JP4537038B2 - Method for producing crosslinked gel - Google Patents

Description

  The present invention relates to a method for producing a crosslinked gel, and more particularly to an improvement in the degree of crosslinking of the crosslinked gel and the uniformity of crosslinking.

  The polymer gel basically consists of a polymer network and a solvent, and this polymer network is formed by crosslinking between polymer chains. For this reason, conventionally, a method of forming a gel by forming a cross-link between polymer chains is generally performed. As one of such methods, a method of forming a crosslink by reacting a polymer with a crosslinker is known. For example, a reactive functional group in the side chain, that is, a hydroxyl group, a carboxyl group, an amino group A polymer having a plurality of functional groups such as an aldehyde group, a hydroxyl group, a carboxylic acid group, an N-hydroxymethyl group, and an epoxy group. By reacting with a functional compound, a crosslinked gel in which polymer chains are crosslinked can be produced. Specific examples of the polymer having a reactive group include a polymer polysaccharide having a hydroxyl group, polyacrylic acid having a carboxyl group, polyacrylamide having an amino group, and the like.

  However, polymers such as the above-mentioned polysaccharides, polyacrylic acid, and polyacrylamide generally have a high viscosity in the state of a polymer solution subjected to the reaction, and the crosslinking reaction proceeds. As the molecular weight of the polymer increases, the viscosity of the reaction solution further increases. And when the viscosity of the reaction solution becomes high in this way, it becomes impossible to stir at all with a stirrer such as a magnetic stirrer, and even if a stirrer such as a propeller mixer or a disperser is used, the stirrer The entire reaction solution cannot be uniformly mixed and stirred only by shearing the periphery of. For this reason, it is difficult to prepare a cross-linked gel having a high degree of cross-linking by uniformly reacting a polymer with a cross-linking agent, and this method is particularly useful when a high-viscosity polymer solution is used. It was extremely difficult to obtain a cross-linked gel.

  On the other hand, a container containing the kneaded material as a conventional device for mixing and stirring a fluid material such as solder paste, dental impression material, fats and oils, resins, dyes, pigments, various powders, etc. It is known that a mixing and stirring device is used that is configured to revolve on its orbit while being held and revolved in a container holder (see, for example, Patent Documents 1 to 3).

Japanese Patent Laid-Open No. 10-43568 JP 2000-271465 A Japanese Utility Model Publication No. 5-32110

  The present invention has been made in view of the above problems, and in a method for producing a crosslinked gel by reacting a polymer and a crosslinking agent, a crosslinked gel having a high degree of crosslinking and uniformly crosslinked is obtained. It is an object of the present invention to provide a novel method for producing a crosslinked gel that can produce a crosslinked gel even when a high-viscosity polymer solution is used.

  As a result of intensive studies by the present inventors in view of the above-mentioned problems, the mixed solution of the polymer and the crosslinking agent is supplied to a mixing and stirring device having a rotation mechanism and a revolution mechanism, and mixed by revolving while rotating. -It has been found that a crosslinked gel having a high degree of crosslinking and uniformly crosslinked can be obtained by stirring. Further, it has been found that a crosslinked gel can be obtained even when a polymer solution having a high viscosity, which has been extremely difficult to prepare a crosslinked gel, has been completed, and the present invention has been completed.

That is, the method for producing a crosslinked gel according to the present invention includes (a) a crosslinkable polymer, (b) a crosslinking agent capable of crosslinking the crosslinkable polymer, and (c) the crosslinkable polymer can be dissolved. and a solvent, only contains the (a) the viscosity of the solution when dissolved crosslinkable polymer in (c) the solvent is contained in a container and the mixture is at least 3000 cps, revolving while rotating the container itself It is characterized by.

  In the method for producing a crosslinked gel, it is preferable that the (a) crosslinkable polymer is a polymer polysaccharide. In the method for producing a crosslinked gel, it is preferable that the (a) crosslinkable polymer is hyaluronic acid or chondroitin sulfate. In the method for producing a crosslinked gel, it is preferable that (b) the crosslinking agent is diepoxide or divinylsulfone.

  According to the method for producing a crosslinked gel according to the present invention, a crosslinked gel having a high degree of crosslinking and uniformly crosslinked can be obtained. In addition, a crosslinked gel can be produced even when a polymer solution having a very high viscosity, which has heretofore been extremely difficult to obtain a crosslinked gel, is used.

Hereinafter, embodiments of the present invention will be described in detail, but the present invention is not limited thereto.
The method for producing a crosslinked gel according to the present invention comprises: (a) a crosslinkable polymer; (b) a crosslinking agent capable of crosslinking the crosslinkable polymer; and (c) a solvent capable of dissolving the crosslinkable polymer; The mixture containing the above is contained in a container, and the container itself is revolved while rotating.
In the present invention, “crosslinked gel” means a polymer gel having a three-dimensional network structure crosslinked by bonding between polymer chains.

  The (a) crosslinkable polymer used in the present invention may be any polymer as long as it can cause crosslinking between polymer chains, and is not particularly limited. Such as hydroxyl group, alkoxy group, oxyalkylene group, carboxyl group, amino group, imino group, mercapto group, sulfonic acid group, halogen atom, nitrile group, isocyanate group, epoxy group, etc. in the side chain, terminal or molecular chain A polymer having a reactive functional group can be used.

  Specific examples of the crosslinkable polymer (a) used in the present invention include starch, agar, carrageenan, glucomannan, pectin, alginic acid, pectic acid, carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, gellan gum and guar gum. , Xanthan gum, hyaluronic acid, chitin, chitosan, curdlan, chondroitin sulfate and other polymeric polysaccharides, gelatin, collagen, ovalbumin, soy protein, casein, fibrin, elastin, keratin and other proteins, polyvinyl alcohol, polyvinyl methyl ether, Polydioxolane, polyethylene glycol, polypropylene glycol, polyacrylic acid, polymethacrylic acid, polyglutamic acid, polyvinyl acetate, polyvinylpyrrolidone, poly Nirupirijin, polyallylamine, polyethyleneimine, polylysine, polyacrylamide, dimethylaminopropyl acrylamide, polystyrene sulfonic acid, poly-chloromethyl styrene, synthetic polymers such as polyacrylonitrile and the like.

  The (b) cross-linking agent used in the present invention may be any as long as it can be cross-linked by bonding the polymer chains of the cross-linkable polymer (a). There is no particular limitation as long as it is present. The (b) crosslinking agent used in the present invention is, for example, a polyfunctional having two or more functional groups capable of forming a covalent bond by reacting with the reactive functional group of (a) the crosslinkable polymer. A compound can be appropriately selected and used depending on the type of (a) the crosslinkable polymer. Specifically, (a) when the crosslinkable polymer has a hydroxyl group or a carboxy group, a diepoxy compound having two epoxy groups that can react with the functional group to form a covalent bond (B) can be used as a crosslinking agent. Similarly, for example, when (a) the crosslinkable polymer has a hydroxyl group or an amino group, (b) a dialdehyde compound or dicarboxylic acid compound as a crosslinking agent, (a) the crosslinkable polymer is a carboxyl group, When it has a halogen atom, an isocyanate group or an epoxy group, (b) a diamine compound as a crosslinking agent, and (a) when the crosslinkable polymer has a carboxyl group, (b) as a crosslinking agent When the aziridine compound, (a) the crosslinkable polymer has a hydroxyl group, a carboxyl group, an amino group or a mercapto group, (b) a diisocyanate compound as the crosslinking agent, (a) the crosslinkable polymer has a diisocyanate group. In this case, a diol compound or a diamine compound can be used as the crosslinking agent (b).

  The (b) crosslinking agent used in the present invention includes, for example, (a) a crosslink between polymer chains by forming a coordinate bond or hydrogen bond with the reactive functional group of the crosslinkable polymer. The resulting compound can also be used. For example, when (a) the crosslinkable polymer has a functional group capable of forming a complex such as a hydroxyl group, a carboxy group or an amino group, a compound having a polyvalent metal ion is used as the (b) crosslinking agent. be able to.

  Examples of the crosslinking agent (b) used in the present invention include alkyl diepoxy compounds, specifically 1-3 butadiene diepoxide, 1,2,7,8-diepoxyoctane, 1,5-hexadiene diene. Epoxides, etc., or glycidyl diethers, specifically ethylene glycol diglycidyl ether, 1,4-butanediol glycidyl ether, bisphenol A glycidyl ether, divinyl sulfone, epichlorohydrin, etc., among these diepoxides Divinyl sulfone can be preferably used.

  The solvent (c) used in the present invention is not particularly limited as long as it can dissolve the (a) crosslinkable polymer. For example, when (a) a water-soluble polymer polysaccharide such as unmodified starch or agar is used as the crosslinkable polymer, water is naturally an aqueous solvent such as ethylene glycol or glycerin ( c) It can also be used as a solvent.

In the method for producing a crosslinked gel according to the present invention, usually, the container containing the mixture containing the essential components (a) to (c) described above is subjected to a mixing and stirring device having a rotation mechanism and a revolution mechanism. The container itself revolves while rotating.
Mixing and stirring devices having a rotation mechanism and a revolution mechanism are known to those skilled in the art. For example, JP-A-61-290946, JP-B-5-32110, JP-A-10-43568, JP-A-11- A mixing and stirring device described in JP-A No. 226376 and JP-A No. 2000-271465 can be used in the present invention.

Hereinafter, the present invention will be further described with reference to specific examples of the method for producing a crosslinked gel according to the present invention.
FIG. 1 shows a mixing and stirring apparatus according to an embodiment of the present invention.
A mixing and agitating device 10 according to an embodiment of the present invention includes a container main body 14 that accommodates a sample and a container lid 12 thereof, a container holder 16 that fixes and holds the container main body 14, and the container holder 16 along a rotation axis 18. A rotation mechanism 20 that rotates, a support portion 22 that supports the rotation mechanism 20, and a revolution mechanism 26 that rotates the support portion 22 along a revolution axis 24 are provided.
(Production example)
1) A mixed solution 30 containing (a) a cross-linkable polymer, (b) a cross-linking agent, and (c) a solvent is accommodated in the container main body 14 of the mixing and stirring device 10, and the container lid 12 is fitted into the container holder 14 Attach to 16.
2) The mixing and stirring device 10 is operated to rotate the rotation mechanism 20 and the revolution mechanism 26.

  In the above manufacturing example, the container holder 16 is rotated along the rotation axis 18 by the rotation mechanism 20, and the support portion 22 that supports the rotation mechanism 20 is rotated along the rotation axis 24 by the revolution mechanism 26. The mixed solution 30 containing (a) a crosslinkable polymer, (b) a crosslinker, and (c) a solvent accommodated in the container holder 16 rotates along the rotation axis 18 and at the same time, the revolution axis 24. Will revolve along.

  As described above, the mixed solution 30 containing (a) the crosslinkable polymer, (b) the crosslinking agent, and (c) the solvent is supplied to the mixing and stirring device 10 having the rotation mechanism 20 and the revolution mechanism 26. By mixing and stirring by revolving while rotating, it is possible to obtain a cross-linked gel that has a high degree of cross-linking and is uniformly cross-linked as compared with conventional mixing and stirring methods. Moreover, it is extremely difficult to prepare a crosslinked gel by the conventional mixing and stirring method, and the crosslinked gel can be obtained even when a high viscosity polymer solution is used.

  Usually, in the production of a crosslinked gel, a solution in which (a) a crosslinkable polymer is dissolved in about 1.0% in (c) a solvent is used. If the viscosity of the solution at this time is 3000 cps or more, In the case of using a conventional mixing and stirring method, for example, a mixing apparatus such as a propeller mixer, a disperser, or a mortar grinder, it is impossible or extremely difficult to prepare a crosslinked gel. On the other hand, according to the method for producing a crosslinked gel according to the present invention, even when the (a) solution of the crosslinkable polymer as described above has a very high viscosity, the degree of crosslinking is high and the crosslinking is uniformly performed. A crosslinked gel can be obtained.

Therefore, method for producing the crosslinked gels of the present invention, Ru der viscosity of the solution above 3000cps when dissolving (a) a crosslinkable polymer in (c) solvent. Furthermore, it is particularly useful when it is 10,000 cps or more. In the present invention, the viscosity of the solution means a viscosity value (cps) measured at 25 ° C.

  Further, the container holder 16 can rotate and revolve simultaneously by the rotation mechanism 20 and the revolution mechanism 26, and the rotation speed can be freely set. The rotation speed of the container holder 16 varies depending on the properties and capacity of the crosslinked gel to be prepared, and the scale of the container holder 16 and the mixing and stirring device 10, but usually the rotation speed is 60 to 1000 rotations / minute, the revolution speed. Is about 300 to 3000 rpm.

  Further, the time for reacting the mixed solution 30 by revolving while rotating the container holder 16 also depends on various conditions such as the properties and capacity of the prepared crosslinked gel and the scale of the apparatus, as in the case of the aforementioned rotation speed. Usually, it is about 10 seconds to 30 minutes.

  The crosslinked gel obtained by the method for producing a crosslinked gel according to the present invention can be used, for example, as a gel-like cosmetic, pharmaceutical, or food as it is or by blending it in an appropriate formulation. In addition, in the method for producing a crosslinked gel according to the present invention, in addition to the essential components (a) to (c) described above, components that are usually used in cosmetics, pharmaceuticals, foods, etc. Further, it can be blended in a blending amount that does not affect the effect.

EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in more detail, this invention is not limited by this.
In order to examine the production method of the crosslinked gel, the present inventors used (a) hyaluronic acid and chondroitin-6-sulfate as the crosslinkable polymer, (c) water as the solvent, the production method of the present invention, An attempt was made to prepare a crosslinked gel by a conventional production method. Table 1 shows the samples used for the production of the crosslinked gel and the evaluation results.
The manufacturing method and evaluation method of a crosslinked gel are as shown below. The viscosity was measured at 25 ° C. using an Ubbelohde viscosity tube.

Example 1-1
1) (c) 18 ml of water as a solvent was poured into the container (internal volume 200 ml) of the rotation-revolution mixing and stirring apparatus shown in FIG. 1, and (b) ethylene glycol diglycidyl ether 1 as a crosslinking agent. .83 g was dissolved. Furthermore, 2.0 g of hyaluronic acid (average molecular weight: 1,500,000) (a) as a crosslinkable polymer was added to this mixed solution, and left overnight at 5 ° C. to obtain a hyaluronic acid solution.
2) Add 2 ml of 2N sodium hydroxide solution to the hyaluronic acid solution of 1), and mix and stir for 5 minutes under the conditions of rotation: 600 rpm, revolution: 2000 rpm using a rotation-revolution mixing stirrer. Preparation was attempted.
* The viscosity of the 10% aqueous solution of hyaluronic acid used in the above test was 20000 cps.

Example 1-2
(A) 2.0 g of chondroitin-6-sulfuric acid (average molecular weight: 300,000) as the crosslinkable polymer, (b) 1.24 g of divinylsulfone as the crosslinking agent, and (c) 18 ml of water as the solvent, Example 1 In the same manner as in Example 1, preparation of a crosslinked gel was attempted.
* The chondroitin-6-sulfuric acid 10% aqueous solution used in the above test had a viscosity of 3000 cps.
Comparative Examples 1-1 and 1-3
Using the same sample as in Examples 1-1 and 1-2, mixing and stirring were performed for 20 minutes with a disperser (TK homodisper: manufactured by Tokushu Kika Kogyo Co., Ltd.) at a rotational speed of 5000 rpm. An attempt was made to prepare a crosslinked gel.
Comparative Examples 1-2 and 1-4
Using the same samples as in Examples 1-1 and 1-2, mixing and stirring were performed for 30 minutes with a propeller mixer (Three One Motor: manufactured by Shinto Kagaku Co., Ltd.) at a rotation speed of 500 rpm to prepare a crosslinked gel. Tried.

It was observed whether or not the product formed a crosslinked gel with a crosslinked gel-forming optical microscope (BX60: manufactured by Olympus Corporation).
○: A crosslinked gel is formed.
X: A crosslinked gel is not formed.

上記表１に示されるように、ディスパーザー、プロペラミキサーといった従来の混合攪拌機を用いた比較例１−１〜１−４では、架橋ゲルを形成することができない。これは、（ａ）架橋剤高分子として用いられるヒアルロン酸及びコンドロイチン−６−硫酸は、（ｃ）溶媒である水に１０％溶解した状態で、それぞれ２００００ｃｐｓ、３０００ｃｐｓと非常に高粘度であり、この高粘度溶液をディスパーザー、あるいはプロペラミキサーのような装置により混合攪拌しようとしても、高粘度溶液がせん断応力に対して容易に変形してしまい、攪拌部や乳棒の周辺部分のみしかせん断することができず、高粘度溶液全体を均一に混合攪拌することができないためである。

As shown in Table 1, in Comparative Examples 1-1 to 1-4 using a conventional mixing stirrer such as a disperser or a propeller mixer, a crosslinked gel cannot be formed. This is because (a) hyaluronic acid and chondroitin-6-sulfuric acid used as the cross-linking agent polymer have a very high viscosity of 20000 cps and 3000 cps, respectively, in a state where 10% is dissolved in (c) water as a solvent, Even if this high-viscosity solution is mixed and stirred by a device such as a disperser or propeller mixer, the high-viscosity solution is easily deformed by shear stress, and only the peripheral part of the stirring part and pestle is sheared. This is because the high viscosity solution cannot be uniformly mixed and stirred.

  On the other hand, in Examples 1-1 and 1-2 using the rotation-revolution mixing and stirring device of FIG. 1, the (a) solution of the crosslinking agent polymer has a very high viscosity, A good cross-linked gel could be formed. Further, when the obtained crosslinked gel was further observed with an optical microscope, it was revealed that the crosslinked gel was uniformly formed.

1 is an overall view of a mixing and stirring device used in a method for producing a crosslinked gel according to an embodiment of the present invention.

Explanation of symbols

DESCRIPTION OF SYMBOLS 10 Mixing and stirring apparatus 12 Container lid 14 Container main body 16 Container holder 18 Rotating shaft 20 Rotating mechanism 22 Support part 24 Revolving shaft 26 Revolving mechanism 30 Mixed solution

Claims (4)

(A) a crosslinkable polymer, (b) said crosslinking agent capable of crosslinking a crosslinkable polymer, seen containing a solvent, a capable of dissolving; (c) crosslinking the polymer, wherein (a) crosslinking (C) A method for producing a crosslinked gel, wherein a mixture of a solution having a viscosity of 3000 cps or more when dissolved in a solvent is contained in a container and revolved while rotating the container itself. 2. The method for producing a crosslinked gel according to claim 1 , wherein the crosslinkable polymer (a) is a polymer polysaccharide. 3. The method for producing a crosslinked gel according to claim 2 , wherein (a) the crosslinkable polymer is hyaluronic acid or chondroitin sulfate. 4. The method for producing a crosslinked gel according to claim 3 , wherein (b) the crosslinking agent is diepoxide or divinyl sulfone.

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