JP4131450B2 - Sugar-containing thermosensitive copolymer and method for producing the same - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a novel heat-responsive copolymer having a biodegradable structure and a method for producing the same.
[0002]
[Prior art]
In recent years, it has been elucidated that sugar chains play an important role in cell recognition and information transmission, and development of pharmaceuticals and functional materials using sugar chains is progressing. Poly (N-isopropylacrylamide), a thermosensitive polymer, exhibits a clear cloud point with respect to temperature changes in aqueous solution, so it can be used for material surface modification, material purification, drug delivery control, etc. Is expected.
[0003]
To date, N-isopropylacrylamide and N-acryloxysuccinimide [J. Control Release, 45: 95-101 (1997)], N-isopropylacrylamide and vinylpyrrolidone [J. Appl. Polym. Sci., 64: 1775 -1784 (1997)] have been reported, but these copolymers are composed of a polyacrylamide skeleton that is not biodegradable, and there is a risk of contaminating living bodies and the environment. In addition, no examples of copolymerization of this N-isopropylacrylamide and a polymerizable sugar ester have been reported so far.
[0004]
[Problems to be solved by the invention]
Accordingly, an object of the present invention is to provide a thermosensitive polymer having a biodegradable structure and a method for producing the same.
[0005]
[Means for Solving the Problems]
The present inventors have made intensive studies to achieve the above object, the polymerizable 6 -O- vinyladipoyl -D- glucose adipic acid vinyl ester is bonded to glucose, and N- isopropylacrylamide azo The present invention was completed by successfully synthesizing a sugar-containing polymer having a biodegradable polyvinyl alcohol skeleton by copolymerization in the presence of a radical polymerization initiator.
That is, according to the present invention, the following general formula (1)
[Chemical formula 5]
(In the formula, R ¹ is tetramethylene group, X represents a glucose residue has been removed is one hydroxyl group from glucose) and a structural unit represented by the following general formula represented by (2)
[Chemical 6]
(Wherein R ² represents a hydrogen atom and R ³ represents an isopropyl group ), and a copolymer containing 4 to 10 mol % of the structural unit (1) is provided. Moreover, according to the present invention, the following general formula (3)
[Chemical 7]
(In the formula, R ¹ is tetramethylene group, X represents a glucose or residues one hydroxyl group is removed from glucose) polymerizable saccharide represented by ester following general formula (4)
[Chemical 8]
Wherein the polymerizable acrylamide represented by (wherein R ² represents a hydrogen atom and R ³ represents an isopropyl group ) is radically polymerized in a solvent in the presence of a polymerization initiator. A manufacturing method is provided.
[0006]
DETAILED DESCRIPTION OF THE INVENTION
The polymerizable sugar ester used for the synthesis of the copolymer of the present invention is represented by the general formula (3). Examples of R ¹ that is an alkylene group include a tetramethylene group. Moreover, glucose is mentioned as the saccharide | sugar compound which gives the sugar residue X.
[0007]
The polymerizable sugar ester used in the present invention is obtained by chemically esterifying a dicarboxylic acid vinyl ester and a sugar compound, or enzymatically using a hydrolase (or a microorganism or the like that produces the enzyme). It can be synthesized by binding (or fermentatively). If by the enzymatic method, the alkaline protease from Bacillus Subtilis is preferably used as the enzyme. In the polymerizable acrylamide represented by the general formula (4) used in the present invention, R ³ represents an isopropyl group .
[0008]
The copolymer of the present invention can be produced, for example, by the following method. That is, the above sugar ester and N-isopropylacrylamide are dissolved in a solvent, and the mixture is dissolved in a radical polymerization initiator, preferably in the presence of an azo-based initiator such as α, α′-azobisisobutyronitrile. It is synthesized by reacting at 40 to 100 ° C. for 3 to 96 hours.
[0009]
The copolymer of the present invention comprises a structural unit represented by the structural unit represented by the structural units and the general formula represented by the general formula (1) (2), the structural unit (1), 4 Contains 10 mol%. In order to obtain a thermosensitive polymer having this biodegradable structure, the structural unit (1) and the structural unit (2) are continuous blocks each having an appropriate size, that is, a biodegradable sugar ester block and a thermosensitive polymer. A block copolymer having a responsive block is preferred.
[0010]
Although there is no restriction | limiting in particular in the molecular weight of the copolymer of this invention, Preferably it is 38000-59100 in a number average molecular weight. The molecular weight can be selected appropriately depending on the intended use of the copolymer. The number average molecular weight of the copolymer of the present invention is preferably 38000 to 59100 in order to be quickly decomposed after use or disposal. Moreover, the biodegradability of the copolymer can be increased by increasing the composition ratio of the polymerizable sugar ester.
[0011]
Since the copolymer of the present invention is a thermosensitive polymer having a sugar branch structure, it can be used as a thermosensitive functional material. Accordingly, the present invention also provides a heat-sensitive material containing the copolymer of the present invention as a main component. The heat-responsive polymer of the present invention can be used as an intelligent material, a substance purification material, a surface modification material, a drug delivery system control material, etc., but may contain other components that are usually used depending on each application. It's okay.
[0012]
【Example】
Hereinafter, the present description will be described in more detail with reference to examples. However, these are merely examples, and do not limit the scope of the present description.
[0013]
Example 1-5 (Synthesis of sugar ester-N-isopropylamide copolymer)
6- O- vinyladipoyl- D- glucose and N-isopropylacrylamide were dissolved together in 4 ml of dimethylformamide (DMF) sufficiently dried with molecular sieves (3A) to a concentration of 3 mol / l. The charged molar ratios of 6- O- vinyladipoyl- D- glucose and N-isopropylacrylamide were 5:95, 10:90, 15:85, 20:80, and 25:75, respectively. Subsequently, 40 mg of α, α′-azobis-isobutyronitrile was added, vacuum degassing was repeated three times, and the solution was heated at 55 ° C. for 24 hours. The reaction solution was dropped into 200 ml of diethyl ether, precipitated and purified, and the resulting copolymer was dried under reduced pressure at room temperature. Table 1 summarizes the composition ratio, number, and weight average molecular weight of the copolymers produced at each charge ratio.
[0014]
Comparative Example 1 (Synthesis of N-isopropylamide homopolymer)
1.36 g of N-isopropylacrylamide was dissolved in 4 ml of dimethylformamide (DMF) sufficiently dried with molecular sieves (3A). Subsequently, 40 mg of α, α′-azobis-isobutyronitrile was added, and after drying under reduced pressure three times, the solution was heated at 55 ° C. for 24 hours. The reaction solution was dropped into 200 ml of diethyl ether, precipitated and purified, and the purified polymer was dried under reduced pressure at room temperature. The composition ratio, number and weight average molecular weight of the N-isopropylamide homopolymer are also shown in Table 1.
[0016]
[Table 1]
[0017]
Test Example 1 (Evaluation 1 of thermal sensitivity)
In order to examine the thermal sensitivity of the five types of copolymers obtained in Examples 1 to 5 in an aqueous solution, transmittance was measured using an absorptiometer, and the cloud point due to temperature change was examined. For comparison, the same test was performed on the N-isopropylamide homopolymer obtained in Comparative Example 1. For the measurement, a 0.2 wt% aqueous solution was used, and the temperature was increased at a rate of 0.2 ° C./min. The results are shown in FIG. It was confirmed that the cloud point temperature of the five types of copolymers increased as the ratio of the sugar ester block increased.
[0018]
Test Example 2 (Evaluation 2 of thermal response)
In order to investigate the thermal responsiveness of the five types of copolymers obtained in Examples 1 to 5 in an aqueous solution, differential scanning calorimetry was performed using a differential scanning calorimeter, and the crystallization calorie change due to temperature change was examined. It was. For comparison, the same test was performed for the N-isopropylacrylamide homopolymer obtained in Comparative Example 1 and (1). For the measurement, a 10 wt% aqueous solution was used, and the temperature was increased at a rate of 0.5 ° C./min. The results are shown in FIG. In the N-isopropylamide homopolymer and the five copolymers, an endothermic peak was observed at a temperature almost the same as the cloud point by the transmittance measurement in Test Example 1, and the transition of the endothermic peak as the ratio of the sugar ester block increased. It was confirmed that the temperature of the spot was rising. Table 2 summarizes the transition points of each copolymer and the N-isopropylamide homopolymer obtained in Comparative Example 1.
[0019]
[Table 2]
[0020]
【The invention's effect】
The sugar-containing thermosensitive polymer of the present invention can sharply control the cloud point even when the copolymer composition ratio is changed, and has a biodegradable structure, so that it has high functionality. It is useful as a pharmaceutical material, a substance purification material and the like.
[Brief description of the drawings]
FIG. 1 is a graph showing the relationship between the temperature and transmittance of aqueous solutions of sugar ester-N-isopropylacrylamide copolymers having different composition ratios.
FIG. 2 is a graph showing the relationship between the temperature of an aqueous solution of sugar ester-N-isopropylacrylamide copolymers having different composition ratios and the change in calorific value.

Claims (2)

The following general formula (1)
(In the formula, R ¹ is tetramethylene group, X represents a glucose residue has been removed is one hydroxyl group from glucose) and a structural unit represented by the following general formula represented by (2)
(Wherein R ² represents a hydrogen atom and R ³ represents an isopropyl group ), and a copolymer containing 4 to 10 mol % of the structural unit (1). The following general formula (3)
(In the formula, R ¹ is tetramethylene group, X represents a glucose residue has been removed is one hydroxyl group from glucose) polymerizable sugar ester and following the general formula represented by (4)
The polymerizable acrylamide represented by the formula (wherein R ² represents a hydrogen atom and R ³ represents an isopropyl group ) is radically polymerized in a solvent in the presence of a polymerization initiator. A method for producing a copolymer of