JP2007119552A - Method for producing (meth)acrylic acid based water-containing gel form and (meth)acrylic acid based water-containing gel form - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method which arbitrarily adjusts the crosslinking rate in producing a water-containing gel form using a (meth)acrylic acid based polymer to be used in a percutaneous absorption preparation and a cosmetic or a cooling sheet and the like. <P>SOLUTION: In mixing a (meth)acrylic acid based polymer (component A) with an aluminum-containing compound (component B) and water (component C) to crosslink the (meth)acrylic acid based polymer, at least one metal salt (component D) selected from the group consisting of metal salts having a monovalent or divalent metallic ion is added to adjust the crosslinking rate of the (meth)acrylic acid based polymer to produce a (meth)acrylic acid based water-containing gel form. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention provides a crosslinking rate by adding a metal salt to a raw material composition at the time of producing a hydrogel body using a (meth) acrylic acid-based polymer, which is used for a transdermally absorbable preparation, a cosmetic or a cooling sheet. The present invention relates to a method for adjusting the cross-linking rate using the change of the.

In recent years, water-containing gel bodies using acrylic polymers have been frequently used in percutaneous absorption preparations, cooling sheets, cosmetics and the like for medical use. As a method for producing this hydrogel body, generally, a polymer such as sodium polyacrylate, polyacrylic acid, acrylic acid-sodium acrylate copolymer or polyacrylic acid crosslinked product is ion-crosslinked using an aluminum compound. (Japanese Patent Laid-Open No. 8-104631 and Japanese Patent Laid-Open No. 2002-
No. 275056).

Generally, an aluminum compound is hardly soluble in water. This is because if a material that is easily soluble in water is used, gel crosslinking proceeds at a stretch and the crosslinking becomes non-uniform. In addition, the crosslinking speed may be too high, resulting in manufacturing inconvenience. For this reason, a method is generally used in which an aluminum compound which is hardly soluble in water is gradually dissolved using an acid to be crosslinked. As the acid, an organic acid, in particular, oxycarboxylic acids having both a hydroxyl group and a carboxyl group in the molecule such as lactic acid and tartaric acid are used (Japanese Patent Laid-Open No. 60-226808).
JP-A-8-104631 JP 2002-275056 A JP 60-226808 A

  However, in practice, it is difficult to adjust the crosslinking rate even if the production is performed under the conditions disclosed in the above-mentioned patent documents, and in most cases, the crosslinking is too fast or too slow. When crosslinking is fast, the gel suddenly becomes hard and coating and molding become difficult. On the other hand, if it is too slow, for example, if it is applied to a nonwoven fabric as a support, it oozes out from the nonwoven fabric and takes time to cure, so the productivity is lowered.

  In order to solve these problems, a chelating agent such as disodium ethylenediaminetetraacetate or tetrasodium ethylenediaminetetraacetate dihydrate is added to slow the cross-linking, and aluminum is temporarily supplemented to progress the cross-linking. The method of delaying was taken. However, this method causes extremely slow crosslinking, and there are many limitations such as the effects on other raw materials and toxicity issues when applied to the human body, and the crosslinking cannot be accelerated. .

  In addition, there is a method of delaying the dissolution of aluminum ions by producing the hydrous gel (= kneading) at a low temperature, but the crosslinking rate is extremely slow and the production cost is increased. There was a problem. On the other hand, as a method for speeding up the crosslinking, there is a method of heating after molding. However, this method has problems that productivity is deteriorated, that it is difficult to mix a thermally unstable compound, and that the gel becomes non-uniform as the water volatilizes.

  From this situation, the problem of the above-mentioned conventional technology is solved, and the crosslinking rate of the (meth) acrylic acid polymer that can be applied to the same manufacturing process as that of the prior art with an extremely simple composition and no toxicity problem is adjusted. There was a need to provide a method.

  As a result of intensive studies in view of such circumstances, the inventors of the present invention have studied that the gel body is formulated by crosslinking the acrylate polymer using an aluminum-containing compound. By adding at least one metal salt selected from the group consisting of metal salts containing divalent metal ions, it was determined that the crosslinking rate of the gel body can be adjusted arbitrarily, and using various metal salts, The present invention has been completed by investigating the influence of the crosslinking rate on the crosslinking rate.

  That is, a metal salt containing at least one monovalent or divalent metal ion in a mixture containing a (meth) acrylic acid polymer (component A), an aluminum-containing compound (component B) and water (component C) It has been found that by adding (Component D), the crosslinking rate of the (meth) acrylic acid polymer can be arbitrarily adjusted.

The constituent features of the present invention are shown in the following [1] to [16].
[1] When the (meth) acrylic acid polymer (component A) is mixed with an aluminum-containing compound (component B) and water (component C) to crosslink the (meth) acrylic acid polymer, 1 Characterized in that the crosslinking rate of the (meth) acrylic acid polymer is adjusted by adding at least one metal salt (component D) selected from the group consisting of metal salts containing divalent or divalent metal ions. The manufacturing method of the (meth) acrylic-acid type hydrous gel body to do.
[2] The method for producing a (meth) acrylic acid-based hydrogel according to [1], wherein the metal salt (component D) is dissolved in water and added in advance.
[3] The method for producing a (meth) acrylic acid-based hydrogel according to [1] or [2], wherein the metal salt (component D) is added in a temperature range of 0 to 40 ° C.
[4] The (meth) acrylic acid polymer includes a repeating unit represented by the general formulas (1), (2) and (3),
—CH ₂ C (R ¹ ) (COOM) — (1)
^{_{-CH 2 C (R 2) (}} COOH) - (2)
-X- (3)
(In the formula, R ¹ and R ² each independently represent a hydrogen atom or a methyl group, M represents NH ₄ ⁺ or an alkali metal, and X represents a divalent organic group derived from an unsaturated monomer.)
(1) / (2) = 100/0 to 0/100 (molar ratio) and the total amount of (1) and (2) / (3) = 100/0 to 10/90 (molar ratio) The manufacturing method of the (meth) acrylic-acid type hydrous gel body in any one of 1]-[3].
[5] The method for producing a (meth) acrylic acid-based hydrogel according to [4], wherein the (meth) acrylic acid-based polymer (component A) is a sodium acrylate-N-vinylacetamide copolymer. .
[6] The M is sodium, and the repeating units (1) and (2) are in the range of (1) / (2) = 0/100 to 100/0 (molar ratio). (3) The method for producing a (meth) acrylic acid-based hydrogel according to [4], which does not contain.
[7] The (meth) acrylic acid according to any one of [1] to [6], wherein the average particle diameter (d50) of the (meth) acrylic acid polymer (component A) is in the range of 30 to 250 μm. A method for producing a water-containing gel body.
[8] The method for producing a (meth) acrylic acid-based hydrogel according to any one of [1] to [7], wherein the metal salt (component D) is sodium chloride.
[9] The method for producing a (meth) acrylic acid-based hydrogel according to any one of [1] to [7], wherein the metal salt (component D) is magnesium chloride.
[10] The method according to any one of [1] to [9], further including a polyhydric alcohol (component E)
A method for producing a (meth) acrylic acid-based hydrous gel.
[11] The process for producing a (meth) acrylic acid-based hydrogel according to [10], wherein the metal salt (component D) is dispersed in a polyhydric alcohol (component E) in advance and added.
[12] A (meth) acrylic acid-based water-containing gel obtained by the method for producing a (meth) acrylic acid-based water-containing gel according to any one of [1] to [11].
[13] The water-containing gel body according to [12], wherein the water-containing gel body contains 5 to 98% by mass of water.
[14] A transdermally absorbable preparation using the hydrogel body according to [12] or [13].
[15] A cooling sheet using the hydrogel as described in [12] or [13].
[16] A cosmetic using the hydrogel as described in [12] or [13].

According to the present invention, the crosslinking rate can be arbitrarily adjusted, and a desired gel can be prepared according to the purpose.
Furthermore, it has a very simple composition, has no toxicity problem, and can be applied to the same manufacturing process as before.

  The obtained gel has excellent properties such as excellent adhesion to the adherend, good usability, little irritation to the skin, and no separation liquid.

In the present invention, when producing a hydrogel body, the crosslinking rate of the (meth) acrylic acid polymer,
When the (meth) acrylic acid polymer (component A) is mixed with an aluminum-containing compound (component B) and water (component C) to crosslink the (meth) acrylic acid polymer, monovalent or 2 It is characterized by adding and adjusting at least one metal salt (component D) selected from the group consisting of metal salts containing a valent metal ion.

Thus, by adding component D, it becomes possible to arbitrarily adjust the crosslinking rate.
Although it is not clear about the reason, the present inventors assume as follows about the mechanism of the crosslinking rate adjustment by addition of a metal salt.

  When crosslinking is accelerated, the concentration of carboxylate increases with the presence of metal ions, and as a result, formation of ionic bonds between aluminum ions and (meth) acrylic acid polymer is promoted. It is done. Here, the tendency to increase the crosslinking rate is strong in a metal salt containing a monovalent metal, particularly a sodium salt.

  On the other hand, when the crosslinking is delayed, the carboxyl group in the (meth) acrylic acid polymer and the metal ion in the added metal salt are ion-bonded before the aluminum ion, and the aluminum ion and the (meth) acrylic acid heavy ion are bonded. This is because the formation of an ionic bond with the carboxyl group in the coalescence is hindered, and thereafter, the metal ion and the aluminum ion are substituted, and the crosslinking between the aluminum ion and the polymer proceeds. At this time, if the metal has a higher ionization tendency than aluminum, it is considered that the replacement of ions is made smoother. Here, it is a metal salt containing a divalent metal, especially a calcium salt, that tends to slow the crosslinking rate. This is because the calcium ions are carboxylated in the (meth) acrylic acid polymer prior to aluminum. This is considered to be because an ionic bond is formed with the group, and as a result, the polymer molecules are aggregated to reduce the gel strength.

(Component D)
Component D includes metal salts containing monovalent or divalent metal ions.
Monovalent metal salts containing lithium include lithium bromide, lithium iodide, lithium nitrate, lithium sulfide, lithium sulfate, lithium chloride, lithium carbonate, lithium fluoride, lithium niobate, lithium peroxide, water Lithium oxide, lithium molybdate, lithium perchlorate, lithium acetate, lithium formate, lithium tungstate, lithium hypochlorite, anhydrous lithium acetate dihydrate, lithium iodide dihydrate, lithium hydrogen sulfate, lithium acetate Dihydrate, lithium bromide monohydrate, lithium sulfate monohydrate, dilithium carbonate, dilithium carbonate, dilithium oxalate, dilithium sulfate, dilithium sulfate, lithium chromate dihydrate, lithium cobaltate, Lithium chromate dihydrate, lithium hydroxide monohydrate, lithium citrate tetrahydrate, Lithium phosphate tetrahydrate, lithium hydroxide monohydrate, lithium trihydrate perchlorate, lithium hexafluorophosphate, and the like lithium perchlorate trihydrate. As a compound containing sodium, sodium azide, sodium acetate, sodium acetylide, sodium bromide, sodium formate, sodium iodide, sodium lactate, sodium nitrate, sodium sulfate, sodium sulfide, sodium borate, sodium bromate, sodium chloride , Sodium hydride, sodium nitrite, sodium sulfite, sodium iodate, sodium phosphate, ecabet sodium, sodium butyrate, sodium heparin, sodium chlorate, sodium citrate, sodium cyanate, sodium cyanide, sodium fluoride, Sodium oleate, sodium oxalate, sodium peroxide, sodium silicate, sodium stannate, sodium carbonate, suramin sodium, sodium benzoate, sodium chlorite Sodium chromate, sodium hydroxide, sodium selenate, sodium selenide, sodium phosphate, sodium laurate, IMP disodium, sodium alginate, sodium perborate, sodium persulfate, sodium phosphite, sodium rhodanide , Disodium arsenate, sodium selenite, ampenac sodium, tolmetin sodium, sodium pyruvate, sodium saccharin, sodium aluminate, sodium gluconate, sodium polysulfide, sodium stearate, sodium valproate, sodium iopodate, Sodium bicarbonate, disodium carbonate, sodium periodate, leviparin sodium, porfimer sodium, carmonam sodium, cefminox sodium, flomoxefna Lithium, cephalothin sodium, cefazolin sodium, latamoxef sodium, sodium glutamate, sodium molybdate, sodium percarbonate, sodium perchlorate, sodium salicylate, sodium thiosulfate, thiamylal sodium, triclofos sodium, sodium bicarbonate, heavy Sodium chromate, sodium dichromate, sodium borofluoride, sodium acid sulfide disodium phosphate, beraprost sodium, cefotetan sodium, ceftezol sodium, faropenem sodium, trisodium citrate, cefapirin sodium, ampicillin sodium, Cefoxitin sodium, cefsulodin sodium, cefuroxime sodium, dantrolene sodium, sodium antimonate Sodium dithionite, sodium propionate, sodium tungstate, sodium pyrosulfite, trisodium phosphate, sodium triphosphate, sodium dithionite, dalteparin sodium, parnaparin sodium, danaparoid sodium, cefodizime Sodium, carmellose sodium, sodium iotaramate, sodium foscarnet, sodium metasulfite, cefotaxime sodium, cefpiramide sodium, sodium cyclamlate, diclofenac sodium, sodium hypochlorite, sodium thiocyanate, thiopental sodium, ticarcillin sodium, Fosfomycin sodium, sodium arsenate, sodium phosphinate, sodium hyaluronate, imitrodast sodium, Radesine sodium, sodium borohydride, sodium glucuronate, sodium aluminum sulfate, cefmetazole sodium, ceftizoxime sodium, cloxacillin sodium, sodium cyclamate, fluorescein sodium, liothyronine sodium, loxoprofen sodium, piperacillin sodium , Sodium hydrosulfite, sodium hypophosphite, sodium naphthionate, sodium permanganate, sodium pyrophosphate, fluvastatin sodium, pravastatin sodium, rabeprazole sodium, sodium methacrylate, amobarbital sodium, cefamandole sodium, cefoperazone sodium, Sodium ferrocyanide, sodium hydrogen sulfide, sodium metavanadate , Sodium fluorosilicate, sodium xanthate, sodium fluoroacetate, sodium lauryl sulfate, sodium cromoglycate, sodium picosulfate, sodium fluoroacetate, sodium metabisulfite, sodium taurocholate, sodium cerivastatin, sodium acetate trihydrate , Ceftriaxone sodium, sodium alginate, carbenicillin sodium, cefbuperazone sodium, monosodium fumarate, sodium levothyroxine, sodium dehydroacetate, sodium hydrogen sulfite, sodium sulfenicillin, sodium borate decahydrate, metavanadium Acid sodium, sodium metaperiodate, sodium cholate hydrate, sodium sulfate decahydrate, sodium dodecyl sulfate, Secobar Vital sodium, lobenzalite disodium, sodium deoxycholate, sodium nitroprusside, disodium carbonate, sodium dicloxacillin, sodium phthalocyanine, sodium thioglycolate, disodium sulfate, sodium sodium thiomalate, sodium 2-biphenylol, sodium cholate n-hydrate, sodium stannate trihydrate, sodium sulfide nonahydrate, disodium calcium edetate, sodium epoprostenol, sodium ferrous citrate, anhydrous sodium carbonate, sodium sulfite heptahydrate, cai aluminum Sodium phosphate, sodium caffeine benzoate, disodium hydrogen arsenate, sodium saccharin dihydrate, dibasic sodium phosphate, sodium trichloroacetate, sodium tripolyphosphate , Sodium peroxodisulfate, bromfenac sodium hydrate, sodium molybdate dihydrate, basic sodium phosphate, tribasic sodium phosphate, sodium trifluoroacetate, tetrasodium pyrophosphate, sodium chromate tetra Hydrate, sodium succinate hexahydrate, sodium dihydrogen citrate, sodium stearyl fumarate, sodium antimony tartrate, sodium cyanoborohydride, sodium dihydrogen phosphate, sodium plasterone sulfate, sodium selenite pentahydrate , Sodium dipicrylamine, sodium hexametaphosphate, sodium perborate tetrahydrate, sodium tetrahydroborate, sodium acyl β-alanine, sodium dihydrogen phosphate, sodium perchlorate monohydrate, (+)-pantothene Acid Thorium, sodium metasilicate (anhydrous), sodium tetrafluoroborate, sodium sulfanilate dihydrate, sodium cellulose sulfate, pantoprazole sodium hydrate, sodium chondroitin sulfate, disodium methylarsonate, disodium methylarsonate, Sodium hexafluorosilicate, sodium riboflavin phosphate, sodium sulfanilate dihydrate, sodium dextran sulfate sulfur, trisodium phosphate dodecahydrate, disodium 5'-guanylate, disodium inosinate Dextran sulfate sodium sulfur 18, sulfobromophthalein sodium, trisodium phosphate dodecahydrate, disodium 5'-cytidylate, sodium lauryl sulfonate, betamethasone sodium phosphate, poly Sodium styrenesulfonate, sodium prednisolone phosphate, pentachlorophenol sodium salt, dichloroisocyanuric acid, sodium salt, dexamethasone sodium phosphate, estramustine sodium phosphate, prednisolone sodium succinate, 1-sodium hydrogen fumarate, hexacyanoiron ( II) Sodium acid, sodium 1-dodecane sulfonate, sodium dihydrogen phosphate dihydrate, sodium carbazochrome sulfonate, sodium hydrocortisone phosphate, sodium 2-hydroxypropanoate, sodium pyrophosphate decahydrate, di pyrophosphate Disodium hydrogen, sodium dihydrogen phosphate dihydrate, disodium dihydrogen pyrophosphate, sodium triacetoxyborohydride, sodium hydrocortisone succinate, dibasic Sodium phosphate dodecahydrate, colistin sodium methanesulfonate, sodium dodecylbenzenesulfonate, chloramphenicol sodium succinate, sodium 2-hydroxypropionate, disodium 2-hydroxysuccinate, (Z) -9 -Sodium octadecenoate, disodium 2-hydroxysuccinate, sodium cyclohexylsulfamate, sodium flavin adenine dinucleotide, disodium uridine-5'-diphosphate, sodium diphenylamine-4-sulfonate, methylprednisolone sodium succinate, inosine 5'-monophosphate sodium salt, inosine-5'-disodium phosphate, cytidine-5'-disodium phosphate, sodium N-cyclohexylsulfamate, cytidine 5 '-[ Disodium acid], disodium guanosine-5′-phosphate, (E) -2-butene dihydrogen 1-sodium, dexamethasone sodium metasulfobenzoate, sodium diphenylamine-4-sulfonate, 2,4-dichlorophenoxy Sodium acetate, sodium (2,4-dichlorophenoxy) acetate, disodium 1,5-naphthalenedisulfonate, pentachlorophenol, sodium salt (industrial), sodium (2,4-dichlorophenoxy) acetate, sodium 4- (2,4-dichloro-m-toluoyl) -1,3-dimethylpyrazole-5-olate, sodium 2-methyl-4-chlorophenoxyacetate, sodium (4-chloro-2-methylphenoxy) acetate, [(4 -Chloro-2-methylphenyl) oxy] sodium acetate, hydrogenated coconut oil Fatty acid sodium glycerol sulfate, sodium 5-ethyl-5,8-dihydro-8-oxofuro [3,2-b] [1,8] naphthyridine-7-carboxylate, 2-hydroxy-1,2,3-propanetricarboxylic acid Acid trisodium, 2-hydroxy-1,2,3-propanetricarboxylic acid trisodium, 2-hydroxy-1,2,3-propanetricarboxylic acid trisodium, 2-hydroxy-1,2,3-propanetricarboxylic acid trisodium Sodium, disodium 1-phenylazo-2-naphthol-4 ′, 6-disulfonate, sodium 1- (p-sodiosulfophenylazo) -2-hydroxynaphthalene-6-sulfonate, 6-hydroxy-5- [ (4-sulfophenyl) azo] -2-naphthalenesulfonate disodium, 2-hydroxy ( , 1′-Azobisnaphthalene) -3,4 ′, 6-trisulfonic acid trisodium, (+)-N-[(R) -2,4-dihydroxy-3,3-dimethylbutyryl] -β- Sodium alanine, disodium 4-[(2,4-dimethylphenyl) azo] -3-hydroxy-2,7-naphthalenedisulfonate, (+)-3-[[(R) -2,4-dihydroxy-3 , 3-Dimethylbutyryl] amino] sodium propionate, [methyl (2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-yl) amino] sodium methanesulfonate Etc.

As metal salts containing potassium, potassium alum, potassium bromide, potassium iodide, potassium nitrate, potassium sulfate, potassium sulfide, potassium acetate, potassium bromate, potassium chloride, potassium nitrite, potassium sulfite, potassium arsenate, potassium iodate , Potassium t-butoxide, potassium carbonate, potassium chlorate, potassium cyanate, potassium cyanide, potassium fluoride, potassium oxalate, potassium silicate, potassium arsenite, potassium stannate, potassium chromate, potassium hydroxide, phosphoric acid Potassium, potassium sorbate, potassium bisulfate, potassium selenate, potassium persulfate, potassium rhodanide, potassium losartan, potassium selenite, potassium tellurite, warfarin potassium, potassium periodate, potassium gluconate, can Potassium nonate, potassium perchlorate, potassium thiosulfate, potassium dichromate, potassium borofluoride, potassium dichromate, potassium molybdate, potassium pyrosulfite, potassium aspartate, pemirolast potassium, potassium hypochlorite, Potassium thiocyanate, potassium clavulanate, potassium aluminum sulfate, potassium cyanide sulfate, potassium boron hydroxide, potassium hypophosphite, potassium metaphosphate, potassium permanganate, potassium pyrophosphate, potassium ferricyanide, potassium ferrocyanide, potassium silicofluoride, Potassium hydrogen sulfate, potassium metavanadate, potassium xanthate, potassium hydrogen oxalate, dipotassium chlorazepate, potassium selenocyanate, dipotassium oxalate, dipotassium oxalate, fluorosilicic acid Potassium, potassium bicarbonate, potassium stannate trihydrate, potassium peroxodisulfate, potassium perchlorate, potassium aluminum sulfate, tetrapotassium pyrophosphate, benzylpenicillin potassium, potassium (methylsulfinyl) methanide, potassium dihydrogen phosphate, Potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium glycyrrhizinate, potassium tetrafluoroborate, potassium guaiacol sulfonate, potassium hexafluorosilicate, potassium aluminum sulfate dodecahydrate, dithio Examples include o-ethyl potassium carbonate, potassium hexacyanoiron (III), potassium phenoxymethylpenicillin, potassium (2E, 4E) -2,4-hexadienoate, potassium (2E, 4E) -2,4-hexadienoate and the like.

  Examples of the compound containing rubidium include rubidium bromide, rubidium iodide, rubidium sulfate, rubidium chloride, rubidium fluoride, rubidium acetate, rubidium hydrogen sulfate, and zirbidium carbonate, and compounds containing cesium include cesium cyanide, Cesium bromide, cesium iodide, cesium nitrate, cesium sulfate, cesium chloride, cesium carbonate, cesium fluoride, dicesium carbonate, dicesium oxalate, dicesium sulfate, dicesium sulfate, L-cesium tartrate, cesium hydroxide monohydrate , Cesium trifluoroacetate, 1-cesium 2,3-dihydroxybutanedioate, 1-cesium hydrogen 2,3-dihydroxybutanedioate, etc., but are not limited thereto.

Moreover, the following are mentioned as a metal salt containing a bivalent metal ion.
Examples of metal salts containing beryllium include beryllium bromide, beryllium iodide, beryllium nitrate, beryllium sulfide, beryllium chloride, beryllium fluoride, beryllium silicate, beryllium distearate, beryllium sulfate tetrahydrate, and acetylacetone beryllium salt. As magnesium-containing metal salts, magnesium orotate, magnesium acetate, magnesium boride, magnesium bromide, magnesium carbide, magnesium iodide, magnesium nitrate, magnesium sulfate, magnesium sulfide, magnesium chloride, magnesium carbonate, magnesium chlorate , Magnesium citrate, magnesium fluoride, magnesium silicate, magnesium silicide, magnesium hydroxide, magnesium phosphide, magnesium orotate, magnesium nitrate Um (II), magnesium stearate, magnesium perchlorate, magnesium myristate, magnesium oxalate, magnesium hydrogen carbonate, magnesium fluorosilicate, magnesium fluorosilicate, phenyl magnesium bromide, magnesium nitrate hexahydrate, phthalocyanine magnesium, Magnesium acetate tetrahydrate, Magnesium benzoate trihydrate, Calcium magnesium carbonate, Magnesium chromate pentahydrate, Magnesium hexafluorosilicate, Magnesium aluminate metasilicate, Bismuth magnesium aluminate silicate, Magnesium aluminum hydroxide And carbonate hydrates. Metal salts containing calcium include calcium bromide, calcium iodide, calcium lactate, calcium nitrate, calcium sulfate, calcium sulfide, calcium carbide, calcium acetate, calcium chloride, calcium nitrite, calcium sulfite, calcium arsenate, hydrogen Calcium fluoride, calcium arsenate, calcium iodate, calcium carbonate, calcium chlorate, calcium fluoride, calcium oxalate, calcium peroxide, calcium silicate, calcium silicide, calcium cyanide, calcium arsenite, heparin calcium, sub- Calcium chlorate, calcium chromate, calcium phosphate, calcium phosphide, calcium folinate, calcium gluconate, calcium stearate, calcium aspartate, calcium hypochlorite, Sufomycin calcium, calcium metasilicate, calcium thiocyanate, calcium hypophosphite, calcium pantothenate, calcium permanganate, fenoprofen calcium, calcium chloride dihydrate, calcium carbonate magnesium, polycarbophil calcium, mupirocin calcium hydrate , Calcium hydrogen phosphate, calcium glycerophosphate, calcium diiodostearate, precipitated calcium carbonate, atorvastatin calcium hydrate, (+)-calcium pantothenate, calcium paraaminosalicylate, calcium tocopherol succinate, calcium polystyrene sulfonate, (+) -Pantothenic acid calcium salt (2: 1), calcium aluminoparaaminosalicylate, 3-hydroxy-4-[(4-methyl-2 Sulfophenyl) azo] -2-naphthalenecarboxylic acid calcium salt and the like, and as a compound containing barium, barium azide, barium acetate, barium bromide, barium iodide, barium nitrate, barium sulfate, barium formate, Barium lactate, barium chloride, barium sulfite, barium carbonate, barium chlorate, barium fluoride, barium peroxide, barium cyanide, barium chromate, barium hydroxide, barium titanate, barium selenate, barium phosphate, barium nitrate (II), barium selenite, barium manganate, barium oxalate, barium stearate, barium perchlorate, barium thiosulfate, barium hypochlorite, barium permanganate, barium chloranilate, barium chloride dihydrate , Barium diacetate, barium bromide Barium dihydrate, barium dipropionate, barium chlorate monohydrate, barium hydroxide octahydrate, barium thiocyanate dihydrate, barium thiosulfate monohydrate, barium acetylacetone dihydrate, etc. However, it is not limited to these. Of the above-mentioned metal salts containing monovalent or divalent metal ions, those containing a metal ion having a higher ionization tendency than aluminum are preferred, and more preferably those containing metals such as sodium, potassium, magnesium or magnesium. It is. Furthermore, sodium chloride, potassium chloride, calcium chloride and magnesium chloride, among them, sodium chloride and magnesium chloride are preferable from the viewpoint of safety and stability of the metal salt.

Component D is added in an amount of 0.01 to 15 mass%, preferably 0.1 to 10 mass%, based on the total composition of components AD.
In particular, when the component A contains [COOM], which will be described later, and the amount of the metal salt is adjusted with respect to the number of moles of COOM, the crosslinking rate can be adjusted more efficiently.

When a monovalent metal salt is added, the addition amount is the ratio of the number of moles of monovalent metal ions to the number of moles of COOM contained in the (meth) acrylic acid polymer. [COOM] / [1
Valent metal ion] = 0.01 to 60.0, and more preferably [COOM].
/ [Monovalent metal ion] = 0.1 to 40.0. When this ratio is larger than 60.0, the effect of adding metal ions may be hardly obtained, whereas when it is smaller than 0.01, a separating solution is likely to be generated after crosslinking, or the gel body has a low pH. In some cases, desired physical properties cannot be obtained, such as a change or a decrease in adhesiveness.

When a divalent metal salt is added, the ratio of the number of moles of divalent metal ions to the number of moles of COOM in the (meth) acrylic acid polymer is [COOM] / [divalent metal ions] = It is preferably 0.01 to 50.0, and more preferably [COOM] / [divalent metal ion] = 0.1 to 30.0. Here, in the case where two or more monovalent metal salts or two or more divalent metal salts are used in combination, the content may be in a range not exceeding the above content. Furthermore, when monovalent and divalent metal salts are used in combination, [COOM] / [monovalent and 2 as in the range of divalent metal ions.
Sum of valent metal ions] = 0.01 to 50.0.

In the case of adjusting the crosslinking rate, when the crosslinking is accelerated by using a monovalent metal ion, the addition amount can be increased to increase the crosslinking rate. In addition, when a divalent metal ion is used, if the amount added is increased, it can be made slower.

Thus, the valence of the metal salt may be changed or the addition amount may be adjusted according to the target crosslinking rate.
In addition, about the addition amount of the (meth) acrylic acid type polymer (component A) in a composition, it shall be in the range mentioned later.
(Component A)
The (meth) acrylic acid polymer (component A) used in the present invention includes repeating units represented by the general formulas (1), (2) and (3),
—CH ₂ C (R ¹ ) (COOM) — (1)
^{_{-CH 2 C (R 2) (}} COOH) - (2)
-X- (3)
(In the formula, R ¹ and R ² each independently represent a hydrogen atom or a methyl group, M represents NH ₄ ⁺ or an alkali metal, and X represents an unsaturated monomer.)
(1) / (2) = 100/0 to 0/100 (molar ratio) and the total amount of (1) and (2) / (3) = 100/0 to 10/90 (molar ratio) preferable.

  Specifically, the component (A) is a homopolymer such as a sodium salt or potassium salt of acrylic acid or methacrylic acid, a homopolymer such as an ammonium salt, a sodium salt of acrylic acid or methacrylic acid, or a potassium salt. Such as alkali metal salt, ammonium salt and acrylic acid copolymer, acrylic acid or methacrylic acid sodium salt, potassium salt alkali metal salt, ammonium salt and methacrylic acid copolymer, etc. Can be mentioned.

  Of all unsaturated monomers used in the component (A) of the present invention, unsaturated monomers other than acrylic acid may be used as long as they are in the range up to 90 mol%. Examples of unsaturated monomers other than acrylic acid include maleic acid, maleic anhydride, fumaric acid, crotonic acid, itaconic acid, vinyl sulfonic acid, styrene sulfonic acid, and 2- (meth) acrylamido-2-methylpropane. Hydrophilic unsaturated monomers containing acid groups such as sulfonic acid, 2- (meth) acryloylethanesulfonic acid, 2- (meth) acryloylpropane sulfonic acid, and salts thereof; N-vinylacetamide, N-methyl-N- Vinylacetamide, acrylamide, methacrylamide, N-ethyl (meth) acrylamide, Nn-propyl (meth) acrylamide, N-isopropyl (meth) acrylamide, N, N-dimethyl (meth) acrylamide, 2-hydroxyethyl (meth) ) Acrylate, 2-hydroxypropyl ( Nonionic hydrophilic unsaturated monomers such as acrylate), methoxypolyethylene glycol (meth) acrylate, polyethylene glycol mono (meth) acrylate, vinylpyridine, N-vinylpyrrolidone, N-acryloylpiperidine, N-acryloylpyrrolidine; N, N-dimethylaminoethyl (meth) acrylate, N, N-diethylaminoethyl (meth) acrylate, N, N-dimethylaminopropyl (meth) acrylate, N, N-dimethylaminopropyl (meth) acrylamide and quaternary thereof Examples include cationic hydrophilic unsaturated monomers such as salts, styrene, vinyl chloride, butadiene, isobutene, ethylene, propylene, stearyl (meth) acrylate, lauryl (meth) acrylate, and the like. One or two or more kinds Bareru be used. Moreover, you may use the unsaturated monomer which forms a hydrophilic resin by hydrolysis of a functional group like methyl (meth) acrylate, ethyl (meth) acrylate, vinyl acetate, etc.

  Among these, N-vinylacetamide, N-methyl-N-vinylacetamide, N-vinylpyrrolidone, methoxypolyethylene glycol (meth) acrylate, N, N-dimethylaminoethyl (meth) acrylate, and acrylamide are particularly preferable.

  Examples of the polymerization method used in the present invention for the unsaturated monomer used in the component (A) include (a) a method using a radical polymerization initiator, (b) a method using radiation, and (c) a method using an electron beam. (D) Known methods such as ultraviolet polymerization using a photosensitizer can be mentioned. Among them, (a) polymerization using a radical polymerization initiator is preferred.

  Examples of the polymerization method (a) include in-frame polymerization, hydrogel polymer fragmentation, various aqueous solution polymerizations such as polymerization under pressure, reverse phase suspension polymerization, and reverse phase emulsion polymerization. Although known polymerization methods such as precipitation polymerization and bulk polymerization can be exemplified, reverse phase suspension polymerization or aqueous solution polymerization is particularly preferred. In the polymerization, there is no particular limitation on the distinction between continuous, semi-batch type, batch type and reduced pressure, pressurized, normal pressure.

In the polymerization, bulk polymerization or precipitation polymerization may be used, but it is preferable to perform polymerization as a solution from the viewpoint of performance and ease of polymerization control. The polymerization solvent is not particularly limited as long as it is a liquid in which an unsaturated monomer is dissolved, and examples thereof include water, methanol, ethanol, acetone, dimethylformamide, dimethyl sulfoxide, and the like, but water or an aqueous solvent is particularly preferable. . In addition, the concentration when the unsaturated monomer is polymerized as a solution is not particularly limited and may exceed the saturated concentration. However, from the viewpoint of various physical properties and reduction of residual monomers, it is usually 20% by mass to the saturated concentration, preferably Is in the range of 25-50% by weight. In the polymerization, a hydrophilic polymer such as a chain transfer agent, starch, cellulose or a derivative thereof, polyvinyl alcohol, or a crosslinked poly-N-vinylacetamide may be added to the unsaturated monomer. The amount used thereof is usually 5 parts by mass or less for the former and 50 parts by mass or less for the latter. Chain transfer agents include hypophosphorous acid such as hypophosphorous acid and sodium hypophosphite, sulfur-containing compounds such as thioacetic acid, thioglycolic acid and mercaptoethanol, disulfides, halides such as carbon tetrachloride, and phosphorous acid. And phosphorous acids such as sodium phosphite.

Examples of the radical polymerization initiator used for such polymerization include persulfates such as potassium persulfate, ammonium persulfate, and sodium persulfate; organic peroxides such as t-butyl hydroperoxide and cumene hydroperoxide; Hydrogen; 2,2′-azobis (2
-Amidinopropane) Azo compounds such as dihydrochloride; and other known polymerization initiators such as chlorite, hypochlorite, ceric salt, permanganate, etc. One or more selected from the group consisting of sulfate, hydrogen peroxide and azo compounds are preferred. In addition, when an oxidizing radical polymerization initiator is used, a reducing agent such as sulfurous acid (hydrogen) salt, iron, or L-ascorbic acid may be used in combination. When an azo polymerization initiator is used, ultraviolet rays are used in combination. You can do it. In addition, although these radical polymerization initiators may be added to the polymerization system all at once or sequentially, the amount used is usually 0.001 to 2 mol% with respect to the unsaturated monomer, Preferably it is 0.01-1 mol%. In order to increase the accuracy of adjustment of the crosslinking rate by adding a metal salt, the average particle diameter d50 of the (meth) acrylic acid polymer is preferably 30 to 250 μm, more preferably 50 to 150 μm. When the average particle size is 30 μm or less, dissolution in water is too early and the reaction between the metal ions and the polymer becomes non-uniform. On the other hand, when the average particle size is 250 μm or more, it takes too much time to dissolve in water. It becomes difficult to control the crosslinking rate of the (meth) acrylic acid polymer.

In the present invention, the (meth) acrylate polymer (component A) is preferably used in a range of 0.5 to 30%, more preferably, based on the total amount of the composition including component A to component D. Is preferably in the range of 2% to 20%. If it is less than 0.5%, the strength of the gel body after cross-linking is remarkably reduced, and as a result, bleeding from the support or skin residue of the gel may occur. If it exceeds 30%, the viscosity of the sol at the time of molding will increase, making it difficult to mold, coat and mix other components.
(Component B)
Aluminum compounds (component B) as a crosslinking agent include aluminum chloride, potash ming bang, ammonium ming bang, aluminum nitrate, aluminum sulfate, EDTA-aluminum, aluminum hydroxide / sodium bicarbonate coprecipitate (for example, Kyowa Chemical Industry Co., Ltd.) ) "Cumlite", etc.), synthetic aluminum silicate, aluminum stearate, aluminum allantoinate, synthetic hydrotalcite (eg Kyowa Chemical Industry's "Alkamak", "Alkamizer", "Kyoward", etc.)) , Alumina hydroxide / magnesium (for example, “SANALMIN” from Kyowa Chemical Industry Co., Ltd.), aluminum hydroxide (for example, “dry aluminum hydroxide gel S-100, low water content type” from Kyowa Chemical Industry Co., Ltd.), Aluminum acetate, dihydroxy aluminum Nitrogen aminoacetates (eg “Glycinal SG, PG or SA” from Kyowa Chemical Industry Co., Ltd.), kaolin, synthetic hydrotalcite, magnesium aluminate metasilicate (eg “Neusilin” from Toyama Chemical), aluminate silicate Including magnesium. These aluminum compounds may be water-soluble or hardly soluble. These aluminum compounds can be used alone or in combination of two or more.

The aluminum compound is 0.01 to 20% by mass relative to the total amount of the components (A) to (D).
In the range of 0.1 to 10% by mass. When the addition amount is less than the lower limit, crosslinking is insufficient and stringing occurs in the base, and when the upper limit is exceeded, the gel strength becomes unstable or the gel body becomes turbid, resulting in poor transparency. End up.

  In addition to the aluminum compound, other cross-linking agents can also be added, such as calcium, tin, iron, magnesium, manganese, zinc, barium and other inorganic acid salts (for example, calcium chloride, magnesium chloride, iron light van, Ferric sulfate, magnesium sulfate, EDTA-calcium, EDTA-magnesium, stannous chloride, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, magnesium carbonate, barium sulfate, magnesium silicate, magnesium stearate, magnesium citrate), Hydroxide (for example, calcium hydroxide, barium hydroxide, magnesium hydroxide (for example, “Kisuma” of Kyowa Chemical Industry Co., Ltd.), ferric hydroxide, stannous hydroxide, etc.), oxide (for example, , Magnesium oxide (for example, “Kyowa from Kyowa Chemical Industry Co., Ltd.) ”,“ Magarat ”and the like)), epoxy compounds such as formaldehyde, ethylene glycol diglycidyl ether, glycerin diglycidyl ether, polyethylene glycol diglycidyl ether, propylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, etc. One or more of these crosslinking agents can be used.

When using a crosslinking agent other than these aluminum compounds, it is desirable to add in an amount of 10% by mass or less, and further 5% by mass or less based on the total amount of the composition.
(Component C)
Water (component C) increases the solubility of the (meth) acrylic acid polymer to increase the viscosity, so that the cross-linking reaction between aluminum and the (meth) acrylic acid polymer proceeds. It is added to disperse and dissolve (Component D). Component C is added in an amount of 5 to 98 mass%, preferably 8 to 95 mass%, based on the total amount of the composition. When the water content is less than the lower limit, the solubility of the (meth) acrylic acid polymer is deteriorated, and the thickening effect and the generated aluminum ions are reduced. There may be a so-called “glue remaining” phenomenon that remains on the surface, a so-called “back-through” phenomenon in which the gel body escapes from the support. On the other hand, if the amount exceeds the above upper limit, the strength of the gel body is remarkably reduced. As a result, the shape retention property is reduced, and a ooze from the support or gel residue may occur.
(Component E)
The (meth) acrylic acid polymer mixture used in the present invention preferably contains a polyhydric alcohol (component E) as necessary. The polyhydric alcohol increases the moisture retention of the hydrogel obtained by crosslinking the (meth) acrylic acid polymer mixture, and increases the solubility and activity of the drug when it is used as an adhesive for patches, Formulated for the purpose of improving transferability to the skin. Furthermore, it is also possible to add a metal salt (component D) by dispersing it in advance in a polyhydric alcohol. Polyhydric alcohols include ethylene glycol, propylene glycol, 1,3-butylene glycol, ethylene glycol monobutyl ether, diethylene glycol, triethylene glycol, 1,4-butylene glycol (dihydric alcohol), glycerin, trioxyisobutane (trihydric alcohol) ), Erythritol, pentaerythritol (tetrahydric alcohol), xylit, adnit (pentahydric alcohol), allozulcit, sorbitol, sorbitol liquid, mannitol (hexahydric alcohol), polyglycerin, dipropylene glycol, etc. Absent. Among these, glycerin is particularly preferable from the viewpoint of safety and affinity with a (meth) acrylic acid polymer. A polyhydric alcohol may be used independently and may use 2 or more types together.

  The polyhydric alcohol is added in a range of up to 90% by mass, and more preferably in a range of up to 60% by mass with respect to the total amount of the composition. When the addition amount exceeds 90% by mass, the thickening effect due to the (meth) acrylic acid polymer is hardly exhibited, and sufficient shape retention may be difficult to obtain.

  In the present invention, a solvent other than polyhydric alcohols can also be added to the (meth) acrylic acid polymer mixture, and these solvents include methanol, ethanol, propanol, benzyl alcohol, phenethyl alcohol, isopropyl alcohol, isobutyl alcohol, Water such as hexyl alcohol, monoethyl alcohol such as 2-ethylhexanol, cyclohexanol, octyl alcohol, butanol, pentanol, ketones such as acetone, methyl ethyl ketone, water such as cellosolve, dioxane, dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide In addition to miscible organic solvents, organic solvents that are not miscible with water, such as ethyl acetate and crotamiton, can be mentioned.

  Furthermore, as a speed adjusting agent for the crosslinking reaction, it is applied to metal ions such as tartaric acid, citric acid, lactic acid, glycolic acid, malic acid, salicylic acid, fumaric acid, methanesulfonic acid, maleic acid, acetic acid, sodium EDTA-2, urea, triethylamine, and ammonia. On the other hand, inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, hydrobromic acid and the like can be used in addition to organic acids, organic acid salts and organic bases having chelate or coordination ability.

  In the present invention, other polymers can be added to the (meth) acrylic acid polymer mixture for the purpose of improving shape retention and adhesiveness. These polymers include polyvinylpyrrolidone, carboxyvinyl polymer which is cross-linked polyacrylic acid, vinylpyrrolidone-ethyl acrylate copolymer, and N-vinylacetamide-sodium acrylate copolymer. Examples thereof include polymers, N-vinylacetamide homopolymers, polyvinylsulfonic acid, N-vinylacetamide cross-linked products, polyitaconic acid, hydroxypropylcellulose, hydroxypropylmethylcellulose and the like. Among these, N-vinylacetamide-sodium acrylate copolymer is particularly preferable from the viewpoint of improving adhesion to the skin. In the N-vinylacetamide-sodium acrylate copolymer, the molar ratio of N-vinylacetamide and sodium acrylate is preferably in the range of 99.9: 0.1 to 50:50, more preferably 95. A range of 0: 5 to 50:50 is preferable.

These polymers are added in a range of up to 20% by weight, more preferably up to 10% by weight, based on the total amount of the (meth) acrylic acid polymer mixture. When the addition amount exceeds 20% by mass, the gel body becomes too hard, and the feeling of adhesion with the skin may deteriorate.
(Adjustment method)
In the present invention, when adjusting the crosslinking rate of the (meth) acrylic acid polymer, the (meth) acrylic acid polymer (component A), the aluminum-containing compound (component B), water (component C) and many A metal salt (component D) containing at least one monovalent or divalent metal ion is added to a mixture containing an optional component such as a monohydric alcohol.

  The metal salt (component D) is desirably dissolved in water in advance. Moreover, when a composition contains a polyhydric alcohol, you may disperse | distribute and add a metal salt to a polyhydric alcohol (component E) previously.

  When adding a metal salt (component D), it is desirable to add in the temperature range of 0-40 degreeC, Preferably 5-40 degreeC, stirring as needed. Within this range, the crosslinking rate can be easily adjusted.

  The content of water contained in the water-containing gel thus obtained is desirably 5 to 98% by mass, preferably 10 to 95% by mass, and is within such a range of water content. Because of its high shape retention and high gel strength, it is suitable for applications such as transdermal absorption preparations, cooling sheets, and cosmetics.

Specifically, it can be applied to the following uses.
(I) Pharmaceuticals: For example, transdermal absorption preparations, transmucosal absorption preparations, etc.
(II) Medical device: For example, a cooling agent for the affected area at the time of fever, a wound healing agent, a therapeutic pad, a liquid absorbent for surgery, a dressing tape, a burn healing agent, and the like.
(III) Cosmetics, quasi drugs: for example, packs, suntan products, acne products, etc.

There are many drugs that can be administered using the gel body of the present invention, for example,
(A) Corticosteroids: Hydrocortisone, prednisone, beclomethasone pyropionate, flumethasone, triamcinolone, triamcinolone acetonide, fluocinolone, fluocinolone acetonide, fluocinolone acetonide acetate, clobetasol propionate, and the like.
(B) Anti-inflammatory analgesic: for example salicylic acid, glycol salicylate, methyl salicylate, 1-menthol, camphor, sulindac, trimethine sodium, naproxen, fenbufen, piroxicam, triamcinolone, hydrocortisone acetate, indomethacin, ketoprofen, acetaminophen, mefenamic acid, Flufenamic acid, ibufenac, loxoprofen, thiaprofen, pranoprofen, fempfen, diclofenac, diclofenac sodium, alclofenac, lornoxicam, mepranoprofen, oxyphenbutazone, ibuprofen, ferpinac, ketronac, vermoprofen, napton, naproxen, Flurbiprofen, fluocinonide, clobetasol propionate, C X-2 inhibitors (celecoxib, rofecoxib, Barekokishibu, parecoxib, Mobikku, Vioxx, Celebrex, Bextra, osteoprotegerin rack, Haipen, Baredekokishibu, ethoxy drag, nimesulide, etc. meloxicam) such.
(C) antifungal agents: for example clotrimazole, tolnaftate, econazole nitrate, omoconazole nitrate, thioconazole nitrate, ketoconazole nitrate, miconazole nitrate, isoconazole nitrate, tolnaftate, thioconazole nitrate, sulconazole nitrate, pyrrolnitrin, bimafucin, undecylenic acid, salicylic acid Siccanin, nystatin, nornaphthate, exalamide, phenyliodoundecinoeha, thianthol, ciclopirox olamine, haloprozin, tricomycin, variotin, pentamycin, amphotericin B and the like.
(D) Antihistamines: for example, antibiotics such as tetracycline hydrochloride, diphenhydramine hydrochloride, chlorpheniramine, diphenylimidazole, chloramphenicol, diphenhydramine, chlorpheniramine maleate and the like.
(E) Hypnotic sedative: For example, phenobarbital, amobarbital, cyclobarbital, lorazepam, haloperidol and the like.
(F) Tranquilizer: For example, fluphenazine, theoridazine, diazepam, flunitrazepam, chlorpromazine and the like.
(G) Antihypertensive agents: for example, clonidine, clinidine hydrochloride, pindolol, propranol, propranolol hydrochloride, bufuranol, indenolol, bucmolol, nifedipine and the like.
(H) Antihypertensive diuretics: for example, hydrothiazide, bendrofluthiazide, cyclopenthiazide and the like.
(I) Antibiotics: For example, penicillin, tetracycline, oxytetracycline, fradiomycin sulfate, erythromycin, chloramphenicol and the like.
(J) Anesthetic agents: for example lidocaine, benzocaine, ethyl aminobenzoate, dibucaine and the like.
(K) Antibacterial substances: for example, benzalkonium chloride, nitrofurazone, nystatin, acetosulfamine, clotrimazole and the like.
(L) Vitamin preparations: For example, vitamin A, ergocalciferol, cholecalciferol, octothiacin, riboflavin butyrate and the like.
(M) Antiepileptic agents: for example, nitrozepam, mepropamate, clonazepam and the like.
(N) Coronary vasodilators: for example, nitroglycerin, nitroglycol, isosorbidinitrate, erythritol tetranitrate, pentaerythritol tetranitrate, propatyl nitrate, etc.
(O) Antihistamine: for example, diphenhydramine hydrochloride, chlorpheniramine, diphenylimidazole and the like.
(P) Antitussives: for example, dextromethorphan, terbutamine, ephedrine,
Ephedrine hydrochloride etc.
(Q) Sex hormone: For example, progesterone, estradiol, testosterone and the like.
(R) Antidepressant: For example, doxepin.
(S) Angina treatment agent: Antiperspirants such as diethylamide and camphor, nitroglycerin, isosorbide nitrate and the like.
(T) Narcotic analgesics: morphine hydrochloride, ethyl morphine hydrochloride, morphine sulfate, cocaine hydrochloride, buprenorphine, pethidine hydrochloride, codeine phosphate, dihydrocodeine phosphate, fentanyl citrate, sufentanil, meperidine hydrochloride and the like.
(U) Herbal medicines: buckwheat, euhi, onji, gadget, chamomile, caroten, licorice, kyoukyo, kyounin, goo, trash, saikachi, psycho, saishin, shizenshi, shouma, senega, sojutsu, sohakuhi, choji, chimney, tokonto, nantenji , Baimo, Bakumondou, Hange, Beaked Jutsu, Hiyos, Bowhou, Xanthohumol, Maow.
(V) Others: In addition to 5-fluorouracil, ethinyl estradiol, norlergetromine, dihydroergotamine, oxybutynin, minoxidil, fentanyl, desmopressin, digoxin, metoclopracid, domperide, scopolamine, scopolamine hydrobromide, Hypnotics, cardiovascular treatments, brain metabolism stimulants, bactericides, enzyme preparations, enzyme inhibitors, biopharmaceuticals (polypeptides), keratosis treatments, narcotics, antineoplastic agents, general anesthetics, anxiolytics , Asthma / nasal allergic agent, anti-parkinsonian agent, chemotherapeutic agent, anthelmintic agent, antiprotozoal agent, hemostatic agent, cardiotonic agent, stimulant / stimulant agent, addictive addiction agent, Chinese medicine, radiopharmaceutical, urogenital and anal drug Hypoglycemic agent, anti-ulcer agent, hair agent, sequestering agent, antiperspirant, tranquilizer, Imitation agent, anti-rheumatic, bentol, trimegestone, metformin, dantrolene sodium, ketorolac, butyrophenone, benzazepine vasopressin antagonist, fukudine, rice grind, rice extract, rice bran, rice enzyme-treated product, ε-polylysine (Anti-inflammatory action for atopy), endothelin antagonist, levosimendan, yucca extract, vardenafil (diabetes), ondansetron, disopyramide or its salt (neuropathic pain), anthranilic acid amide (antiarrhythmic), genus genus genus Extracts of plants belonging to the group, tolperisone, astaxanthin, levodopa, acotine-type alkaloids extracted from aphid root etichis, Lamiaceae Rosmarinus extract, acetylated hyaluronic acid, elcampur extract, pine extract, berberi , Co-Q10, α-lipoic acid, carnitine, ginkgo biloba extract, norlergestromine, extract of yawer pilpyri, ethinyl estradiol (possibly already), betahistine mesylate, propofol (sedative, anesthesia), Examples include, but are not limited to, astilbine, mugwort extract, γ-aminobutyric acid, benzocaine (anti-inflammatory), eperisone, tolperisone, axesazein, anti-gout agent and anticoagulant. Two or more kinds of these drugs can be used in combination as required, and the compounding ratio of the drug is 0.01 to 30% by mass, preferably 2 to 20% by mass with respect to the total weight of the adhesive for a patch. It is preferable to adjust to%.

  The drug can be included after solution stage (or gel suspension stage) or after aging for cross-linking reaction. The preferred method depends on the initial objectives for the drug's physical properties, site of administration and release rate.

Adjuvants that promote the absorption of these drugs can also be added, such as ethyl alcohol, isopropyl alcohol, butanol, 1,3 butanediol, propylene glycol, polyethylene glycol # 400, glycerin, crotamiton, benzyl alcohol, phenylethyl Alcohol, propylene carbonate, hexyl decanol, propanol, salicylic acid, allantoin, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, diisopropyl adipate, diethyl sebacate, ethyl laurate, lanolin, azone, 1-geranyl azasilroheptan-2-one ( GACH), fatty acid dialkyrolamide, salicylic acid, salicylic acid derivatives, keratin softeners such as urea and sulfur, moisturizing pyrrolidone carboxylic acids, etc. , Surfactants such as propylene glycol monooleate, polyoxyethylene sorbitan monostearate, sorbitan monostearate, glycerin monostearate, esters such as isopropyl myristate, diethyl sebacate, oleyl alcohol, stearyl alcohol, lauryl alcohol, etc. Fatty acids such as stearic acid, hexanoic acid, nonanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid, oleic acid, linoleic acid, menthol, menthone, limonene, pinene, piperiton, terpinene, Terpene compounds such as terpinolene, terpinolol, and carpeol, and surfactants, allantoin, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, dii Auxiliary agents such as propyl adipate, diethyl sebacate, ethyl laurate, lanolin, aison, and other cooling agents such as menthol and camphor as needed, almond oil, olive oil, camellia oil, persic oil, mint oil, sesame oil, Oil components such as soybean oil, mink oil, cottonseed oil, corn oil, safflower oil, coconut oil, eucalyptus oil, castor oil, liquid paraffin, petrolatum, squalene, squalane, lanolin, gelling agent such as carboxyvinyl polymer, diisopropanol One or more neutralizing agents such as amines can be blended, but considering skin irritation and the like, the blending amount is desirably 0.1 to 5 parts by mass with respect to 100 parts by mass of the drug.

  In the (meth) acrylic acid polymer mixture used in the present invention, in order to express the characteristics more or to improve processing / moldability and quality, the dispersibility and stability of the drug in the gel body For the purpose of improvement or the like, an additive selected according to the purpose can be further arbitrarily blended to such an extent that the performance of the gel is not impaired.

Examples of the additive include the following.
(1) Wetting agent: For example, glycerin, propylene glycol, sorbit, 1,3-butylene glycol, dl-pyrrolidone carboxylic acid, sodium lactate and the like.
(2) Astringent: citric acid, tartaric acid, lactic acid, aluminum chloride, aluminum sulfate, allantochlorohydroxyaluminum, allantoindihydroxyaluminum, aluminum phenolsulfonic acid, zinc paraphenolsulfonate, zinc sulfate, aluminum chlorohydroxide and the like.
(3) Moisturizer: Polyglycols such as glycerin, propylene glycol, 1,3-butylene glycol, sorbitol, polyglycerin, polyethylene glycol, dipropylene glycol, NMF components such as sodium lactate, hyaluronic acid, collagen, muco Water-soluble polymers such as polysaccharides and chondroitin sulfate.
(4) Thickeners: eg gum arabic, tragacanth gum, locust bean gum, guar gum, echo gum, karaya gum, agar, starch, carrageenan, alginic acid, alginates (eg sodium alginate), propylene glycol alginate, dextran, dextrin, amylose, gelatin , Collagen, pullulan, pectin, amylopectin, starch, amylopectin sodium semiglycolate, chitin, albumin, casein and other natural polymers, polyglutamic acid, polyaspartic acid, methylcellulose, ethylcellulose, propylcellulose, ethylmethylcellulose, hydroxyethylcellulose, hydroxy Propylcellulose, hydroxypropylmethylcellulose, carboxymethyl starch, alk Semi-synthetic polymers such as metal carboxymethyl cellulose, alkali metal cellulose sulfate, cellulose graft polymer, crosslinked gelatin, cellulose acetate phthalate, starch-acrylic acid graft polymerization, phthalic anhydride modified gelatin, succinic acid modified gelatin, polyvinyl alcohol, Polyvinyl pyrrolidone, polyvinyl methyl ether, carboxyvinyl polymer, vinyl pyrrolidone-ethyl acrylate copolymer, vinyl pyrrolidone-styrene copolymer, vinyl pyrrolidone-vinyl acetate copolymer, vinyl acetate- (meth) acrylic acid copolymer, N-vinylacetamide copolymers such as polyvinyl acetate-crotonic acid copolymer, N-vinylacetamide-sodium acrylate copolymer, polyvinylsulfonic acid, N-vinyl Acetamide crosslinked product, polyitaconic acid, polyhydroxyethyl acrylate, polyacrylamide, styrene - maleic acid anhydride copolymer, acrylamide - polymers of synthesis such as acrylic acid copolymer.
(5) Tackifying substance: For example, various sticky substances such as silicone rubber, polyisobrengon, styrene-block copolymer rubber, acrylic rubber, and natural rubber.
(6) Antidiarrheal agents: camphor, thymol, menthol, polyoxyethylene lauryl ether, antihistamine, ethyl aminobenzoate and the like.
(7) Keratin softening release agent: for example, sulfur, thioxolone, selenium sulfide, salicylic acid, resorcin.
(8) Incorrect eating prevention substances: for example, chili powder, chili pepper essence, etc.
(9) Powder raw materials: For example, montmorillolate, anhydrous silicic acid, stone kou, carbon black, diatomaceous earth, bengara, calcium carbonate, hydrotalcite, talc, glass, kaolin, bentonite, metal soap, aerosil, mica titanium, oxy Bismuth chloride, fish scale foil, zinc white, titanium dioxide, etc.
(10) Oily raw materials: Almond oil, olive oil, hydrogenated oil, camellia oil, castor oil, owl oil, coconut oil, beeswax, whale wax, lanolin, carnauba wax, candelilla wax, liquid paraffin, petrolatum, microcrystalline wax, ceresin , Squalene, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid, lauryl alcohol, cetanol, stearyl alcohol, oleyl alcohol, octyldodecanol, cholesterol, hexyldecanol, wite sterol, cetyl lactate, isopropyl myristate, Hexyl laurate, myristyl myristate, isopropyl palmitate, octyldodecanol myristate, butyl stearate, cacao oil, tree wax, jojoba oil, grape Oil, avocado oil, mink oil, egg yolk oil, beeswax, lanolin, carnauba wax, candelilla wax, liquid paraffin, ceresin wax, paraffin wax, behenic acid, isopropyl adipate, octyldodecyl oleate, octyldodecyl oleate, Such as cholesterol oleate.
(11) Surfactant: For example, lauryl sulfate, polyoxyethylene alkyl ether sulfate, alkylbenzene sulfonate, polyoxyethylene alkyl ether phosphate, polyoxyethylene alkylphenyl ether phosphate, N-acyl amino acid salt, stearin Anionic surfactants such as sodium acid, potassium palmitate, sodium cetyl sulfate, sodium lauryl sulfate, triethanolamine palmitate, sodium polyoxyethylene lauryl phosphate, sodium acylglutamate, surfactin, benzalkonium chloride, benzethonium chloride, Cationic surfactants such as stearyltrimethylammonium chloride, distearyldimethylammonium chloride, stearyldimethylbenzylammonium chloride, alkyl hydrochloride Amphoteric surfactants such as diaminoethylglycine, 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine, lauryldimethylaminoacetic acid betaine, lecithin, polyol fatty acid ester, glyceryl monostearate, lipophilic monoolein Acid glycerin, ethylene glycol monostearate, propylene glycol monostearate, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene alkylphenol ether, polyoxyethylene sorbitol fatty acid ester , N-acyl amino acid ester, sucrose fatty acid ester, fatty acid alkylolamide, polyoxyethylenated sterol Non-ionic surfactants such as polyoxyethylene lanolin and polyoxyethylene hydrogenated castor oil.
(12) Colorant: For example, yellow iron oxide, red iron oxide, black iron oxide, ultramarine blue, carbon black, chromium hydroxide, chromium oxide, tar dye, lake, red No. 2, red No. 3, red No. 102, red No. 201, Yellow No. 4, Yellow No. 5, Blue No. 1, Blue No. 2, etc.
(13) Perfume: eg coconut oil, orange oil, pepper oil, jasmine oil, cedar oil, ginger oil, terpin oil, orange flower oil, rose oil, eucalyptus oil, lime oil, lemon oil, Japanese mint oil, rosemary Plant fragrances such as oil, animal fragrances such as musk, reibiko, kairikou, ryusenkou, hydrocarbon fragrances such as bromostyrol, pinene and limonene, alcoholic fragrances such as benzyl alcohol and l-menthol, ethyl acetate, methyl salicylate Ester-based fragrances such as benzaldehyde, salicylaldehyde, aldehyde-based fragrances such as camphor, muscone, musk ketone, and l-menton, ether-based fragrances such as safrole, and phenol-based fragrances such as thymol, Lactones, flavors such as phenylacetic acid, nitrogen such as indole Such as case-based perfume.
(14) Ultraviolet blocking agents: for example, benzophenone series such as ASL-24, Cyasorb UV-9, Uvinul M-40, benzoic acid series such as Salol, azole series such as Tinuvin P, nitrile series such as Uvinul N-35, Ancour Urea such as UA, Neo
Paraamino acids such as Heliopan Give tan F, 2-hydroxy-4-methoxybenzophenone, octyldimethylparaaminobenzoate, ethylhexylparamethoxycynamate, salicylic acid, benzofuran, coumarin, and azole.
(15) Preservative fungicides: acids such as benzoic acid, salicylic acid, dehydroacetic acid, sorbic acid, boric acid and their salts, phenol, chlorocresol, chlorxylenol, isopropylmethylphenol, resorcin, orthophenylphenol, paraoxybenzoic acid ester , Phenols such as phenoxyethanol, thymol, hinokitiol, and thioxolone, halogenated bisphenols such as hexachlorophene, 2,4,4'-trichloro-2'-hydroxydiphenyl ether, trichlorocarbanilide, halocarban, and decylenic acid monoethanolamide Amide compounds such as benzalkonium chloride, alkylisoquinolinium bromide, benzethonium chloride, quaternary ammonium compounds such as cetylpyridinium chloride, lauryl di (amino Amphoteric surfactants such as ethyl) glycine, 2-pyridinethiol-1-oxide zinc salt, gluconic acid, chlorhexidine, thiram, N-trichloromethylthio-4-cyclohexene-1.2-dicarboximide, chlorobutanol and the like. (16) Antioxidants: For example, nordihydroguaiaretic acid, guaiac fat, propyl gallate, butylhydroxyanisole, dibutylhydroxytoluene (BHT), tocopherol (vitamin E), 2,2′-methylenebis (4-methyl- 6-t-butyl) phenol and the like.
(17) Chelating agent: For example, edetate, pyrophosphate, hexametaphosphate, citric acid, tartaric acid, gluconic acid and the like.
(18) Ultraviolet scattering agent: For example, titanium oxide, kaolin, talc and the like.
(19) pH adjuster: for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammore, ammonia water, triethanolamine, dimethylamine, diethylamine, trimethylamine, triethylamine, triisopropanolamine, trisodium phosphate , Disodium hydrogen phosphate, dipotassium hydrogen phosphate, monoethanolamine, diethanolamine, diisopropanolamine, polyethanolamine and other alkali metal hydroxides, alkaline earth metal hydroxides, primary, secondary or Tertiary alkylamines or alkalis such as primary, secondary or tertiary alkanolamines, and acids such as citric acid, tartaric acid, lactic acid, glycolic acid, hydrochloric acid, nitric acid, malic acid, phosphoric acid Other, acidic or alkaline In addition, for example, alginic acid, polyglutamic acid, polyaspartic acid, starch-acrylic acid graft polymer, polyacrylic acid, polyvinyl acetate-crotonic acid copolymer, vinyl acetate- (meth) acrylic acid copolymer , Vinyl acetate-crotonic acid copolymer, polyvinyl sulfonic acid, polyitaconic acid, styrene-maleic anhydride copolymer, acrylamide-acrylic acid copolymer, and the like. However, it is not limited to these.

In addition, stabilizers, fillers, preservatives, plasticizers, softeners, deterioration inhibitors and the like can be added, and these additives are arbitrarily added within a range that does not affect the properties of the resulting hydrogel.
The hydrogel obtained by the production method of the present invention is directly mixed with various raw materials and then poured into an appropriate mold in a sol state, where it is crosslinked and molded, or the crosslinked gel is directly molded into an appropriate molding machine, tableting It is prepared into various molded products using a machine or the like. The mixing of the raw materials can be performed by appropriately selecting and using, for example, a kneader, a kneader, a kneader ruder, an azimuth homomixer, a planetary mixer, a double planetary mixer, and the like. In addition, when kneading the hydrogel, bubbles may be generated in the hydrogel. There are several ways to suppress this, and examples are given below.

  First, a mixed liquid such as water and tartaric acid is put into a container (A) for kneading, and vacuuming is performed. Next, a polymer (such as an aluminum-containing compound, a polyhydric alcohol, and a (meth) acrylic acid copolymer) is dispersed in a container (B) that is directly connected to the container (A) and separated by a lid with a packing or the like. The container (B) is evacuated. Here, it may be determined as appropriate to which container the metal salt is put. After that, when the two containers are sufficiently depressurized, the lid that separates the containers (A) and (B) is opened while the liquid in the container (A) is stirred, so that the polyhydric alcohol, the aluminum-containing compound, and (meta) A dispersion of a polymer such as an acrylic acid copolymer is charged into the container (A). By this method, kneading is performed in a state in which the gas in the container is eliminated as much as possible, so that the generation of bubbles in the hydrogel can be suppressed.

  In order to make a hydrogel body into a sheet, paper, wood, metal, glass fiber, cloth (nel, woven fabric, non-woven fabric, etc.), synthetic resin (polyurethane, ethylene vinyl acetate copolymer, polyvinyl chloride, polyester (eg polyethylene) Terephthalate), polyolefin (eg, polyethylene, polypropylene, etc.), polyamide (eg, nylon 6, nylon 66, etc.), polyvinylidene chloride, polytetrafluoroethylene, etc., metal foils such as aluminum, rubber or cellulose derivatives, and plastic films What is necessary is just to apply an appropriate amount of a hydrogel body to one or both sides of a support such as a molded product such as a laminated film, a sheet (foil) or a tape. , Silicon or other on the surface coated with hydrogel Affixing a release sheet treated by an appropriate method, or treating a surface not coated with a hydrogel body with silicon or other suitable method to form a release surface, and a surface not coated with gel It is desirable to roll or overlap each other, as the release sheet, polyethylene film, polypropylene film, release paper, cellophane, polyvinyl chloride, polyester, etc. are used.

EXAMPLES Next, the usefulness of the present invention will be described with reference to examples, but the present invention is not limited thereto. In addition, when there is no notice in particular, a part shows a mass part.
[Method for measuring crosslinking rate]
The crosslinking rate was measured using gel strength as a parameter. The gel strength was measured using a digital force gauge (Nidec Sympo Co., Ltd. DFG-0.2K) and its dedicated stand on the principle of a card tension meter.

The sensory axis (made of aluminum) was a cylinder with a diameter of 10 mm and a height of 12 mm, the moving distance was 30 mm, and the moving speed was 5 mm / sec. The gel is poured into a resin sample bottle when it is in a sol state.
= 3.

  Table 1 shows the correlation between the measurement value of this measurement method and the sensitivity test using the tentacles.

[Examples 1 to 3, Comparative Examples 1 and 2]: Adjustment (blending) of crosslinking rate with sodium chloride
A composition was prepared with the formulation shown in Table 2.

(Prescription)
As shown in Table 2, a polymer, aluminum hydroxide and glycerin dispersion was gradually added to a mixed aqueous solution of tartaric acid and sodium chloride and kneaded until uniform.
(result)
The results are shown in Table 3.

In the table, the gelation rate is an increase in gel strength per day (gf / day), that is, gel strength on day 1-gel strength on day 0. From the table, it can be seen that the gelation rate is clearly faster when sodium chloride is added.
[Examples 4 to 6, Comparative Example 3]: Adjustment of crosslinking rate with potassium chloride (mixing)
The formulation is shown in Table 4. Comparative Example 1 is the same as Comparative Example 1 described above.

(Prescription)
A polymer, aluminum hydroxide and glycerin / 1,3-butanediol dispersion were gradually added to a mixed aqueous solution of tartaric acid and potassium chloride, and kneaded until uniform.
(result)
The results are shown in Table 5. It can be seen that the gelation rate is faster with the addition of potassium chloride.

[Examples 7 to 9, Comparative Example 4]: Adjustment of crosslinking rate with calcium chloride (formulation)
The formulation is shown in Table 6. Comparative Example 1 is the same as Comparative Example 1 described above.

(Prescription)
In order to obtain the composition shown in Table 6, a polymer, aluminum hydroxide, or a dispersion of glycinal and glycerin / propylene glycol was gradually added to a mixed aqueous solution of tartaric acid and calcium chloride, and kneaded until uniform.
(result)
The results are shown in Table 7. It can be seen that the addition of calcium chloride has a very low initial gelation rate (that is, easy to mold), and then the gelation proceeds.

[Examples 10 to 12, Comparative Example 5]: Adjustment of crosslinking rate with magnesium chloride (formulation)
The formulation is shown in Table 8. Comparative Example 1 is the same as Comparative Example 1 described above.

(Prescription)
To a composition shown in Table 8, a polymer, aluminum hydroxide, or a dispersion of glycinal and glycerin was gradually added to a mixed aqueous solution of tartaric acid and calcium chloride, and kneaded until uniform.
(result)
The results are shown in Table 9. It can be seen that the addition of magnesium chloride has a very low initial gelation rate (that is, easy to mold), and then the gelation proceeds.

Claims (16)

  When the (meth) acrylic acid polymer (component A) is mixed with an aluminum-containing compound (component B) and water (component C) to crosslink the (meth) acrylic acid polymer, monovalent or 2 And adding at least one metal salt (component D) selected from the group consisting of metal salts containing a valent metal ion to adjust the crosslinking rate of the (meth) acrylic acid polymer (meta ) A method for producing an acrylic acid-based hydrogel.   The method for producing a (meth) acrylic acid-based hydrogel according to claim 1, wherein the metal salt (component D) is dissolved in water and added in advance.   The method for producing a (meth) acrylic acid-based hydrogel according to claim 1 or 2, wherein the metal salt (component D) is added in a temperature range of 0 to 40 ° C. The (meth) acrylic acid polymer includes a repeating unit represented by the general formulas (1), (2) and (3),
—CH ₂ C (R ¹ ) (COOM) — (1)
^{_{-CH 2 C (R 2) (}} COOH) - (2)
-X- (3)
(In the formula, R ¹ and R ² each independently represent a hydrogen atom or a methyl group, M represents NH ₄ ⁺ or an alkali metal, and X represents a divalent organic group derived from an unsaturated monomer.)
(1) / (2) = 100/0 to 0/100 (molar ratio) and the total amount of (1) and (2) / (3) = 100/0 to 10/90 (molar ratio) The manufacturing method of the (meth) acrylic-acid type water-containing gel body in any one of 1-3.   The method for producing a (meth) acrylic acid-based hydrogel according to claim 4, wherein the (meth) acrylic acid-based polymer (component A) is a sodium acrylate-N-vinylacetamide copolymer.   The M is sodium, and the repeating units (1) and (2) are in the range of (1) / (2) = 0/100 to 100/0 (molar ratio), and the repeating unit (3) The manufacturing method of the (meth) acrylic-acid type hydrous gel body of Claim 4 which does not contain.   The average particle size (d50) of the (meth) acrylic acid polymer (component A) is in the range of 30 to 250 µm. The production of the (meth) acrylic acid hydrogel according to any one of claims 1 to 6. Method.   The said metal salt (component D) is sodium chloride, The manufacturing method of the (meth) acrylic-acid type water-containing gel body in any one of Claims 1-7.   The method for producing a (meth) acrylic acid-based hydrogel according to any one of claims 1 to 7, wherein the metal salt (component D) is magnesium chloride.   Furthermore, the manufacturing method of the (meth) acrylic-acid type water-containing gel body in any one of Claims 1-9 containing a polyhydric alcohol (component E).   The method for producing a (meth) acrylic acid-based water-containing gel according to claim 10, wherein the metal salt (component D) is dispersed in a polyhydric alcohol (component E) in advance and added. A (meth) acrylic acid-based water-containing gel obtained by the method for producing a (meth) acrylic acid-based water-containing gel according to any one of claims 1 to 11.   The water-containing gel body according to claim 12, wherein the content of water contained in the water-containing gel body is 5 to 98 mass%.   A transdermally absorbable preparation using the hydrogel according to claim 12 or 13.   A cooling sheet using the hydrogel body according to claim 12 or 13. Cosmetics using the water-containing gel body according to claim 12 or 13.