) and the following chemical formula (D)
Is a copolymerization with N-vinyl amide represented by CH ₂ ═CHNHCOR ¹ (C) The substituent R ¹ is a straight or branched chain having 2 to 8 carbon atoms such as ethyl group, propyl group, isopropyl group, isobutyl group, n-butyl group, hexyl group, 2-ethylhexyl group. Or a cycloaliphatic or aromatic hydrocarbon group having 4 to 8 carbon atoms such as a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group and a toluyl group. Of these, R ¹ is an isopropyl group, that is, N-vinylbutyric acid amide is particularly preferable because of ease of monomer synthesis or polymer reaction. CH ₂ ═CHNHCOR ² (D) The substituent R ² includes a hydrogen group, a methyl group, and an ethyl group, but a methyl group, that is, N-vinylacetamide is particularly preferable because of ease of monomer synthesis or polymer reaction.

Further, these N-vinyl acid amides (C)
(D) is a non-conjugated vinyl monomer and can be polymerized with a usual radical initiator. Specifically, peroxides such as benzoyl peroxide, cumyl peroxide, t-butyl oxide and ammonium persulfate,
Azobis compounds such as azobisisobutyronitrile and azobis-2-amidinopropane) dihydrochloride, and redox type initiators such as peroxide / amine type can be used.

Further, the present invention can be achieved by copolymerizing N-vinyl amide, but since these are vinyl monomers, a third monomer can also be copolymerized. Specific examples thereof include vinyl acetates such as vinyl acetate, vinyl propionate and vinyl butyrate, non-conjugated monomers such as vinyl chloride and N-vinylpyrrolidone, methyl (meth) acrylate, ethyl (meth) acrylate and (meth) acrylate. ) (Meth) such as butyl acrylate
Examples thereof include acrylic acid esters, acrylamides such as acrylamide, N, N-dimethylacrylamide, and N-isopropylacrylamide. The copolymerization ratio of these monomers is not particularly limited as long as it does not affect the temperature responsiveness. Further, in the present invention, upon polymerization, a polyfunctional monomer such as butylene bis-N-vinyl acetamide, methylene bis acrylamide, divinyl succinic acid ester, divinyl benzene is copolymerized in the range of 0.1 to 10 mol% to introduce a crosslinking point, and water is added. It is also possible to make an insoluble temperature-responsive highly hydrous hydrogel.

Specific examples of the latter include polyvinylamine obtained by hydrolysis of poly-N-vinylcarboxylic acid amide such as poly-N-vinylcarbazole or poly-N-vinylacetamide, and repeating unit (A).
A method of reacting with an acid chloride or acid anhydride of an organic carboxylic acid which induces an acid amide group in (B),
Alternatively, a method of amidating these organic carboxylic acids with a dehydrating condensing agent such as carbodiimide can be mentioned. In this polymer reaction, chlorides of polyvalent carboxylic acids such as succinic acid dichloride and terephthalic acid dichloride and / or
Alternatively, a polyhydric carboxylic acid anhydride may be used to introduce a crosslinked structure to form a water-insoluble temperature-responsive highly hydrous hydrogel.

The molecular weight of the temperature-responsive polymer of the present invention is preferably in the range of 10,000 to 500,000, more preferably 50,000 to 300,000.

The temperature-responsive polymer material of the present invention is a linear polymer material which is water-soluble at a transition temperature or lower, a high water-containing temperature-responsive hydrogel which is water-insoluble even at a transition point or lower, and a high water-containing temperature-responsive hydrogel. It can be used for a material that is coated or grafted on the surface of a molecular material. In addition, the transition temperature is room temperature to 1
Since it can be controlled arbitrarily within the range of 00 ° C or higher, its application is controlled release of drugs, separation and purification of biological components such as proteins,
It can be used in various industrial fields, including being able to develop into medical applications such as cell culture and biotechnology fields.

[0026]

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited thereto.

Examples 1 to 3 N-vinylbutyric acid amide and N-vinylacetamide synthesized by thermally decomposing N- (α-propoxyethylisobutyric acid amide) at 500 ° C. were used together with ammonium persulfate as an initiator. Polymerization was carried out, and the composition ratio of the resulting copolymer is shown in Table 1. The temperature response of the obtained polymer aqueous solution is shown in FIG. FIG.
The light transmittance of was measured with a spectrophotometer at 500 nm. Since the homopolymer of N-vinyl butyric acid amide has a transition temperature of 26 ° C., this result shows that the transition point can be arbitrarily controlled by copolymerizing N-vinyl acetamide.

Example 4 Poly-N-vinylacetamide was hydrolyzed in hydrochloric acid to prepare polyvinylamine hydrochloride. 1.3 mmol of this hydrochloride together with isobutyric acid (5 mmol) and water-soluble carbodiimide (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide 5 mmol and triethylamine (5 mmol) in a water solvent-
The reaction was carried out at 3 ° C. for 6 hours to obtain a polymer having 80% by weight of isobutyric acid amide groups introduced. This polymer was quantitatively reacted with acetyl chloride / pyridine in DMF to obtain a polymer having a target structure (20% by weight of acetylamide group). When the temperature response of this polymer aqueous solution was observed in the same manner as in Example 1, a sharp transition point was observed at around 42 ° C.

(Comparative Example 1) The copolymerization ratio was 80/20 (wt).
/ Wt) N-vinyl butyric acid amide and N, N-dimethyl acrylamide were synthesized and the temperature response was examined. The transition temperature was 31 ° C. Was small. Moreover, the responsiveness was also slow.

[0030]

[Table 1]

[0031]

EFFECT OF THE INVENTION The temperature-responsive polymer material of the present invention comprises a conventional N-isopropylacrylamide-based material, polyvinylmethyl amide-based material, and polyvinylmethylamide-based material by constituting the material with a copolymer of N-vinylamide having a specific chemical structure. Compared with an ether-based material, the transition temperature of the material can be controlled over a wide range from room temperature to around 100 ° C. while maintaining the sharp temperature response of the material. Therefore, it can be applied to a wide range of applications such as drug release control, chromatographic separation gel, cell culture bed, various mechanochemical materials, and actuators.

[Brief description of drawings]

FIG. 1 is a graph showing a relationship between temperature and light transmittance of a temperature-responsive polymer material according to the present invention.

[Explanation of symbols]

 -○-N-vinyl acetamide 50% (temperature rising process)-●-N-vinyl acetamide 50% (temperature decreasing process)-□-N-vinyl acetamide 40% (temperature rising process)-■-N-vinyl acetamide 40% (Cooling process)-△ -N-vinylacetamide 20% (Raising temperature process)-▲ -N-vinylacetamide 20% (Cooling process)

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Akira Mochizuki 1500 Inoguchi, Nakai-cho, Ashigarakami-gun, Kanagawa Terumo Corporation (72) Inventor Toru Kawashima 1500 Inoguchi, Nakai-cho, Ashigagami-gun, Kanagawa Terumo Corporation (72) Inventor Keitaro Morishita 1500 Inoguchi, Nakai-cho, Ashigarakami-gun, Kanagawa Prefecture Terumo Corporation

Claims (6)

[Claims] 1. A repeating unit (A) represented by the following structural formula:
And a temperature-responsive polymer material comprising a copolymer containing (B) as a main component. Embedded image Embedded image In the formula, R ¹ represents a linear or branched aliphatic hydrocarbon group having 2 to 8 carbon atoms or an alicyclic or aromatic hydrocarbon group having 4 to 8 carbon atoms, and R ² represents a hydrogen group or methyl group. Group represents an ethyl group. 2. The acid amide group (-of the repeating unit (A).
The temperature responsive polymer material according to claim 1, wherein NHCOR ¹ ) is an isobutyric acid amide group. 3. The acid amide group (-of the repeating unit (B).
NHCOR ² ) is an acetamide group, The temperature-responsive polymer material according to claim 1 or 2, characterized in that 4. The temperature-responsive polymer material according to claim 1, wherein the weight composition ratio of the repeating unit (A) and the repeating unit (B) is 95: 5 to 40:60. 5. N-represented by the following chemical formulas (C) and (D):
It synthesize | combines by the copolymerization of vinylic acid amide, The manufacturing method of the temperature-responsive polymer material of Claim 1 characterized by the above-mentioned. _{CH 2 = CH-NH-CO} -R 1 (C) CH 2 = CH-NH-CO-R 2 (D) Incidentally, wherein R ¹ is a linear or branched aliphatic hydrocarbon having 2 to 8 carbon atoms Represents a group or an alicyclic or aromatic hydrocarbon group having 4 to 8 carbon atoms, and R ² represents a hydrogen group, a methyl group or an ethyl group. 6. The method for producing a temperature-responsive polymer material according to claim 1, which is synthesized by acid amidation of polyvinylamine in a polymer reaction.