JP2007126397A - Plaster - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a plaster composed of a hydrophilic base and having both of the basic physical properties of the base such as adhesiveness to the skin and shape-retaining property and the efficient release property of a medicine. <P>SOLUTION: The plaster is obtained by applying an aqueous gel paste comprising a base for plaster containing (a) a water-soluble polymer being a mixture of water-soluble polymer containing (a1) a polymer obtained by carrying out homo-polymerization of one kind of monomer selected from 2-acrylamide-2-methylpropanesulfonic acid and/or its salt, styrenesulfonic acid and/or its salt and N-vinylpyrrolidone or one or more kinds of polymers obtained by copolymerizing the above monomer with the other monomer which is copolymerizable with one or more kinds of monomers selected from the above monomers with (a2) a polyacrylic acid and/or its salt, in which 20-60 mol% of the acid is neutralized, being fine powder and having ≤0.5 mass% content of unreacted monomer, (b) a polyhydric alcohol, (c) a polyvalent metal compound, (d) a surfactant and (e) water, and a medicine having transdermal absorption properties or a cosmetic component onto a support. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a patch obtained by applying a hydrous gel plaster comprising a base for a patch, a drug component, moisture and the like to a support. More specifically, the present invention relates to a patch excellent in the release of a drug or cosmetic ingredient from a plaster and having high adhesiveness and shape retention.

Patches with a plaster containing a hydrophilic or water-soluble polymer and water as the main component and a moisturizing agent or drug are spread on a support such as a nonwoven fabric are widely used. is doing. Along with this, research and development of patch bases and patches have been promoted for the purpose of improving the transdermal absorbability of drugs and improving the sustainability of cooling time.
A hydrophilic polymer such as polyvinyl alcohol, carboxymethyl cellulose, or polyacrylic acid (salt) is used as a hydrophilic base for patch. In general, hydrophilic bases have higher safety against the skin and better water retention than non-aqueous bases, but have insufficient adhesive strength. When trying to increase the adhesive strength, there is a problem that the cohesive force of the hydrophilic polymer decreases, and the plaster tends to remain on the skin when the plaster is peeled from the skin.

In the hydrophilic base, in place of the conventional hydrophilic polymer, a cross-linked hydrophilic polymer is used, or a polyvalent metal salt is added to the base of the hydrophilic polymer to cause intermolecular crosslinking. Attempts have been made to improve the adhesiveness and shape retention of the agent.
For example, 2-acrylamido-2-methylpropanesulfonic acid (salt) and acrylic acid (salt) are copolymerized in the presence of a polyfunctional crosslinking agent as a base composed of a crosslinked polymer having a sulfonic acid group. 2 or more of cataplasms (see Patent Document 1), 2-acrylamido-2-methylpropanesulfonic acid (salt), acrylic acid (salt) and ethylenically unsaturated bonds made of a crosslinked water-soluble polymer A cross-linked hydrophilic polymer obtained by cross-linking polymerization of a cross-linkable monomer is disclosed (see Patent Document 2).
In the plaster using such a crosslinked hydrophilic polymer, the granular gel particles themselves constituting the plaster have a certain degree of shape retention, but each gel particle does not have fluidity. Therefore, the paste containing these gel particles is inferior in spreadability on the support, and it is difficult to finish the surface of the paste layer smoothly. Moreover, since each gel particle is completely bridge | crosslinked, a paste becomes poor in adhesive force. Therefore, if the cross-linking reaction after spreading on the support is eased to increase the adhesive strength, the plaster is insufficient in shape retention, and it is impossible to achieve both adhesive strength and shape retention. Will not function sufficiently.
In addition to polyacrylic acid (salt), a plaster is disclosed in which a crosslinked superabsorbent polymer having a sulfonic acid group and a polyvalent metal compound for intermolecular crosslinking are added. However, when the amount of the superabsorbent polymer having a sulfonic acid group is large, there are problems such as insufficient adhesive strength and the smoothness of the surface of the plaster (see Patent Document 3).

On the other hand, in the method of shaping the gel composition into a sheet, a hydrophilic polymer obtained by polymerizing monomer components such as acrylic acid and 2-acrylamido-2-methylpropanesulfonic acid is used as a component such as a drug. Knead and uniformly apply to the support, or the raw material monomer, cross-linking agent and drug, and other additives constituting the hydrophilic polymer are pre-mixed and poured into the support or formwork. There is a method of polymerizing and shaping by ultraviolet irradiation or the like in the state.
For example, by copolymerizing 2-acrylamido-2-methylpropanesulfonic acid (salt) and a crosslinkable monomer together with a polyhydric alcohol as a wetting agent in an aqueous medium having a pH of 5.5 or more, A highly adhesive hydrogel is obtained (see Patent Document 4). In addition, a method for producing a base for a percutaneous absorption preparation, in which a composition containing a monomer having an ethylenically unsaturated bond, a drug, and a photopolymerization initiator is photopolymerized with active energy rays (see Patent Document 5). Or a solution containing a monofunctional monomer composed of 2-acrylamido-2-methylpropanesulfonic acid, acrylic acid, etc., a crosslinkable monomer having two or more ethylenically unsaturated bonds, a humectant, a drug, etc. There exists the method of apply | coating on a film and making it superpose | polymerize and gelatinize by irradiating an ultraviolet-ray (refer patent document 6).
These methods have the advantage that a plaster layer is formed at the same time as the formation of a hydrophilic polymer by polymerization, so it is easy to mix a low-viscosity monomer solution, and photopolymerization can be used to perform a crosslinking reaction in a short time. There is. However, there are problems that it is not possible to use a medicine that decomposes by ultraviolet rays, and that a large amount of unreacted monomer tends to remain in the plaster layer obtained by such a direct polymerization method. It is also difficult to purify the plaster layer itself.

  In addition, as an attempt to improve the drug release from the base, a topical external skin containing a specific non-steroidal anti-inflammatory agent, a plurality of water-soluble polymers such as polyacrylic acid (salt) and a plurality of polyvalent metal elements An agent (Patent Document 7) is disclosed, but it is difficult to say that drug release is sufficient. Furthermore, a gel composition containing a poorly water-soluble drug, a polyhydric alcohol, a polymer that can be dissolved or swollen in the polyhydric alcohol, and an electrolyte is also disclosed (Patent Document 8). However, even if the drug release is improved to some extent, since the electrolyte is blended in the plaster gel, the adhesive properties and the shape retention of the plaster gel cannot be compatible, and the basic performance of the patch cannot be satisfied.

JP-A-4-91021 (Claims) JP-A-9-124466 (page 1-2) Japanese Patent Application No. 2001-353185 (Claims) JP-A-6-200224 (paragraphs [0006] to [0008]) JP-A-9-124465 (column 4) Japanese Patent Publication No. 5-502239 (page 1-2) JP-A-11-199515 (Claims) JP 2005-162692 A (Claims)

  As described above, conventional patches using hydrophilic bases have insufficient drug release properties, so that the drug efficacy corresponding to the blending amount cannot be obtained, or alcohol is used to improve the drug release properties. If it is necessary to add a large amount of liquid components such as fatty acids and long-chain fatty acids and their esters, the adhesiveness to the skin is inferior, the plaster oozes out from a support such as a nonwoven fabric, When peeled from the skin, the plaster remained on the skin, and there was a problem that it could not be peeled cleanly. In other words, as a patch, it was not fully satisfactory in terms of achieving both the physical properties of the base such as adhesion to the skin, water retention, shape retention and hardness, and effective drug release. .

As a result of intensive studies to solve the above problems, the present inventors have
(A) The water-soluble polymer is a single monomer selected from 2-acrylamido-2-methylpropanesulfonic acid and / or a salt thereof, styrenesulfonic acid and / or a salt thereof, and N-vinylpyrrolidone. One or more polymers obtained by polymerization or obtained by copolymerizing one or two or more other monomers copolymerizable with the above monomers, and polyacryl A water-soluble polymer mixture containing an acid and / or a salt thereof, wherein 20 to 60 mol% of the acid is neutralized, and the content of unreacted monomer in a fine powder is 0.5% by mass or less Sex polymer,
(B) a polyhydric alcohol,
(C) a polyvalent metal compound,
(D) a surfactant,
(E) A patch obtained by applying an aqueous gel plaster containing a water-based patch base and a transdermally absorbable drug or cosmetic ingredient on a support is an adhesive as a conventional base. The present invention was completed by discovering that it has excellent properties, shape retention and spreadability, as well as excellent drug and cosmetic ingredient release properties from the plaster, and no exudation of the plaster or persistence on the skin.

The patch of the present invention is excellent in the releasability of the drug or cosmetic ingredient from the plaster. In addition, it has excellent adhesion to the skin and shape retention, no exudation of the plaster from a support such as a non-woven fabric, and there is no residue of the plaster on the skin and can be applied for a long time.
In addition, after obtaining a water-soluble polymer, an aqueous gel plaster is prepared by blending drugs or cosmetic ingredients, so that the content of unreacted residual monomers as impurities is low, red spots, rashes, rashes Can prevent skin disorders such as.

1. Composition of Patch The patch of the present invention is obtained by applying an aqueous gel plaster containing a base for patch and a transdermally absorbable drug or cosmetic ingredient on a support.

[1.1] Base for patch The base for patch is described in detail below. (A) Water-soluble polymer, (b) Polyhydric alcohol, (c) Polyvalent metal compound, (d) Surfactant And (e) water is an essential component.

(A) Water-soluble polymer The water-soluble polymer is a single monomer selected from 2-acrylamido-2-methylpropanesulfonic acid and / or a salt thereof, styrenesulfonic acid and / or a salt thereof, and N-vinylpyrrolidone. A monomer mixture obtained by homopolymerizing a monomer, or a monomer mixture further comprising one or two or more of the above monomers and other copolymerizable monomers added as required is copolymerized. One or more kinds of polymers obtained in this manner, and a small amount of a polyfunctional radical polymerizable crosslinking agent or the like may be added at the time of polymerization to moderately branch or crosslink, but usually obtained by polymerization without a crosslinking agent. The linear polymer obtained is preferable from the viewpoint of high adhesiveness, and is composed of this polymer (homopolymer or copolymer) and a water-soluble polymer mixture containing polyacrylic acid and / or a salt thereof. It is a functional polymer.

  One or more monomers selected from 2-acrylamido-2-methylpropane sulfonic acid and / or salt thereof, styrene sulfonic acid and / or salt thereof, and N-vinyl pyrrolidone have a hardness of the plaster. It is used to increase the release of drugs or cosmetic ingredients contained in the plaster in addition to imparting and maintaining the shape-retaining property. The amount used during polymerization, that is, substantially constituting the polymer The amount to be added is preferably 40 to 100 mol% based on the total number of moles of all monomer units constituting the water-soluble polymer.

If it is less than 40 mol%, alcohol or fatty acid is blended, or if moisture is contained, the shape retention will be insufficient and the paste will ooze out from the support, or the hardness of the paste will decrease and the paste will peel off when peeled off. Easily remain.
Examples of the salt of 2-acrylamido-2-methylpropanesulfonic acid or the salt of styrenesulfonic acid include alkali metal salts such as sodium and potassium, ammonium salts, and organic amine salts such as triethylamine and triethanolamine. These can be easily obtained by neutralizing 2-acrylamido-2-methylpropanesulfonic acid or styrenesulfonic acid with a corresponding alkali.

  This water-soluble polymer is one or more monomers selected from 2-acrylamido-2-methylpropanesulfonic acid and / or a salt thereof, styrenesulfonic acid and / or a salt thereof, and N-vinylpyrrolidone. Are essential constituent monomer units. In the present invention, other copolymerizable monomers can be used in combination with these. The amount of the other copolymerizable monomer used is preferably 0 to 60 mol% based on the total number of moles of all single unit units.

  Examples of other copolymerizable monomers include unsaturated carboxylic acids such as methacrylic acid, crotonic acid, itaconic acid, maleic acid, alkali metal salts thereof, ammonium salts, and 2-acrylamido-2-methylpropanesulfonic acid. Other than (meth) acrylamide alkylalkane sulfonic acid, allyl sulfonic acid, methallyl sulfonic acid, vinyl sulfonic acid and other unsaturated sulfonic acid, its alkali metal salt, ammonium salt, (meth) acrylamide, (meth) acrylonitrile, vinyl acetate , Dimethylaminoethyl (meth) acrylate, hydroxyethyl (meth) acrylate, hydroxypropyl (meth) acrylate, polyethylene glycol mono (meth) acrylate, polypropylene glycol mono (meth) acrylate, methoxypolyethylene glycol (meth) ) Acrylate, methyl (meth) acrylate, ethyl (meth) acrylate, and the like, and one or more of these can be used.

The water-soluble copolymer can be appropriately branched or cross-linked by using a radical polymerizable cross-linking agent and adding a small amount within a range that does not impair the water-solubility of the obtained copolymer. The case where the water solubility referred to in the present invention is impaired is the case where the amount of insoluble matter determined by the measurement method described later exceeds 10 ml.
Examples of the radical polymerizable crosslinking agent include ethylene glycol di (meth) acrylate, polyethylene glycol [average added mole number of oxyethylene (hereinafter abbreviated as EO) = 2 to 30 mol] .di (meth) acrylate. , N, N′-methylenebis (meth) acrylamide, divinylbenzene, trimethylolpropane / tri (meth) acrylate, tri (meth) allylamine, dimethyldi (meth) allyl ammonium chloride, and the like, Two or more kinds can be used.

The neutralization rate of the water-soluble polymer is 60 to 100 mol%. When the neutralization rate is less than 60 mol%, there may be a case where the transdermal absorbable drug or cosmetic ingredient cannot be sufficiently released from the aqueous gel.
The neutralization rate is the total amount of 2-acrylamido-2-methylpropanesulfonic acid, styrenesulfonic acid and acrylic acid, and other monomers containing all other acid groups used as necessary and their salts. It shows the ratio of the salt to.
A water-soluble polymer having the desired neutralization rate is obtained by polymerizing using an acid and a salt as monomers, or by neutralizing the obtained acid polymer with an alkali during the polymerization of the acid. To be prepared.

In the water-soluble polymer, the content of the unreacted monomer remaining in the polymer is 0.5% by mass or less based on the total mass of the polymer. An unreacted residual monomer content exceeding 0.5% by mass is not preferable in terms of skin irritation.
The water-soluble polymer has a weight average molecular weight of 100,000 to 5,000,000 according to an aqueous gel permeation chromatography (hereinafter abbreviated as GPC) method using polyethylene oxide as a reference substance.
When the molecular weight is less than 100,000, the shape retention is insufficient and the plaster oozes from the support, or the plaster tends to remain on the skin when it is peeled off due to a decrease in the hardness of the plaster. If the molecular weight exceeds 5,000,000, a water-insoluble gel may be generated or it may be difficult to obtain a water-soluble copolymer.

The water-soluble polymer used in the patch base of the present invention is a fine powder or an aqueous solution.
In the case of fine powder, the solid content is preferably 90% by mass or more. The solid content is preferably 90% by mass or more. If the solid content is less than 90% by mass, the dispersion stability of the polymer with respect to the polyhydric alcohol may deteriorate.
Further, it is more preferable that the fine powder has a particle size distribution in which 90% by mass or more is composed of particles having a particle diameter of 180 μm or less and 75 μm or less is 80% by mass or less with respect to the total amount of the powder. If the particle size is more than 10% by mass, the surface of the paste may be difficult to finish smoothly. If the particle diameter is less than 75 μm, the molecular weight tends to decrease and the workability may deteriorate.
In the case of an aqueous solution, the viscosity is preferably 100 to 100,000 mPa · s from the viewpoint of excellent operability. What is necessary is just to adjust solid content concentration so that it may enter into this viscosity range.

A known polymerization method can be employed for the synthesis of the water-soluble polymer. Specific examples include gel polymerization, aqueous solution polymerization, and reverse phase suspension polymerization.
As the polymerization initiator, a redox polymerization initiator is preferable. Instead of the redox polymerization initiator, a monomer aqueous solution containing a photopolymerization initiator may be irradiated with active energy rays such as ultraviolet rays to be radically polymerized. it can.
Specific examples of the polymerization initiator include alkali metal persulfates such as sodium persulfate and potassium persulfate, persulfates such as ammonium persulfate, hydrogen peroxide, cumene hydroperoxide, benzoyl peroxide, and t-butyl peroxide. , Organic peroxides such as benzoyl peroxide, 2,2′-azobis (4-cyanovaleric acid), 2,2′-azobis [2-methyl-N- (2-hydroxyethyl) -propionamide], 2 Azo compounds such as 2,2′-azobis (2-amidinopropane) dihydrochloride, 2,2′-azobisisobutyronitrile, and the like.

In the polymerization, it is preferable to use a reducing agent for redox formation such as transition metal salt, sulfite, hydrogen sulfite, L-ascorbic acid (salt), erythorbic acid (salt), amine compound and the like.
The amount of the polymerization initiator to be added is adjusted according to the type of the polymerization initiator to be used, the composition of the target polymer, the degree of polymerization, the viscosity, and the like. Usually, 5 to 10,000 ppm by mass is used based on the total amount of all monomers. Preferably 10 to 5,000 mass ppm, more preferably 15 to 3,000 mass ppm.

The content of the water-soluble polymer in the base is usually 0.5 to 29.5% by mass, preferably 0.5 to 14.5% by mass, based on the total amount of the base. . It adjusts so that the total amount with the polyacrylic acid shown below and / or its salt may be 1-30 mass% preferably 3-15 mass% on the basis of the base whole quantity.
When the amount of the water-soluble polymer used is less than 0.5% by mass, sufficient release of the transdermally absorbable drug or cosmetic ingredient from the aqueous gel plaster may not be obtained. Moreover, when it exceeds 29.5 mass%, the balance of the hardness and adhesive force of the obtained paste may become impossible.

The water-soluble polymer constituting the patch base of the present invention is a mixture of the water-soluble polymer and a water-soluble polymer comprising water-soluble polyacrylic acid and / or a salt thereof.
Water-soluble polyacrylic acid and / or a salt thereof can be blended as a thickener or a tackifier in order to enhance or improve the skin adhesion and gel strength of the plaster. As polyacrylic acid and / or a salt thereof, all of the carboxyl groups of acrylic acid are in the form of salts, some of the carboxyl groups are in the form of salts, all of the carboxyl groups remain as acid groups, or Any of a mixture of two or more of them can be used.
When a part or all of the carboxyl group of polyacrylic acid is a salt, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, ammonium salt and the like can be mentioned. Of these, sodium salts are preferred from the viewpoints of safety and productivity.

Since water-soluble polyacrylic acid and / or a salt thereof that can be suitably used are commercially available, they may be used as they are.
Examples of commercially available water-soluble polyacrylic acid and / or salts thereof include, for example, powdered polyacrylic acid partial neutralized product (trade name “Aronbis AH-105”) manufactured by Nippon Pure Chemical Co., Ltd., manufactured by Nippon Pure Chemical Co., Ltd. Powdered sodium polyacrylate (trade name “Aronbis S”), polyacrylic acid aqueous solution (concentration 20 mass%, trade name “Julimar AC-10H”) manufactured by Nippon Pure Chemical Co., Ltd., powder manufactured by Nippon Pure Chemical Co., Ltd. And cross-linked polyacrylic acid (trade name “Junron PW-110”). These may be used alone or in combination of two or more.

  The amount of its use is 0.5-29.5 mass% normally on the basis of the base whole quantity, Preferably it is 0.5-14.5 mass%. The total amount with the water-soluble polymer is adjusted so as to be 1 to 30% by mass, preferably 3 to 15% by mass based on the total amount of the base. When the amount of water-soluble polyacrylic acid and / or salt thereof used is less than 0.5% by mass, the adhesiveness of the resulting base may be reduced, or the gel strength of the plaster may be insufficient. . On the other hand, if it exceeds 29.5% by mass, the hardness and adhesive strength of the base obtained may not be balanced.

(B) Polyhydric alcohol The base for patch of this invention has a polyhydric alcohol as an essential component, and this polyhydric alcohol acts as a moisturizing agent or a water retaining agent.
Specific examples of the polyhydric alcohol preferably used include, for example, glycerin, sorbitol, mannitol, xylitol, ethylene glycol, diethylene glycol, 1,3-propanediol, 1,4-butanediol, polyethylene glycol, propylene glycol, polypropylene glycol. Etc.
The amount used is usually 1 to 50% by mass, preferably 5 to 30% by mass, based on the total amount of the base. When the amount used is less than 1% by mass, water is volatilized and dried from the obtained base, and the drug may precipitate in the base. On the other hand, if it exceeds 50% by mass, the hardness and adhesive strength of the resulting base may not be balanced.

(C) Multivalent metal compound The base for a patch of the present invention contains a polyvalent metal compound as an essential component. This polyvalent metal compound releases a polyvalent metal ion, and the released polyvalent metal ion is ion-bonded with an anion group (carboxylic acid group, sulfonic acid group, etc.) in the water-soluble polymer. By forming a crosslinked structure, the base is imparted with properties such as adhesiveness, gel-forming ability, high water content, shape retention and hardness.
Examples of such polyvalent metal compounds include polyvalent metal compounds that release polyvalent metal ions such as aluminum ions, magnesium ions, calcium ions, zinc ions, cadmium ions, titanium ions, chromium ions, manganese ions, and iron ions. Can be mentioned.
The patch of the present invention is used by directly sticking to human skin and the like, and needs to be safe. From this point, as the polyvalent metal compound, an aluminum compound, a magnesium compound, a calcium compound and a zinc compound which are excellent in safety are preferably used.

  Specific examples of the polyvalent metal compound preferably used include aluminum succinate, aluminum glycinate, aluminum acetate, aluminum hydroxide, aluminum sulfate, aluminum chloride, aluminum oxide, aluminum silicate, calcium hydroxide, calcium carbonate, and chloride. Calcium, calcium sulfate, calcium nitrate, calcium phosphate, calcium acetate, calcium oxide, magnesium hydroxide, magnesium carbonate, magnesium chloride, magnesium sulfate, magnesium nitrate, magnesium phosphate, magnesium acetate, magnesium oxide, magnesium hydroxide alumina, aluminum metasilicate Examples include magnesium silicate, magnesium aluminate silicate, potassium alum, ammonium alum, iron alum and the like. Moreover, these 1 type (s) or 2 or more types can be used.

Among these, aluminum hydroxide, aluminum glycinate, and aluminum chloride are preferable because the gel strength is increased.
The amount used is usually from 0.001 to 3% by mass, preferably from 0.003 to 1% by mass, more preferably from 0.005 to 0.5% by mass, based on the total amount of the base. is there. When the amount of the polyvalent metal compound used is less than 0.001% by mass, it becomes difficult to form a crosslinked structure with the anionic group in the water-soluble copolymer (a), and adhesion, gel formation and retention are prevented. It becomes difficult to impart characteristics such as moldability. Moreover, when it exceeds 3 mass%, it may bridge | crosslink too much and adhesive force may be insufficient.

(D) Surfactant The base for patch of the present invention is formulated with a surfactant as an essential component. The surfactant used in the base for patch of the present invention is so made that the concentration of components such as these drugs is uniform in the aqueous gel plaster by solubilizing and / or dispersing the following drugs or cosmetic ingredients. And in order to release the components such as the drug from the aqueous gel plaster uniformly and stably without variation. Therefore, the surfactant to be used varies depending on the kind of components such as a drug to be blended, but a nonionic surfactant is preferable because it can be solubilized and / or dispersed with a small amount of addition and is excellent in safety. .

Specific nonionic surfactants include polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate, polyoxyethylene sorbitan monooleate, Polyoxyethylene sorbitan fatty acid ester (EO = 6 to 20) such as polyoxyethylene sorbitan trioleate; polyoxyethylene hydrogenated castor oil (EO = 5 to 100); polyoxyethylene alkyl ether (C = 12 to 14, EO = 3-12); polyoxyethylene alkylphenyl ether (C = 6-12, EO = 3-40) such as polyoxyethylene octylphenyl ether (EO = 3-40); polyoxyethylene oleyl ether (EO) 2-50), polyoxyethylene and ethers of higher aliphatic alcohols such as polyoxyethylene stearyl ether (EO = 2 to 20), and the like.
Of these, particularly preferred nonionic surfactants are polyoxyethylene sorbitan monooleate (EO = 20) and polyoxyethylene hydrogenated castor oil (EO = 40).
The usage-amount of surfactant is 0.01-10 mass% normally on the basis of the base whole quantity, Most preferably, it is 0.03-5 mass%. When the amount of the surfactant used is less than 0.01% by mass, it becomes difficult to solubilize and / or disperse each component of the drug or cosmetic ingredient. When the amount used exceeds 10% by mass, the aqueous gel There are cases where air bubbles are remarkably produced during the preparation of the plaster, making it difficult to produce a patch, or the release of components such as drugs from the plaster may be reduced.

(E) Water The base used in the patch of the present invention is used as an aqueous base and contains water as an essential component. As water, water such as purified water is usually used.
The specific amount of water used depends on the amount of the above components (a) to (d), which is determined according to the characteristics required for the patch base, but is usually 10 to 85 mass. %.

(F) Organic acid having a hydroxyl group or a salt thereof The patch of the present invention may contain an organic acid having a hydroxyl group or a salt thereof in addition to the essential components (a) to (e). .
The organic acid having a hydroxyl group or a salt thereof facilitates dissolution of the hardly soluble metal compound by the hydroxyl group and carboxyl group in the molecule so that the polyvalent metal ion can be easily released from the component (c) polyvalent metal compound. To do.
Examples of the organic acid having a hydroxyl group or a salt thereof include tartaric acid, lactic acid, citric acid, malic acid, glycolic acid, gluconic acid, and alkali metal salts thereof from the viewpoint of irritation to skin and safety. Particularly preferred are tartaric acid, citric acid, malic acid and alkali metal salts thereof. For example, tartaric acid is also preferable in that the gel curing rate is increased by the combined use with aluminum hydroxide or aluminum glycinate, which is the above-mentioned (c) polyvalent metal compound.
The amount used is preferably 0.001 to 5% by mass, particularly preferably 0.003 to 2% by mass, based on the total amount of the base.

(G) C2-C6 monohydric alcohol The patch of this invention mix | blends C2-C6 monohydric alcohol according to the objective other than the said essential component (a)-(e). Can do.
The monohydric alcohol having 2 to 6 carbon atoms acts as a solubilizing agent for uniformly dissolving a refreshing agent, a hydrophobic drug or an additive in the base, or as a transdermal absorption enhancer.
As the monohydric alcohol having 2 to 6 carbon atoms, ethanol and isopropanol are preferably used from the viewpoint of safety and effects. Particularly preferred is ethanol.
The amount used is preferably 0.1 to 20% by mass, more preferably 1 to 15% by mass, based on the total amount of the base. When the amount used exceeds 20% by mass, rash and inflammation tend to occur on the skin.

(H) Long-chain fatty acid and / or ester thereof The long-chain fatty acid and / or ester thereof can be blended in the patch base of the present invention depending on the purpose. This long-chain fatty acid and / or ester thereof is used as a hydrophobic additive blended in the base, as a drug solubilizing agent, or for improving the transdermal absorbability of the drug.
As long-chain fatty acids or esters thereof, oleic acid, linoleic acid, linolenic acid, myristic acid, and esters thereof are preferably used from the viewpoint of safety and effects.
The amount used is preferably 0.1 to 20% by mass, more preferably 1 to 10% by mass, based on the total amount of the base. When the amount used is less than 0.1% by mass, it hardly contributes to the improvement of the solubility of the hydrophobic additive or drug, and the additive or drug precipitates in the base or the drug transdermally. Absorbability may be reduced.
The components (f) to (h) described above may be added and used alone or in combination with the essential components (a) to (e).

[1.2] Drug or Cosmetic Ingredient The patch of the present invention is used for a pharmaceutical patch or a cosmetic patch, and when used in such applications, the above-mentioned [1.1] base for a patch contains a drug or cosmetic. Mix ingredients.
Examples of such drugs or cosmetic ingredients include pharmaceutical agents such as anti-inflammatory agents, analgesics, bronchodilators, anti-asthma agents and cardiotonics, and cosmetic ingredients such as whitening agents.
Specific examples of the drug include, for example, indomethacin, ketoprofen, methyl salicylate, glycol salicylate, flurbiprofen, ibuprofen, suprofen, loxoprofen, felbinac, proxycam, meloxicam, tulobuterol, diphenhydramine, dibucaine, procaine, lidocaine, nitroglycerin, Examples include isosorbide nitrate, nicotine, and vitamins.

Specific examples of whitening agents as cosmetic ingredients include, for example, ascorbic acid such as sodium ascorbate, magnesium L-ascorbyl phosphate, disodium L-ascorbate sulfate, ascorbyl palmitate, ascorbyl dipalmitate, stearyl ascorbate Derivatives and salts thereof, kojic acid and derivatives thereof, licorice extract, placenta extract, hydroquinone and derivatives thereof, arbutin, isoflavone derivatives, p-hydroxycinnamic acid derivatives, geraniin, gallic acid, cysteine, glutathione, colloidal sulfur, tepanolene, 2- Examples include chromanone derivatives and spiro ether compounds.
The blending ratio of the drug or cosmetic ingredient is preferably 0.01 to 20% by mass based on the total amount of the patch.

[1.3] Other components In addition to the above-described components, the patch of the present invention includes additives generally used in patches, that is, an antioxidant, in order to improve the suitability during production and the quality during use. One or more of various components such as preservatives and emulsifiers can be blended.
Such other components include L-menthol, camphor, thymol, peppermint oil, castor oil, fennel oil, daikyo oleo oil, cinnamon oil, clove oil, thiamine oil, terpyrene oil, eucalyptus oil, lavender oil, lemon oil, Fragrances and refreshing agents such as orange oil, bergamot oil, rose oil; warming sensates such as chili extract and salamander extract; antioxidants such as dibutylhydroxytoluene and butylhydroxyanisole; methyl paraoxybenzoate, propyl paraoxybenzoate Preservatives such as: emulsifiers; inorganic powders such as kaolin, titanium oxide, and silicic anhydride.
A specific example of the blending ratio of the fragrance / cooling agent, inorganic additive, etc. is 0.1 to 20% by mass based on the total amount of the patch.

2. Method for preparing aqueous gel plaster The method for preparing the aqueous gel plaster constituting the patch of the present invention is not particularly limited.
In general, (a) a water-soluble polymer, (b) a polyhydric alcohol, (c) a polyvalent metal compound, (d) a surfactant, and other ingredients as necessary, and [1.2] a drug or The dispersion slurry mixed with the cosmetic ingredients is mixed with (e) water (f) an organic acid having a hydroxyl group or a salt thereof and an aqueous ingredient containing other ingredients as needed, at room temperature. It can be kneaded until uniform and defoamed under reduced pressure to obtain a hydrous swelling gel (aqueous gel paste).
Preferably, (d) a surfactant or [1.2] drug or cosmetic component is previously solubilized and / or dispersed, and the above components (a) to (c) and other components are added as necessary. Create a dispersed slurry. Separately, (e) (f) an organic acid having a hydroxyl group or a salt thereof is dissolved in water and mixed with an aqueous component containing other components as necessary, and mixed at room temperature in the same manner as above. It knead | mixes until it becomes and it defoams under reduced pressure, and can obtain an aqueous gel plaster body.

3. Method for producing patch The method for producing the patch of the present invention is not particularly limited.
Generally, the above-mentioned 2. consisting of [1.1] patch base and [1.2] drug or cosmetic ingredient, and [1.3] other ingredients as required. The aqueous gel plaster is applied in layers by spreading on a support made of nonwoven fabric, knitted fabric, woven fabric, paper, plastic film or the like.
Then, if necessary, the patch can be produced by covering the surface with a releasable film or sheet such as a polyethylene film. In use, these releasable films can be peeled off and applied directly to the skin.

4). Application of Patch The patch of the present invention can be used for various applications.
For example, pharmaceuticals such as anti-inflammatory agents, bronchodilators, asthma and angina treatments, cosmetics such as whitening agents and face masks, cooling agents and cooling sheets, medical devices such as warming agents and portable warmers It can also be used as a patch in areas such as daily necessities.

Hereinafter, the present invention will be described more specifically with reference to examples and comparative examples.
In the following examples, “%” when not specifically displayed means “% by mass”.

<Synthesis of Polymer 1>
A monomer aqueous solution was prepared by charging 1200 g (corresponding to 100 mol%) of a 50 mass% aqueous solution of sodium 2-acrylamido-2-methylpropanesulfonate and 1800 g of pure water into a 3 L separable flask and mixing them. While the contents of the separable flask were stirred at a stirring speed of 300 rpm (rotation / min), nitrogen bubbling was performed at a flow rate of 4 L / min for 1 hour until the dissolved oxygen concentration was sufficiently reduced. Subsequently, when the temperature of the contents of the separable flask was controlled to 40 ° C. and the temperature was stabilized, 1.00 g of a 3% by mass aqueous solution of t-butyl hydroperoxide, 3.00 g of an aqueous 10% by mass sodium persulfate solution and 5% by mass Polymerization was initiated by adding 1.20 g of an aqueous sodium erythorbate solution.
Thereafter, the temperature of the contents was raised from 40 ° C. to 55 ° C. for 30 minutes, from 55 ° C. to 70 ° C. for 2 hours, and then from 70 ° C. to 85 ° C. over 30 minutes, gradually increasing to 85 ° C. The polymerization was terminated by maintaining for 3 hours. When the temperature of the contents reached 80 ° C. during the polymerization reaction, 3.60 g of a 10% by mass aqueous sodium persulfate solution was added. Then, it cooled to 60 degreeC and took out polymer aqueous solution. In this way, an aqueous polymer 1 having a solid concentration of 20% by mass was obtained.

(Synthesis Example 2)
<Synthesis of Polymer 2>
A monomer aqueous solution was prepared by charging 886.7 g (corresponding to 100 mol%) of 81.2% by mass of sodium styrenesulfonate and 2113.3 g of pure water into a 3 L separable flask and mixing them. Otherwise in the same manner as in Synthesis Example 1, an aqueous polymer 2 having a solid content concentration of 24% by mass was obtained.

(Synthesis Example 3)
<Synthesis of Polymer 3>
21.2 g (corresponding to 3 mol%) of 81.2 wt% sodium styrenesulfonate, 1167.5 g (corresponding to 97 mol%) of 50 wt% aqueous solution of sodium 2-acrylamido-2-methylpropanesulfonate and 1812 pure water .5 g was charged into a 3 L separable flask and mixed to prepare an aqueous monomer solution. Otherwise in the same manner as in Synthesis Example 1, an aqueous polymer 3 having a solid concentration of 20% by mass was obtained.

(Synthesis Example 4)
<Synthesis of Polymer 4>
30.7 g (corresponding to 10 mol%) of N-vinylpyrrolidone, 1138.6 g (corresponding to 90 mol%) of a 50 mass% aqueous solution of sodium 2-acrylamido-2-methylpropanesulfonate and 1830.7 g of pure water in a 3 L capacity A separable flask was charged and mixed to prepare an aqueous monomer solution. Otherwise in the same manner as in Synthesis Example 1, an aqueous polymer 4 having a solid concentration of 20% by mass was obtained.

(Comparative Synthesis Example 1)
<Synthesis of Comparative Polymer 1>
Monomer having a monomer concentration of 30% by mass by mixing 566.2 g (corresponding to 50 mol%) of a 36% by mass aqueous solution of sodium acrylate, 156.2 g (corresponding to 50 mol%) of acrylic acid and 477.6 g of pure water. 1.2 kg of aqueous solution was prepared. This aqueous monomer solution was charged into a stainless steel dewar (reaction vessel), and nitrogen bubbling was performed for 30 minutes while adjusting the temperature in the reaction vessel to 10 ° C. Then, as a polymerization initiator, 30 ppm of t-butyl hydroperoxide (converted on a mass basis with respect to the total amount of all monomers, the same shall apply hereinafter), 200 ppm of sodium persulfate and 30 ppm of sodium erythorbate were added and left as they were for 8 hours. The adiabatic stationary redox polymerization was carried out. After the completion of the reaction for 8 hours, the produced hydrogel polymer was taken out from the reaction vessel, put into a chopper and chopped into ground meat. The chopped water-containing gel was dried with a hot air dryer and pulverized with a pulverizer. Further, particles larger than 180 μm were removed using an 83 mesh stainless steel standard sieve (JIS Z 8801, inner diameter 200 mm, aperture 180 μm), and then finish-dried to obtain a fine powdered comparative polymer 1.

(Comparative Synthesis Example 2)
<Synthesis of Comparative Polymer 2>
Monomer having a monomer concentration of 29% by mass by mixing 449.8 g (corresponding to 40% by mole) of a 36% by weight aqueous solution of sodium acrylate, 186.1g of acrylic acid (corresponding to 60% by mole) and 564.1g of pure water. 1.2 kg of aqueous solution was prepared. Otherwise in the same manner as in Comparative Synthesis Example 1, the target powdery comparative polymer 2 was prepared.

  Next, the physical properties of the polymers 1 to 4 obtained in Synthesis Examples 1 to 4 and Comparative Polymers 1 and 2 obtained in Comparative Synthesis Examples 1 and 2 were performed according to the test methods shown below. The results are shown in Table 1.

(Test method)
◇ Solid content Each of the polymers obtained in Synthesis Examples 1 to 4 and Comparative Synthesis Examples 1 and 2 was weighed into 1.00 g aluminum cups, heated for 3 hours in a dryer at 105 ° C., and the solid content was determined from the heat loss. It was.

◇ 10% by mass aqueous solution viscosity The aqueous polymer obtained in Synthesis Examples 1 to 4 was added with pure water so that the solid content concentration was 10% by mass, stirred for 3 hours, fully dissolved, and 10% by mass. % Aqueous polymer solution was prepared. The viscosity of the polymer aqueous solution was measured with a B-type viscometer (manufactured by Tokyo Keiki Co., Ltd., model: BM type) at 25 ° C. and 6 rpm rotor speed.

◇ 0.2 wt% aqueous solution viscosity 1.00 g of each of the powdered polymers obtained in Comparative Synthesis Examples 1 and 2 was added to 500 ml of pure water, stirred for 3 hours, fully dissolved and 0.2 wt% A polymer aqueous solution having a concentration was prepared. The viscosity of the polymer aqueous solution was measured with a B-type viscometer (manufactured by Tokyo Keiki Co., Ltd., model: BM type) at a rotor rotation speed of 30 ° C. and 30 rpm.

◇ Content of unreacted monomer (residual monomer) Solid content of 1.00 g each of the polymers obtained in Synthesis Examples 1 to 4 and Comparative Synthesis Examples 1 and 2 in 20 ml of 80% by volume acetonitrile aqueous solution Then, after stirring for 1 hour, the mixture was left to stand for 1 hour for extraction. The supernatant was collected, measured by high performance liquid chromatography, and quantified by a calibration curve method using each monomer. The separation column used was HPLC packed column # 3056 manufactured by Hitachi, Ltd., and the eluent was 0.1% by mass phosphate buffer. The content of the unreacted monomer was calculated by mass% with respect to the total solid content of the polymer.

Weight average molecular weight The molecular weights of the polymers obtained in Synthesis Examples 1 to 4 and Comparative Synthesis Examples 1 and 2 were measured by an aqueous GPC method. The separation column used was two Tosoh Corporation water-based GPC columns TSKgel-G6000PWXL and one Tosoh Corporation water-based GPC column TSKgel-G3000PWXL. These three were connected in series. . As an eluent, an aqueous solution containing sodium sulfate (1.33 g / l) and sodium hydroxide (0.33 g / l) as solutes was used. The weight average molecular weight was calculated by preparing a calibration curve using polyethylene oxide as a reference substance.

◇ Insoluble content For the polymers obtained in Synthesis Examples 1 to 4 and Comparative Synthesis Examples 1 and 2, 10% by mass concentration prepared in the same manner as the measurement of the 10% by mass aqueous solution viscosity and 0.2% by mass aqueous solution viscosity, and 400 ml of a 0.2% by mass polymer aqueous solution was filtered with an 83 mesh stainless steel standard sieve (JIS Z 8801, inner diameter 200 mm), and the volume of insoluble matter remaining on the sieve was measured.

表中の略号は以下のものを示す。
ATBS-Na：２−アクリルアミド−２−メチルプロパンスルホン酸ナトリウム
ANa：アクリル酸ナトリウム
AA：アクリル酸
NaSS：スチレンスルホン酸ナトリウム
NVP：Ｎ−ビニルピロリドン
尚、ATBSは東亞合成株式会社の登録商標である。

The abbreviations in the table indicate the following.
ATBS-Na: Sodium 2-acrylamido-2-methylpropanesulfonate
ANa: Sodium acrylate
AA: Acrylic acid
NaSS: Sodium styrene sulfonate
NVP: N-vinylpyrrolidone ATBS is a registered trademark of Toagosei Co., Ltd.

Examples 1 to 4 and Comparative Examples 1 and 2
[Manufacturing method of patch]
1) Preparation of base for patch A base for patch was prepared by mixing the components shown in Table 2 below in the proportions (parts by mass) shown in Table 2. First, a drug or cosmetic ingredient was added to the surfactant and moderately warmed and solubilized. Glycerol was added thereto and mixed well, and then a water-soluble polymer, polyacrylic acid (salt), polyvalent metal compound and other components were added and stirred to prepare a glycerin slurry. Separately, an aqueous solution (aqueous phase) in which tartaric acid is dissolved in purified water is prepared, the aqueous phase is added to the glycerin slurry, and the mixture is stirred and then kneaded using a mixing device (kneader) until it is uniform at room temperature. The base for a patch which is an aqueous gel plaster was prepared by defoaming below.
2) Manufacture of the patch The aqueous gel plaster obtained in 1) above was applied to a stretchable nonwoven fabric (polyester nonwoven fabric having a basis weight of 105 g / m ² ) at a coating amount of 12 g / 140 cm ² and covered with a release film. To produce a patch.
3) Packaging and molding The patch obtained in 2) above was sandwiched from both sides of the patch using two foil laminate films, and then the periphery of the film was heat-sealed and hermetically packaged. This was stored and molded at 25 ° C. and 65% RH for 720 hours.

[Evaluation method of patch]
The molded patch was taken out from the airtight packaging material and evaluated for the following items.

a) Adhesiveness:
The time until the patch was applied to 5 or more arms and peeled off was measured, and the adhesiveness was evaluated from the average value according to the following criteria.
A: The average time until peeling off is 5 hours or more.
○: The average time until peeling off is 3 hours or more and less than 5 hours.
Δ: Average time to peel off is less than 3 hours.

b) Bleed resistance:
The back surface of the polyester nonwoven fabric was visually observed and evaluated according to the following criteria.
○: There is no bleeding.
Δ: Some exudation.
X: There is oozing throughout.

c) Remaining plaster:
The patch was affixed to the arm and lightly pressure-bonded with the palm, and the patch was immediately peeled off. The presence or absence of the plaster remaining on the arm was visually observed and evaluated according to the following criteria.
○: No plaster remains on the arm.
Δ: Part of the plaster remained on the arm.

d) Hardness:
The patch was applied to the outside of the elbow bent at about 90 ° and lightly crimped with the palm, and then the elbow was stretched and the contact state was visually observed.
(Double-circle): There is no floating part and it is adhering favorably.
○: Some floating was observed, but the entire surface was stably adhered.
(Triangle | delta): The part which floated on the whole elbow was seen.

e) Finished state of the plaster surface:
The release film was peeled off, and the finished state of the plaster surface of the patch was visually observed and evaluated according to the following criteria.
○: The surface is smooth and flat, and the finish is good.
Δ: Some irregularities are seen on the surface.

f) Drug release properties:
The patch was cut into a circular shape having a diameter of 35 mm and used as a test piece. Then, inner diameter φ20mm,
A receiver solution (phosphate buffer / PEG) is added to a glass Franz diffusion cell with a volume of 20 ml.
400 = 60/40% by mass), the liquid temperature was adjusted to 32 ° C., and the gel surface of the test piece was contacted with the receiver liquid through a cellulose membrane and sealed. The receiver solution is collected after 30 minutes, 1, 2, 3, 4, 5 hours, measured by high performance liquid chromatography, and quantified by the calibration curve method to determine the cumulative drug concentration at each time. Asked. The separation column used was
This was a HPLC column UG120 manufactured by Shiseido Co., Ltd., and a 0.1 mol% phosphate buffer / acetonitrile mixture was used as the eluent.

<Indomethacin>
A: Cumulative drug concentration after 5 hours is 10 ppm or more.
○: Cumulative drug concentration after 5 hours is 5 ppm or more and less than 10 ppm.
Δ: Cumulative drug concentration after 5 hours is less than 5 ppm.
<Sustainability>
Sustainability (time) was defined as the time when the increase in cumulative drug concentration increased per hour was less than 10%.

表中の名称は以下のものを示す。
PEOSM(EO=20モル)：ポリオキシエチレンソルビタンモノオレート
アロンビスAH-105：粉末状ポリアクリル酸部分中和物（日本純薬製）
尚、「アロンビス」は日本純薬株式会社の登録商標である。

The names in the table indicate the following.
PEOSM (EO = 20 mol): Polyoxyethylene sorbitan monooleate Aronbis AH-105: Powdered polyacrylic acid partially neutralized product (Nippon Pure Chemicals)
“Aronbis” is a registered trademark of Nippon Pure Chemicals Co., Ltd.

As shown in Table 2, the patch of the example gave better results than the comparative example.
That is, in each of the patches in Examples 1 to 4, the basic properties of the base were adhesion and hardness, and the drug release was also good.
On the other hand, as a water-soluble polymer, none of 2-acrylamido-2-methylpropanesulfonic acid, styrenesulfonic acid, and N-vinylpyrrolidone is used, and a conventional polyacrylic acid partial neutralized product (Comparative Polymer 1 or 2). In Comparative Examples 1 and 2 using only), there were problems in adhesion, anti-bleeding, and hardness, and the drug release was also significantly inferior to the Examples.

  The patch of the present invention has excellent drug or cosmetic ingredient release properties from the plaster, excellent base adhesion and shape retention, and does not ooze or remain on the skin. Is possible. Moreover, since the content of unreacted monomer in the water-soluble polymer constituting the base is small, and skin disorders such as red spots, rashes, and rashes can be prevented, patches in the pharmaceutical and cosmetic fields are widely used. It can be applied to medical devices and daily necessities.

BRIEF DESCRIPTION OF THE DRAWINGS It is drawing which shows the drug release property of Examples 1-4 (drug: indomethacin).

Claims (6)

An aqueous gel plaster containing a base for patch and a transdermally absorbable drug or cosmetic ingredient characterized by containing the following (a) to (e) as essential components: A patch.
(A) the water-soluble polymer is
It is obtained by homopolymerizing one monomer selected from 2-acrylamido-2-methylpropanesulfonic acid and / or a salt thereof, styrenesulfonic acid and / or a salt thereof, and N-vinylpyrrolidone, or A water-soluble polymer containing one or more polymers obtained by copolymerizing one or more monomers and other monomers copolymerizable with polyacrylic acid and / or a salt thereof A water-soluble polymer in which 20 to 60 mol% of the acid is neutralized and the content of unreacted monomer is fine powder and 0.5% by mass or less,
(B) polyhydric alcohol (c) polyvalent metal compound (d) surfactant (e) water 2. The patch for a patch according to claim 1, wherein the blending ratio of each component is as follows based on the total amount of the base.
(A) Water-soluble polymer: 1 to 30% by mass
(B) Polyhydric alcohol: 1 to 50% by mass
(C) Multivalent metal compound: 0.001 to 3% by mass
(D) Surfactant: 0.01 to 10% by mass
(E) Water: balance (A) The water-soluble polymer constituting the patch base is based on the total amount of the base,
It is obtained by homopolymerizing one monomer selected from 2-acrylamido-2-methylpropanesulfonic acid and / or a salt thereof, styrenesulfonic acid and / or a salt thereof, and N-vinylpyrrolidone, or 0.5% to 29.5% by weight of one or more polymers obtained by copolymerizing one or more monomers with other monomers copolymerizable with polyacrylic The acid and / or salt thereof is a water-soluble polymer containing 29.5 to 0.5% by weight (the total amount is 1 to 30% by mass as a water-soluble polymer). Or the patch according to 2. A patch, wherein the patch base according to any one of claims 1 to 3 further contains one or more of the following components.
(F) Organic acid having a hydroxyl group or a salt thereof (g) Monovalent lower alcohol having 2 to 6 carbon atoms (h) Long chain fatty acid and / or ester thereof The patch according to any one of claims 1 to 4, wherein a transdermal drug or cosmetic ingredient is solubilized and / or dispersed by a surfactant. The patch according to any one of claims 1 to 5, wherein the surfactant is a nonionic surfactant.

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