JP3491917B2 - Thermoreversible hydrogel material - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a hydrogel material that retains a large amount of water in a gel, and more particularly to a thermoreversible hydrogel material that reversibly gels with a change in temperature. The hydrogel material of the present invention can be used, for example, as a material separating material, a drug, an agricultural chemical, a cosmetic, or the like.

[0002]

2. Description of the Related Art Among water-soluble polymers, there are some water-soluble polymers which form hydrogels in a reversible manner and are widely used in industry. As such a water-soluble polymer,
It is well known that gelatin, which is a protein, and agar, which is a polysaccharide, are typical, and that these aqueous solutions lose their fluidity upon cooling to become jelly-like hydrogels, and return to the aqueous solution again by heating.

Contrary to this, an aqueous solution of methylcellulose, which is a polysaccharide derivative, is one that becomes a hydrogel by heating. However, a problem common to these systems is that it is difficult to secure quality stability because all of these water-soluble polymers are made of natural materials. In addition, in any of the systems, it takes a long time from reaching the gelation temperature to gelation, which has been a factor of reducing productivity when these systems are industrially used.

On the other hand, among the nonionic surfactants, there is one in which the aqueous solution thereof forms a hydrogel reversibly. For example, Pluronic F-12 in which polyethylene oxide is bonded to both ends of polypropylene oxide
7 (trade name, manufactured by Asahi Denka Kogyo Co., Ltd.)
It is known that a hydrogel is formed at a temperature higher than about 20 ° C, and an aqueous solution is formed at a lower temperature (eg, Intern
ational Journal of Pharmaceutics, 12, 147-152 (198
2)).

However, in the case of this material, about 20 w
There was a problem that the hydrogel was formed only at a high concentration of t% or more, and the water content in the hydrogel was low. Further, even if the gelation temperature is maintained above the gelation temperature at a high concentration of about 20 wt% or more, there is a problem that the gel will be dissolved by further adding water. Further, in the case of this material, since a high-concentration aqueous solution of about 20 wt% or more exhibits a very high osmotic pressure because it has a relatively low molecular weight, and easily penetrates cell membranes, etc., it is intended for use in cells, organisms, and living bodies. Sometimes caused inconvenience.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel thermoreversible hydrogel material which solves the problems of the conventional thermoreversible hydrogel material as described above.

[0007]

The above-mentioned object is to provide a thermoreversible hydrogel material of the present invention, that is, a block copolymer in which polypropylene oxide and another water-soluble polymer are bound to each other. A block copolymer having a degree of polymerization of propylene oxide of 2 to 200, two or more polypropylene oxide moieties present in the block copolymer, and a molecular weight of the block copolymer of at least 30,000 or more. It is achieved by a thermoreversible hydrogel material characterized in that

In the present invention, "polypropylene oxide" means a polymer of propylene oxide. This "polypropylene oxide" is sometimes called polypropylene oxide, polypropylene glycol, polyoxypropylene, or the like.

In the polypropylene oxide used in the present invention, the polymerization degree of propylene oxide is 2 to 2.
00, preferably 10 to 100. This degree of polymerization 2
In the range of up to 200, the aqueous solution of polypropylene oxide has a cloud point, and the cloud point decreases as the degree of polymerization increases. In the present invention, the cloud point of the aqueous solution of polypropylene oxide is preferably 0 to 90 ° C (further 0 to 40 ° C).

In the present invention, the cloud point of the polypropylene oxide aqueous solution can be measured, for example, as follows.

After cooling a polypropylene oxide aqueous solution having a concentration of 1 wt% to obtain a transparent uniform solution, the temperature is gradually raised (temperature rising rate 1 ° C./min), and the clouding point is the temperature at which white turbidity occurs for the first time.

In the thermoreversible hydrogel material of the present invention, it is important that the polypropylene oxide portion has a cloud point. As long as the polypropylene oxide portion has the cloud point, another alkylene oxide such as ethylene can be added to the polypropylene oxide portion. Oxide or tetramethylene oxide may be contained. In the present invention, the type of the terminal group of polypropylene oxide is not particularly limited,
The polypropylene oxide has, as an end group, a reactive functional group that can be used for binding to another hydrophilic polymer, for example, a hydroxyl group, an amino group, a carboxyl group, an isocyanate group, or a polymerizable group (for example, an acryloyl group). It is preferable to have. Normally, the number of reactive functional groups in one polypropylene oxide is preferably two, but may be one or three or more.

In the present invention, as the "other water-soluble polymer" which constitutes the thermoreversible hydrogel material in combination with the above-mentioned polypropylene oxide, water-soluble polymers other than polypropylene oxide can be used without particular limitation. is there. More specifically, for example, as such a water-soluble polymer, methyl cellulose, dextran, polyethylene oxide, polyvinyl alcohol, poly N-
Vinylpyrrolidone, polyvinyl pyridine, polyacrylamide, polymethacrylamide, poly N-methyl acrylamide, polyhydroxymethyl acrylate, polyacrylic acid, polymethacrylic acid, polyvinyl sulfonic acid, polystyrene sulfonic acid and salts thereof, poly N, N-dimethyl Examples thereof include aminoethyl methacrylate, poly N, N-diethylaminoethyl methacrylate, poly N, N-dimethylaminopropyl acrylamide and salts thereof.

The bond between the polypropylene oxide and the water-soluble polymer is, for example, anionic polymerization or cationic polymerization, and propylene oxide and a monomer (for example, ethylene oxide) constituting "another water-soluble polymer" are repeatedly and sequentially polymerized. By doing so, a block copolymer in which polypropylene oxide and “another water-soluble polymer” (for example, polyethylene oxide) are bound can be obtained.
Such a block copolymer can also be obtained by introducing a polymerizable group (for example, an acryloyl group) at the terminal of polypropylene oxide and then copolymerizing a monomer constituting the water-soluble polymer.

Furthermore, the hydrogel material of the present invention can be obtained by introducing into the water-soluble polymer a functional group capable of undergoing a binding reaction with a functional group at the terminal of polypropylene oxide (for example, a hydroxyl group) and reacting both. be able to. The hydrogel material of the present invention can also be obtained by connecting a material such as Pluronic F-127 (trade name, manufactured by Asahi Denka Kogyo Co., Ltd.) in which polyethylene glycol is bonded to both ends of polypropylene glycol. it can.

According to the knowledge of the present inventor, the block copolymer of the present invention obtained by the above means is water-soluble at a temperature lower than the cloud point of the polypropylene oxide portion in the molecule and becomes a uniform aqueous solution. However, at temperatures above the cloud point, the aqueous solution loses fluidity and can form hydrogels. According to the knowledge of the inventor,
Even if a large amount of water is added to the hydrogel at a temperature above the cloud point, the hydrogel will not dissolve.

The present inventor has observed that such a phenomenon also occurs in an aqueous solution of the block copolymer having a low concentration (10 wt% or less), because the block copolymer has a plurality of polypropylene oxide moieties in its molecule. Further, the present invention was completed by discovering that it is limited to the case where the molecular weight of the block copolymer is 30,000 or more.

The abundance ratio of the polypropylene oxide moiety in the block copolymer of the present invention is preferably in the range of about 5 wt% to about 90 wt%, and 30 to 70 w.
More preferably, it is in the range of about t%. When the abundance ratio of polypropylene oxide portion is less than 5 wt%, gelation becomes difficult, and when it exceeds 90 wt%, the water content of the hydrogel becomes low.

As described above, the hydrogel material of the present invention contains a specific block copolymer formed by binding polypropylene oxide and a water-soluble polymer. In such an aqueous solution of the block copolymer, In addition, a block copolymer composed of other polypropylene oxide and a water-soluble polymer may be mixed. That is,
Even if a block copolymer having only one polypropylene oxide in the molecule or a block copolymer having a molecular weight of less than 30,000 is mixed, the above-described thermoreversible gel of the aqueous solution of the block copolymer of the present invention is used. The chelation behavior is usually not disturbed. Thus, in the case where the block copolymer of the present invention is mixed with another polypropylene oxide and a block copolymer composed of a water-soluble polymer, 10 parts by weight of the block copolymer of the present invention may be mixed with other components. The amount of the "block copolymer consisting of polypropylene oxide and water-soluble polymer" is preferably 10 parts by weight or less, more preferably 1 part by weight or less.

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to the following examples.

[0021]

Example 1 10 g of polypropylene oxide-polyethylene oxide copolymer (propylene oxide / ethylene oxide average degree of polymerization of about 60/180, Asahi Denka Co., Ltd .: Pluronic F-127) was dried with 30 ml of dry chloroform.
0.13 g of hexamethylene diisocyanate was added in the presence of phosphorus pentoxide, and the mixture was reacted for 6 hours under reflux of boiling point. After distilling off the solvent under reduced pressure, the residue was dissolved in distilled water and subjected to ultrafiltration using an ultrafiltration membrane (Amicon PM-30) having a molecular weight cut off of 30,000 to obtain a high molecular weight polymer and a low molecular weight polymer. Fractionated. The resulting aqueous solution is freeze-dried to obtain F-12
7 high polymer and F-127 low polymer were obtained.

The above F-127 high polymer (hydrogel material of the present invention) was dissolved in distilled water at a concentration of 8 wt% under ice cooling. When this aqueous solution is gradually heated,
The viscosity gradually increased from 0 ° C and solidified at about 27 ° C to form a hydrogel. When this hydrogel is cooled, 2
It returned to an aqueous solution at 1 ° C. This change was repeatedly observed reversibly.

On the other hand, the above F-127 low polymer dissolved in distilled water at a concentration of 8 wt% under ice cooling was 60 ° C.
No gel was formed at all even when heated above.

Example 2 To 1 mol of trimethylolpropane, 160 mol of ethylene oxide was added by cationic polymerization to obtain polyethylene oxide triol. 0.02 mol of this polyethylene oxide triol was added to 1000 m of distilled water.
0.1 mol of potassium permanganate was added, and an oxidation reaction was carried out at 25 ° C. for 60 minutes to obtain a polyethylene oxide tricarboxylate. 10 g of this polyethylene oxide tricarboxylate and 10 g of polypropylene oxide diamino (propylene oxide average degree of polymerization of about 65, Jefferson Chemical Co., USA: Jeffamine D-4000) 1000 g of carbon tetrachloride
Was added to the reaction mixture, 1.2 g of dicyclohexylcarbodiimide was added, and the mixture was reacted for 6 hours under reflux of boiling point. After cooling and filtering the reaction solution, the solvent was distilled off under reduced pressure, and the residue was vacuum dried to obtain the hydrogel material of the present invention.

8% by weight of this hydrogel material under ice cooling
It was dissolved in distilled water at a concentration of. When this aqueous solution is slowly heated, the viscosity gradually increases from 5 ° C to about 10 ° C.
It solidified and became a hydrogel. When this hydrogel was cooled, it returned to an aqueous solution at 5 ° C. This change was repeatedly observed reversibly. Further, when this hydrogel was put into a large amount of distilled water at 25 ° C., the hydrogel did not dissolve.

Example 3 11.1 g of N-vinylpyrrolidone (produced by Kanto Chemical Co., Inc.)
And acryloxysuccinimide (manufactured by Kokusan Kagaku Co., Ltd.)
0.9 g (molar ratio 95/5) of chloroform 400 m
0.135 g of azobisisobutyronitrile in 1
Was used as an initiator for radical polymerization at 60 ° C. for 6 hours to synthesize a random copolymer having an average molecular weight of about 200,000.

10 g of this random copolymer and a polypropylene oxide monoamino compound (propylene oxide / ethylene oxide average degree of polymerization of about 32/3, manufactured by Jefferson Chemical Company, USA: Jeffamine M-200)
5) 20 g was dissolved in 100 ml of chloroform and reacted at room temperature overnight. After adding an excess amount of ethanolamine to the reaction solution, the solvent was distilled off under reduced pressure. The residue was dissolved in distilled water, purified by dialysis, and freeze-dried to obtain the gel material of the present invention.

This gel material was dissolved in distilled water at a concentration of 8 wt% under ice cooling. When this aqueous solution was gradually heated, the viscosity gradually increased from 15 ° C and solidified at about 20 ° C to form a hydrogel. When this hydrogel was cooled, it returned to an aqueous solution at 15 ° C. This change was repeatedly observed reversibly.

Example 4 Chloroform was added with 10 g of polypropylene oxide diamino compound (average degree of polymerization of propylene oxide of about 65, manufactured by Jefferson Chemical Company: Jeffamine D-4000) and 0.85 g of acryloxysuccinimide (manufactured by Kokusan Kagaku Co., Ltd.). React in 100 ml at 25 ° C for 6 hours,
Polymerizable groups were introduced at both ends of polypropylene oxide.

After the solvent was distilled off under reduced pressure, the residue was distilled water 1000
Dissolved in ml. To this, 5 g of acrylamide, 0.5 g of ammonium persulfate, and 20 μl of tetramethylethylenediamine were added, and the mixture was reacted overnight under an ice-cooled nitrogen atmosphere. After purification by dialysis, it was freeze-dried to obtain the gel material of the present invention.

This gel material was dissolved in distilled water at a concentration of 8 wt% under ice cooling. When this aqueous solution was gradually heated, the viscosity gradually increased from 5 ° C and solidified at about 10 ° C to form a hydrogel. When this hydrogel was cooled, it returned to an aqueous solution at 5 ° C. This change was repeatedly observed reversibly.

[0032]

As described above, the present invention provides a novel thermoreversible hydrogel material comprising a block copolymer in which polypropylene oxide and another water-soluble polymer are bound. The aqueous solution of the thermoreversible hydrogel material of the present invention is an aqueous solution at a temperature lower than a specific temperature (gelling temperature), and can form a hydrogel at a temperature higher than the temperature. Since this gelling temperature depends on the cloud point of the polypropylene oxide portion in the thermoreversible gel material of the present invention, the gelling temperature can be arbitrarily controlled by adjusting the degree of polymerization of the propylene oxide.

Since the thermoreversible hydrogel material of the present invention is a synthetic material, it does not contain unknown impurities as found in natural materials and can easily guarantee the uniformity of composition and stability of performance. Further, since the thermoreversible hydrogel material of the present invention is a polymer having a large molecular weight, there is no concern about toxicity, and it can be used without problems in applications intended for cells, organisms, and living bodies. Further, in the hydrogel composed of the thermoreversible hydrogel material of the present invention, when the temperature is higher than the gelation temperature, there is a problem that the gel is dissolved even if water is further added to the hydrogel. Since it does not occur, the gel can be used in a state of being dispersed in water.

Further, since the aqueous solution of the thermoreversible hydrogel material of the present invention is capable of gelation even at a low concentration of 10 wt% or less, the water content of the hydrogel is high, and the separation of substances, pharmaceuticals, agricultural chemicals, cosmetics, etc. It can be preferably used for such purposes.

─────────────────────────────────────────────────── --Continued from the front page (58) Fields surveyed (Int.Cl. ⁷ , DB name) C08G 81/00 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A two or more polypropylene oxide portion
Is a block copolymer formed by bonding via other water-soluble polymer moieties ; the degree of polymerization of propylene oxide in the polypropylene oxide moiety is 2 to 200 , and the molecular weight of the block copolymer is at least 30,000 or more ; lower than cloud point of polypropylene oxide portion in the molecule
Water-soluble at temperatures, and soluble in water at temperatures above the cloud point
Contains a block copolymer that forms a hydrogel
Separation characterized by containing a thermoreversible hydrogel material
Material or cosmetics . 2. The separation material or cosmetic according to claim 1, wherein the polypropylene oxide gives a cloud point of 0 to 90 ° C. as an aqueous solution thereof .