JP6801554B2 - A method for manufacturing a skin adhesive, a skin adhesive, and a skin adhesive with a peeling sheet-like member. - Google Patents

Description

The present invention relates to a skin patch containing a transdermal drug, a skin patch using the adhesive, and a method for producing a skin patch with a peeling sheet-like member.

Conventionally, various skin-adhesive adhesives have been used to fix skin wounds and medical devices to the skin. In addition, as a transdermal preparation for administering a transdermal drug through the skin into the living body, a transdermal external application such as a plaster, a poultice using an adhesive, or a transdermal adhesive sheet is applied. Agents are being developed. Among them, a transdermal adhesive sheet containing a transdermal drug in the adhesive has attracted attention because the administration operation is relatively easy and the dose can be controlled.

Since such a transdermal adhesive sheet is used by attaching an adhesive layer containing a transdermal drug to the skin surface, it is not irritating to the skin and has adhesiveness (adhesion) to the skin surface. Gender) is required. In addition, in order to improve the therapeutic effect more reliably, it is expected to develop a transdermal patch that can continuously administer the drug to the affected area for a long time. Therefore, it is required to improve the drug solubility of the pressure-sensitive adhesive and the drug release property from the pressure-sensitive adhesive.

In order to meet such demands, rubber adhesives, acrylic adhesives, and silicone adhesives are often used as adhesives for skin application.

For example, the rubber-based pressure-sensitive adhesive contains styrene-isoprene-styrene block copolymer, polybutene, polyisobutylene, polyisoprene, ethylene-vinyl acetate copolymer, natural rubber, and the like as main components, and a pressure-imparting agent and a softening agent. , Stabilizer added is used.
Patent Document 1 discloses a pressure-sensitive adhesive containing a styrene-isoprene-styrene block copolymer, a paraffinic hydrocarbon having 10 to 30 carbon atoms and / or a naphthenic hydrocarbon and an alicyclic hydrocarbon resin.
Patent Document 2 discloses a sticking sheet or tape made of a thermoplastic elastomer made of an ABA-type block copolymer, a liquid component compatible with the thermoplastic elastomer, and a tackifier.
Patent Document 3 discloses a patch characterized by containing two types of synthetic rubbers having different fluidities in the pressure-sensitive adhesive layer.

Further, as the silicone-based pressure-sensitive adhesive, those using silicone rubber, dimethylsiloxane base, diphenylsiloxane, or the like are known.
Patent Document 4 discloses a pressure-sensitive silicone adhesive comprising an adhesive strength enhancer such as a silicone liquid, a silicone resin, and a nonionic surfactant.
Patent Document 5 discloses a pressure-sensitive adhesive composition containing an organosiloxane-based polymer and an acrylic polymer containing a (meth) acrylic acid ester as a main component.
Patent Document 6 discloses a silicone-based adhesive for skin that contains a silicone resin and a modified silicone oil compatible with the silicone resin and is emulsified in water in oil.

Further, as an acrylic pressure-sensitive adhesive, Patent Document 7 describes a monomer containing a carboxyl group or a hydroxyl group, a copolymer obtained by copolymerizing a (meth) acrylic acid ester as an essential component, and a salt structure in a side chain. Disclosed is a transdermal absorption preparation using a monomer having a nitrogen atom that does not have it and a copolymer obtained by copolymerizing a (meth) acrylic acid ester as an essential component.
Patent Document 8 describes a pressure-sensitive adhesive composition comprising a water-insoluble copolymer containing N-vinyl-2-pyrrolidone as a constituent and a polymer containing a monoalkyl ester of maleic anhydride as a constituent. Disclose.

Further, Patent Documents 9 to 12 disclose external preparations, which are characterized by containing a low molecular weight amine oxide as an additive, for the purpose of improving the transdermal absorbability of the drug.

Further, Patent Document 13 discloses a hair cosmetic resin composition prepared by using an amine oxide group-containing resin solution.

Japanese Unexamined Patent Publication No. 5-17346 Japanese Unexamined Patent Publication No. 2004-115774 Japanese Unexamined Patent Publication No. 2006-75588 Japanese Unexamined Patent Publication No. 5-194201 Japanese Unexamined Patent Publication No. 2005-314618 Japanese Unexamined Patent Publication No. 2009-273674 Japanese Unexamined Patent Publication No. 2000-44904 Japanese Unexamined Patent Publication No. 9-176604 Japanese Unexamined Patent Publication No. 1-224329 Japanese Unexamined Patent Publication No. 9-67272 Japanese Unexamined Patent Publication No. 2000-7584 Japanese Unexamined Patent Publication No. 2014-80419 Japanese Unexamined Patent Publication No. 2010-043066

Rubber-based adhesives such as Patent Documents 1 to 3 and silicone-based adhesives such as Patent Documents 4 to 6 have high hydrophobicity, so that the solubility of the drug is insufficient and the selection range of the drug composition is wide. It had the drawback of being narrow.
In acrylic pressure-sensitive adhesives such as Patent Documents 7 and 8, in order to secure the cohesive force of the pressure-sensitive adhesive, monomers having a carboxyl group or a hydroxyl group are copolymerized, but depending on the drug used, the influence of these functional groups may occur. In response to this, there was a problem that the amount of drug released was reduced. Moreover, the drug solubility is not sufficient.
When a low molecular weight amine oxide is used as an additive as disclosed in Patent Documents 9 to 12, the drug solubility is insufficient when a small amount is added, and when a large amount is added, bleed out from the adhesive. There is a risk of reduced stickiness and skin irritation.
Note that Patent Document 13 does not suggest the use of an amine oxide group-containing resin as a skin-adhesive adhesive.

In view of the above circumstances, the present invention provides skin suitable for a skin patch having excellent skin irritation, adhesiveness to the skin surface, exfoliation property from the skin, drug solubility, and drug release property from the adhesive. It is an object of the present invention to provide an adhesive for sticking.

Generally, in order to impart cohesive force to a polymer or improve the solubility of a drug, a method of introducing a highly polar group such as a carboxyl group or a hydroxyl group is known, but it is strongly mutual with the drug. It is easy to act, and it is difficult to balance drug release and drug solubility.
Therefore, the present inventors have developed skin irritation and adhesion to the skin surface by using a polymer containing a specific amount of highly hydrophilic amine oxide groups and having a glass transition temperature and a mass average molecular weight in a specific range. We have found that it is possible to provide a patch having excellent properties, peelability when peeled from the skin, drug solubility, and drug release property, and have arrived at the present invention.
That is, the present invention contains an amine oxide group of 0.25 to 3 mmol / g, has a glass transition temperature of −60 ° C. to −5 ° C., and has a mass average molecular weight of 10,000 to 1,000,000. The present invention relates to a pressure-sensitive adhesive for skin application, which comprises a polymer (a) and a transdermal agent (b).

The polymer (a) is preferably selected from the group consisting of vinyl-based polymers and urethane-based polymers.

Further, the polymer (a) may be a reaction product of a polymer having a tertiary amino group and an oxidizing agent, or a polymer obtained by polymerizing a monomer having an amine oxide group and another monomer. preferable.

Further, it is preferable that the vinyl polymer has at least one of the structures represented by the following general formulas (1) to (3).

(During the ceremony,
X is a divalent binding group or a direct bond,
y is 0 or 1,
R ¹ is an alkylene group having 1 to 6 carbon atoms,
R ² and R ³ are independently alkyl groups having 1 to 4 carbon atoms, respectively.
R ⁴ is a hydrogen atom or a methyl group,
Four of R ^{5 to} R ⁹ represent a hydrogen atom and an alkyl group having 1 to 6 carbon atoms, and one of R ^{5 to} R ⁹ represents a bonding position with the main chain of a vinyl polymer.
* Indicates the bonding position of the vinyl polymer with the main chain. )

Further, it is preferable that the urethane-based polymer has at least one of the structures represented by the following general formulas (4) to (6).

(During the ceremony,
R ¹⁰ , R ¹² , and R ¹⁵ each independently have an alkylene group having 1 to 6 carbon atoms.
R ¹¹ _, R ¹³ , R ¹⁴ , R ¹⁶ and R ¹⁷ independently have an alkyl group, an aryl group, an aralkyl group, and a pyridyl group.
Y represents O or N
** represents the bonding position of the urethane polymer with the main chain. )

Further, in the skin-sticking pressure-sensitive adhesive of the present invention, the polymer (a) contained in 100% by mass of the skin-sticking pressure-sensitive adhesive is preferably 20 to 99% by mass.

The present invention also relates to a skin patch having a sheet-like base material and a layer of the skin patch adhesive of the present invention.

Furthermore, in the present invention, the pressure-sensitive adhesive coating liquid containing the pressure-sensitive adhesive for skin application and the liquid medium of the present invention is applied to a sheet-like base material or a peeling sheet-like member to remove the liquid medium. Then, a skin-adhesive pressure-sensitive adhesive layer containing a transdermal absorbable agent is formed on the sheet-like base material or the peel-off sheet-like member, and the peel-off sheet-like member or the sheet-like base material is formed on the pressure-sensitive adhesive layer. The present invention relates to a method for producing a skin patch with a peeling sheet-like member to be laminated.

By using a polymer (a) containing a specific amount of amine oxide groups and having a glass transition temperature and a mass average molecular weight in a specific range, skin irritation, adhesiveness to the skin surface, peelability when peeled from the skin, It was possible to provide a pressure-sensitive adhesive for skin application, which has excellent drug solubility and drug release property from the pressure-sensitive adhesive.

The pressure-sensitive adhesive for skin application of the present invention is characterized by containing a polymer (a) having an amine oxide group.
<Polymer (a)>
The image of the polymer having an amine oxide group is shown by the following formula (7). In the formula, R ¹⁸ , R ¹⁹ and R ²⁰ each independently represent an organic group.

In the polymer (a) having an amine oxide group, at least one of R ¹⁸ , R ¹⁹ , and R ²⁰ is linked to the polymer.
By having an amine oxide group, it is possible to enhance the cohesive force of the polymer and to impart excellent drug solubility and drug release property.

The type of the polymer (a) includes vinyl-based polymer, urethane-based polymer, polyester, polyamide and the like, and is not particularly limited, but vinyl-based polymer or urethane-based polymer is preferable.

In the present invention, the polymer having an amine oxide group can be obtained by the following two methods.
That is, a polymer having an amine oxide group can be obtained by polymerizing a monomer having an amine oxide group with another monomer.
Alternatively, after obtaining a polymer having a tertiary amino group which can be said to be a precursor functional group of an amine oxide group, an oxidizing agent can be reacted with the tertiary amino group to introduce an amine oxide group into the polymer. The latter method is preferable in that a reaction is unlikely to occur. The reaction of an oxidizing agent with a tertiary amino group is also referred to as "oxidation" below.

<Vinyl polymer>
Specifically, the vinyl-based polymer preferably contains at least one structure represented by the following general formulas (1) to (3), and more particularly includes a structure represented by the general formula (1). Those are particularly preferable.

(During the ceremony,
X is a divalent binding group or a direct bond,
y is 0 or 1,
R ¹ is an alkylene group having 1 to 6 carbon atoms,
R ² and R ³ are independently alkyl groups having 1 to 4 carbon atoms, respectively.
R ⁴ is a hydrogen atom or a methyl group,
Four of R ^{5 to} R ⁹ represent a hydrogen atom and an alkyl group having 1 to 6 carbon atoms, and one of R ^{5 to} R ⁹ represents a bond position with the main chain of a vinyl polymer.
* Indicates the bonding position of the vinyl polymer with the main chain. )

As described above, the vinyl polymer having such a structure can be obtained by two methods.
That is, the tertiary amino group-containing unsaturated monomer (A) is oxidized and then polymerized with another monomer, or the tertiary amino group-containing unsaturated monomer (A) is polymerized with another monomer and then oxidized. How to do it.

<Unsaturated monomer containing tertiary amino group (A)>
Among the tertiary amino group-containing unsaturated monomers (A) as precursors before oxidation, the one for forming the structure of the formula (1) is
For example, N, N-dimethylaminoethyl (meth) acrylate, N, N-diethylaminoethyl (meth) acrylate, N, N-dimethylaminopropyl (meth) acrylate, N, N-diethylaminopropyl (meth) acrylate, N, N-Dimethylaminoethyl (meth) acrylamide, N, N-diethylaminoethyl (meth) acrylamide, N, N-dimethylaminopropyl (meth) acrylamide, N, N-diethylaminopropyl (meth) acrylamide, N, N-dimethylamino Vinyl propionate, vinyl N, N-diethylaminopropionate, N, N-dimethylacrylamide, N, N-dimethylallylamine, p-dimethylaminomethylstyrene, p-dimethylaminoethylstyrene, p-diethylaminomethylstyrene, p-diethylamino Ethylstyrene, N, N-dimethylvinylamine, N, N-diethylvinylamine, N, N-diphenylvinylamine,
Alternatively, a reaction product of an unsaturated group-containing acid anhydride such as maleic anhydride, itaconic anhydride, or citraconic anhydride with N, N-dimethyl-1,3-propanediamine, or the like.
Examples thereof include reaction products of epoxy group-containing unsaturated compounds such as glycidyl (meth) acrylate and N, N-dimethyl-1,3-propanediamine and the like.
In the present invention, "(meth) acrylic" means both "acrylic" and "methacrylic".

Examples of the structure for forming the structure of the formula (2) include 2-vinylpyridine, 3-vinylpyridine, 4-vinylpyridine, 2-methyl-3-vinylpyridine, 3-methyl-4-vinylpyridine, and the like. 2-Methyl-5-vinylpyridine, 3-methyl-5-vinylpyridine, 4-methyl-5-vinylpyridine, 6-methyl-5-vinylpyridine, 2-lauryl-4-vinylpyridine, 2-lauryl-5 -Vinylpyridine, 2- (t-butyl) -4-vinylpyridine, 2- (t-butyl) -5-vinylpyridine and the like can be mentioned.

Examples of the structure for forming the structure of the formula (3) include 1-vinylimidazole, 2-methyl-1-vinylimidazole, 4-methyl-1-vinylimidazole, 5-methyl-1-vinylimidazole, 2 -Lauryl-1-vinylimidazole, 4- (t-butyl) -1-vinylimidazole and the like can be mentioned.

When obtaining a vinyl polymer, in addition to the monomer (A), a monomer (B) having one ethylenically unsaturated group in one molecule and an alkyl group having 1 to 12 carbon atoms can be used. .. By introducing the structure based on the monomer (B), the polarity and Tg can be appropriately controlled, and excellent adhesiveness, drug solubility and drug release property can be obtained.

Examples of the monomer (B) having one ethylenically unsaturated group and an alkyl group having 1 to 12 carbon atoms in one molecule include methyl (meth) acrylate, ethyl (meth) acrylate, and propyl (meth) acrylate. , Butyl (meth) acrylate, pentyl (meth) acrylate, heptyl (meth) acrylate, 2-ethylhexyl (meth) acrylate, octyl (meth) acrylate, nonyl (meth) acrylate, decyl (meth) acrylate, dodecyl (meth) acrylate. Alkyl (meth) acrylates such as;
Examples thereof include α-olefin ethylenically unsaturated monomers such as 1-propylene, 1-butene, 1-pentene, 1-hexene, 1-octene, 1-nonene and 1-decene.

<Monomer (C)>
When obtaining a vinyl-based polymer, other monomers (C) other than the above-mentioned monomers (A) and (B) can also be used.

<Monomer (C1)>
Among the monomers (C), those having a hydroxyl group, a carboxylic acid group, an anhydrous carboxylic acid group, a phosphoric acid group, a sulfonic acid group, a 1-3-class amide group, a quaternary amino group, and a polyether chain in the molecular structure are used. Let it be C1). The vinyl-based polymer can have a polar functional group by having a structure based on the monomer (C1) having a polar functional group.

The monomer (C1) is not particularly limited, and is, for example, 2-hydroxyethyl (meth) acrylate, 2-hydroxypropyl (meth) acrylate, 4-hydroxybutyl (meth) acrylate, 2- (meth) acryloyloxy. Monomers with hydroxyl groups such as ethyl-2-hydroxyethylphthalic acid, glycerol mono (meth) acrylate, 4-hydroxyvinylbenzene, 1-ethynyl-1-cyclohexanol, allyl alcohol;
Maleic acid, fumaric acid, itaconic acid, citraconic acid, or alkyl or alkenyl monoesters of these, phthalic acid β- (meth) acryloxyethyl monoester, isophthalic acid β- (meth) acryloxyethyl monoester, terephthalic acid Monomer having a carboxylic acid group such as β- (meth) acryloxyethyl monoester, succinic acid β- (meth) acryloxyethyl monoester, acrylic acid, methacrylic acid, crotonic acid, citraconic acid, or an anhydride thereof;
Monomers having sulfonic acid groups such as vinyl sulfonic acid and styrene sulfonic acid;
Monomer having a phosphate group such as (2-hydroxyethyl) methacrylate acid phosphate;
(Meta) acrylamide, N-vinyl-2-pyrrolidone, N-methoxymethyl- (meth) acrylamide, N-ethoxymethyl- (meth) acrylamide, N-propoxymethyl- (meth) acrylamide, N-butoxymethyl- (meth) ) Acrylamide, N-pentoxymethyl- (meth) acrylamide, N, N-di (methoxymethyl) acrylamide, N-ethoxymethyl-N-methoxymethylmethacrylamide, N, N-di (ethoxymethyl) acrylamide, N- Ethoxymethyl-N-propoxymethylmethacrylamide, N, N-di (propoxymethyl) acrylamide, N-butoxymethyl-N- (propoxymethyl) acrylamide, N, N-di (butoxymethyl) acrylamide, N-butoxymethyl -N- (methoxymethyl) metaacrylamide, N, N-di (pentoxymethyl) acrylamide, N-methoxymethyl-N- (pentoxymethyl) metaacrylamide, N, N-dimethylaminopropylacrylamide, N, N- Monomers having 1-3-order amide groups such as diethylaminopropyl acrylamide, N, N-dimethylacrylamide, N, N-diethylacrylamide, diacetone (meth) acrylamide;
Dimethylaminoethylmethyl chloride salt (meth) acrylate, trimethyl-3- (1- (meth) acrylamide-1,1-dimethylpropyl) ammonium chloride, trimethyl-3- (1- (meth) acrylamidepropyl) ammonium chloride, And monomers with quaternary amino groups such as trimethyl-3- (1- (meth) acrylamide-1,1-dimethylethyl) ammonium chloride;
Polyethylene glycol (meth) acrylate, methoxypolyethylene glycol (meth) acrylate, ethoxypolyethylene glycol (meth) acrylate, propoxypolyethylene glycol (meth) acrylate, n-butoxypolyethylene glycol (meth) acrylate, n-pentoxypolyethylene glycol (meth) Acrylate, phenoxypolyethylene glycol (meth) acrylate, polypropylene glycol (meth) acrylate, methoxypolyethylene glycol (meth) acrylate, ethoxypolyethylene glycol (meth) acrylate, propoxypolyethylene glycol (meth) acrylate, n-butoxypolyethylene glycol (meth) acrylate , N-pentoxypolyethylene glycol (meth) acrylate, phenoxypolyethylene glycol (meth) acrylate, polytetramethylene glycol (meth) acrylate, methoxypolytetramethylene glycol (meth) acrylate, phenoxytetraethylene glycol (meth) acrylate, hexaethylene Examples thereof include monomers having a polyether chain such as glycol (meth) acrylate and methoxyhexaethylene glycol (meth) acrylate.

<Monomer (C2)>
In addition to the monomers (A), (B) and (C1), the vinyl-based polymer of the present invention may further have a structure based on another monomer (C2) having an ethylenically unsaturated group.

Examples of the monomer (C2) include stearyl (meth) acrylate, cetyl (meth) acrylate, cyclohexyl (meth) acrylate, isobonyl (meth) acrylate, methoxyethyl (meth) acrylate, ethoxyethyl (meth) acrylate, and propoxyethyl (meth). Acrylate (meth) acrylates such as acrylates, butoxyethyl (meth) acrylates, and ethoxypropyl (meth) acrylates;
Aromatic ester (meth) acrylates such as phenyl (meth) acrylate, benzyl (meth) acrylate, and phenoxyethyl (meth) acrylate;
Allyl (meth) acrylate, 1-methylallyl (meth) acrylate, 2-methylallyl (meth) acrylate, 1-butenyl (meth) acrylate, 2-butenyl (meth) acrylate, 3-3-butenyl (meth) acrylate Butenyl, (meth) acrylic acid 1,3-methyl-3-butenyl, (meth) acrylic acid 2-chloroallyl, (meth) acrylic acid 3-chloroallyl, (meth) acrylic acid o-allylphenyl, (meth) acrylic acid 2- (Allyloxy) ethyl, allyllactyl (meth) acrylate, citronellyl (meth) acrylate, geranyl (meth) acrylate, loginyl (meth) acrylate, cinnamyl (meth) acrylate, diallyl maleate, diallyl itaconic acid, Ethyl unsaturated group-containing (meth) acrylic acid esters such as (meth) vinyl acrylate, vinyl crotonate, vinyl oleate, vinyl linolenate, and 2- (2'-vinyloxyethoxy) ethyl (meth) acrylate. ;
Perfluoromethylmethyl (meth) acrylate, perfluoroethylmethyl (meth) acrylate, 2-perfluorobutylethyl (meth) acrylate, 2-perfluorohexylethyl (meth) acrylate, 2-perfluorooctylethyl (meth) acrylate , 2-Perfluoroisononyl ethyl (meth) acrylate, 2-perfluorononyl ethyl (meth) acrylate, 2-perfluorodecylethyl (meth) acrylate, perfluoropropylpropyl (meth) acrylate, perfluorooctylpropyl (meth) ) Perfluoroalkyl group-containing ethylenically unsaturated monomer having a perfluoroalkyl group having 1 to 20 carbon atoms such as acrylate, perfluorooctyl amyl (meth) acrylate, and perfluorooctyl undecyl (meth) acrylate (meth). Examples thereof include acrylate-based monomers.

Examples of the monomer (C2) include (meth) acrylate-based monomers having a polymer structure in the side chain such as an ethylenically unsaturated compound having a polyester chain such as a lactone-modified (meth) acrylate.

The monomer (C2) is, for example, an aromatic vinyl monomer such as styrene, α-methylstyrene, 2-methylstyrene, chlorostyrene, allylbenzene, and ethynylbenzene;
Nitrile group-containing ethylenically unsaturated monomers such as (meth) acrylonitrile;
Fatty acid vinyl compounds such as vinyl acetate, vinyl butyrate, vinyl propionate, vinyl hexanoate, vinyl caprylate, vinyl laurate, vinyl palmitate, vinyl stearate;
Vinyl ether-based ethylenically unsaturated monomers such as butyl vinyl ether and ethyl vinyl ether;
Allyl monomers such as allyl acetate and allyl cyanide;
Vinyl monomers such as vinyl cyanide, vinyl cyclohexane, vinyl methyl ketone;
Ethynyl monomers such as acetylene and ethynyltoluene Perfluorobutylethylene, perfluorohexylethylene, perfluorooctylethylene, perfluoroalkyl such as perfluorodecylethylene, perfluoroalkyl group-containing ethylenically unsaturated compounds such as alkylenes, etc. Examples thereof include monomers having an ethylenically unsaturated bond that is not a (meth) acrylate.

In the present invention, the ethylenically unsaturated bond group contained in the monomer (C) is preferably a (meth) acrylate group or an aromatic vinyl group from the viewpoint of polymerizable property.

Oxidation before polymerization and oxidization after polymerization will be described.
An oxidizing agent is added to a solution containing a tertiary amino group-containing unsaturated monomer (A) before polymerization and to a solution containing a polymer obtained by polymerizing a monomer requiring a tertiary amino group-containing unsaturated monomer (A) after polymerization. The tertiary amino group can be oxidized by adding the above and reacting in the range of 20 ° C. to 100 ° C. for 0.1 to 100 hours, preferably 1 to 50 hours.

As the oxidizing agent, an oxidizing agent such as peroxide or ozone is used.
Examples of the peroxide include hydrogen peroxide, ammonium persulfate, sodium persulfate, peracetic acid, metachloroperbenzoic acid, benzoyl peroxide, t-butyl hydroperoxide and the like. Hydrogen peroxide is preferable, and usually an aqueous solution is used. Used in form. Peroxides also function as radical generators, albeit to varying degrees, so in the case of vinyl polymers using a tertiary transamination-containing unsaturated monomer (A) as an essential raw material, It is preferable to oxidize after polymerization. Further, in the case of the urethane-based polymer described later, it is preferable to oxidize after the polymerization so that a side reaction does not occur.
Generally, the amount of the oxidizing agent used is 0.2 to 3 times the molar equivalent of the functional group that can be oxidizable, that is, the tertiary amino group, and further 0.5 to 2 times. It is more preferable to use molar equivalents.
The obtained polymer solution can also be used after treating the remaining peroxide by a known method. Specific examples thereof include a reducing agent addition treatment, an ion exchange treatment, an activated carbon treatment, and a treatment with a metal catalyst.

The obtained polymer solution can be used as it is, but if necessary, the amine oxide group-containing polymer can be isolated and used by a known method such as reprecipitation or solvent distillation. Further, the isolated amine oxide group-containing polymer can be further purified by reprecipitation, solvent washing, membrane separation, adsorption treatment and the like, if necessary.

As the vinyl polymer in the present invention, as described above, the tertiary amino group-containing unsaturated monomer (A) is oxidized and then polymerized with another monomer, and the tertiary amino group-containing unsaturated monomer (A) In addition to those obtained by polymerizing a monomer that requires the above and oxidizing after obtaining a polymer, as the monomer, for example, an unsaturated compound containing an epoxy group such as glycidyl (meth) acrylate or an isocyanate such as 2-isocyanate ethyl (meth) acrylate. A polymer obtained by copolymerizing a group-containing unsaturated compound with an amine oxide group-containing compound such as hydroxyethyl-N or N-dimethylamine oxide can also be used.

<Urethane polymer>
Specifically, the urethane-based polymer in the present invention preferably contains a structure represented by the following general formulas (4), (5) and (6).

(During the ceremony,
R ¹⁰ , R ¹² , and R ¹⁵ each independently have an alkylene group having 1 to 6 carbon atoms.
R ¹¹ _, R ¹³ , R ¹⁴ , R ¹⁶ and R ¹⁷ independently have an alkyl group, an aryl group, an aralkyl group, and a pyridyl group.
Y represents O or N
** represents the bonding position of the urethane polymer with the main chain. )

Further, the urethane-based polymer in the present invention contains a polyol component, a polyisocyanate component, and a monomer as an introduction source of an amine oxide group as essential components, and a polyamine component, a monofunctional hydroxyl group component, or a monofunctional monomer used as necessary. It is a reaction product with an amine component.

In the present invention, the urethane-based polymer containing the structure is polymerized after oxidizing a tertiary amino group-containing monomer as a precursor for forming the structure, or a precursor for forming the structure. It may be obtained by any method such as polymerizing a tertiary amino group-containing monomer as used to obtain a polymer having a tertiary amino group and then oxidizing the polymer.

Here, examples of the tertiary amino group-containing monomer as a precursor before oxidation include a tertiary amino group-containing diol having 1 to 20 carbon atoms. For example, N-alkyldialkanolamines and N, N-dialkylmonoalkanolamines can be mentioned.
Examples of N-alkyldialkanolamines include N-methyldiethanolamine, N-ethyldiethanolamine, N-propyldiethanolamine, N-butyldiethanolamine and N-methyldipropanolamine.
Examples of the N, N-dialkyl monoalkanolamine include N, N-dimethylethanolamine.
In addition, N, N-bis (2-hydroxyethyl) benzylamine, N, N-bis (2-hydroxyethyl) cyclohexylamine, diethanol-p-toluidine, diisopropanol-p-toluidine, N, N-bis (2) -Hydroxyethyl) aniline, N, N-bis (2-hydroxypropyl) aniline, N, N-bis (2-hydroxyethyl) -3-chloroaniline, N, N-bis (2-hydroxyethyl) -4- Pylincarbamide, N, N-bis (2-hydroxyethyl) -α-aminopyridine, 1,4-bis (2-hydroxyethyl) piperazine, 3-diethylaminopropane-1,2-diol, 3-dimethylaminopropane Examples of the tertiary amino group-containing monomer include -1,2-diol and the like.

[Polycarbonate component]
The polyol component is not particularly limited, but glycols such as ethylene glycol, 1,4-butanediol, neopentyl glycol, butylethylpentanediol, glycerin, trimethylolpropane, and pentaerythritol, polyester polyol, and polyether. Examples thereof include polyols, polyester polyols, polybutadiene polyols, hydrogenated polybutadiene polyols, polyisoprene polyols, hydrogenated polyisoprene polyols, polyurethane polyols which are reactants of polyether polyols and polyisocyanates, and polyether adducts of polyhydric alcohols.

[Polyisocyanate component]
Examples of the polyisocyanate component include aromatic polyisocyanates, aliphatic polyisocyanates, aromatic aliphatic polyisocyanates, and alicyclic polyisocyanates.

Examples of the aromatic polyisocyanate include 1,3-phenylenediocyanate, 4,4'-diphenyldiisocyanate, 1,4-phenylenediocyanate, 4,4'-diphenylmethane diisocyanate, 2,4-tolylene diisocyanate, and 2,6-triisocyanate. Range isocyanate, 4,4'-toluidin diisocyanate, 2,4,6-triisocyanate toluene, 1,3,5-triisocyanate benzene, dianisidine diisocyanate, 4,4'-diphenyl ether diisocyanate, 4,4', 4 " -Triphenylmethane triisocyanate and the like can be mentioned.

Examples of the aliphatic polyisocyanate include trimethylene diisocyanate, tetramethylene diisocyanate, hexamethylene diisocyanate, pentamethylene diisocyanate, 1,2-propylene diisocyanate, 2,3-butylene diisocyanate, 1,3-butylene diisocyanate, dodecamethylene diisocyanate, 2, Examples thereof include 4,4-trimethylhexamethylene diisocyanate.

Examples of the aromatic aliphatic polyisocyanate include ω, ω'-diisocyanate-1,3-dimethylbenzene, ω, ω'-diisocyanate-1,4-dimethylbenzeneω, ω'-diisocyanate-1,4-diethylbenzene, 1, Examples thereof include 4-tetramethylxylylene diisocyanate and 1,3-tetramethylxylylene diisocyanate.

Examples of the alicyclic polyisocyanate include 3-isocyanate methyl-3,5,5-trimethylcyclohexylisocyanate, 1,3-cyclopentanediisocyanate, 1,3-cyclohexanediisocyanate, 1,4-cyclohexanediisocyanate, and methyl-2,4. -Cyclohexanediisocyanate, methyl-2,6-cyclohexanediisocyanate, 4,4'-methylenebis (cyclohexylisocyanate), 1,4-bis (isocyanatemethyl) cyclohexane, 1,4-bis (isocyanatemethyl) cyclohexane and the like can be mentioned. it can.

Further, a so-called adduct body formed by adding a trifunctional alcohol such as trimethylolpropane to the polyisocyanate, a biuret body obtained by reacting the polyisocyanate with water, and the polyisocyanate forming an isocyanurate ring. A trimer or the like can also be used together. The above-mentioned reaction product of the polyhydric alcohol polyether adduct and diisocyanate can also be used as a polyisocyanate component.

As the polyisocyanate used for obtaining the urethane-based polymer, 4,4'-diphenylmethane diisocyanate, hexamethylene diisocyanate, 3-isocyanate methyl-3,5,5-trimethylcyclohexylisocyanate (isophorone diisocyanate) and the like are preferable.

[Polyamine component]
When obtaining a urethane-based polymer, a polyamine component can be used if necessary. Examples of the polyamine component include ethylenediamine, isophoronediamine, phenylenediamine, 2,2,4-trimethylhexamethylenediamine, tolylenediamine, hydrazine, piperazine, hexamethylenediamine, propylenediamine, dicyclohexylmethane-4,4-diamine, and the like. Examples thereof include diamines such as 2-hydroxyethylethylenediamine, di-2-hydroxyethylethylenediamine, di-2-hydroxyethylpropylenediamine, 2-hydroxypropylethylenediamine, and di-2-hydroxypropylethylenediamine. Isophorone diamine and 2,2,4-trimethylhexamethylenediamine are preferable because the reaction can be easily controlled and the hygiene is excellent.
By using the polyamine component, a urea bond having a higher cohesive force than the urethane bond is formed, so that a pressure-sensitive adhesive having a large cohesive force can be obtained.

[Monofunctional hydroxyl group component]
The monofunctional hydroxyl group component used as one of the terminal terminators when obtaining a urethane polymer is not particularly limited, and methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1- Hexanol, 1-octanol and the like can be mentioned, and one or more selected from these groups can be used. Ethanol is preferable because it has low skin irritation even if it remains in the patch.

[Monofunctional amine component]
Similar to the monofunctional hydroxyl component, the monofunctional amine component used as one of the terminal terminators is not particularly limited, and hexylamine, octylamine, diethylamine, dodecylamine, hexadecylamine, octadecylamine, stearylamine, etc. Examples thereof include oleylamine, cyclohexylamine, monoethanolamine, monopropanolamine, diethanolamine and dipropanolamine.
By using these monofunctional hydroxyl group components and / or monofunctional amine components as end-capping agents, the stability over time of urethane-based polymers can be improved.

In the present invention, the urethane polymer is prepared by using a polyol component which is an essential component, a polyisocyanate component, and a monomer which is a source for introducing an amine oxide group as necessary, a polyamine component, a monofunctional hydroxyl group component, or a monofunctional monomer. All of the amine components of the above may be reacted at the same time (one-shot method), or may be reacted sequentially. In order to ensure that the desired urethane-based polymer is produced as the main product, a sequential reaction in which at least one of these components is sequentially reacted is preferable. When preparing a urethane-based polymer by a sequential reaction, for example, the following method can be applied.

A step of reacting a polyol component, a polyisocyanate component, and a monomer that is a source for introducing an amine oxide group under conditions of excess polyisocyanate component to obtain a urethane prepolymer having an isocyanate group at the terminal, and then the urethane prepolymer and polyamine. A method comprising reacting a component with a polyurethane polyurea having an isocyanate group at the end, and finally reacting the remaining isocyanate group with a monofunctional hydroxyl group component and / or a monofunctional amine component.

The method of proceeding with the sequential reaction is not limited to the method exemplified above.

The urethane-based polymer of the present invention may be produced by reacting raw materials in a solvent-free environment, or by reacting them in an organic solvent.
Examples of the organic solvent include ketone compounds such as acetone, methyl ethyl ketone, methyl isobutyl ketone and cyclohexanone, ester compounds such as methyl acetate, ethyl acetate, butyl acetate, ethyl lactate and methoxyethyl acetate, and ethers such as diethyl ether and ethylene glycol dimethyl ether. Various solvents such as system compounds, aromatic compounds such as toluene and xylene, aliphatic compounds such as pentane and hexane, and halogenated hydrocarbon compounds such as methylene chloride, chlorobenzene and chloroform can be used.

Further, when synthesizing the urethane-based polymer, a catalyst can be added as needed, for example, a metal-based catalyst such as dibutyltin diacetate, dibutyltin dilaurate, dioctyltin dilaurate, dibutyltin dimarate; 1,8-diazabicyclo (5,4,0) Undecene-7, 1,5-diazabicyclo (4,3,0) Nonen-5,6-dibutylamino-1,8-diazabicyclo (5,4,0) Undecene-7, etc. 3 Primary amines; reactive tertiary amines such as triethanolamine, etc. may be mentioned, and these may be used alone or in combination of two or more.
The isocyanate group-containing urethane prepolymer is preferably obtained by reacting the above-mentioned polyol component, polyisocyanate component, and monomer which is a source for introducing an amine oxide group in an organic solvent in the presence of a catalyst at 120 ° C. or lower. It is more preferable to react at ~ 110 ° C. for 1 to 20 hours. When the temperature is higher than 110 ° C., it becomes difficult to control the reaction rate, and it becomes difficult to obtain a urethane prepolymer having a predetermined molecular weight and structure.
The reaction between the isocyanate group and the polyamine component is preferably carried out in an organic solvent at 60 ° C. or lower. If the temperature is higher than that, it becomes difficult to control the reaction rate, and it becomes difficult to obtain a urethane polymer having a predetermined molecular weight and structure.

<Amine oxide group content>
Although the amine oxide group itself is highly hydrophilic, the polymer (a) can be made water-insoluble by controlling the amount contained in the polymer (a). In the present invention, the term "water-insoluble" means that 1 g of a polymer is placed in 99 g of ion-exchanged water at 25 ° C., stirred, left at 25 ° C. for 24 hours, water is removed, and the polymer is dried under reduced pressure to reduce mass. Is 5% or less. Since the polymer (a) is water-insoluble, water resistance can be imparted to the adhesive layer, and peeling of the adhesive layer from the skin due to contact with water can be suppressed.
The amine oxide group content of the polymer (a) in the present invention is 0.25 to 3 mmol / g, preferably 0.3 to 2.5 mmol / g, and preferably 0.35 to 2 mmol / g. Is particularly preferable. When it is 0.25 mmol / g or more, excellent drug solubility and cohesive force can be imparted. Further, when the content is 3 mmol / g or less, the wettability to the skin is improved, so that excellent skin adhesiveness can be imparted and the water resistance of the adhesive can be improved.
When the monomer having an amine oxide group is polymerized to obtain the polymer (a), the amine oxide group content in the polymer (a) can be determined from the amount of the monomer having an amine oxide group used in the polymerization.
On the other hand, when the obtained polymer is oxidized after polymerizing a monomer that requires a tertiary amino group-containing monomer, it can be calculated by the following formula 1.

<Glass transition temperature>
The glass transition temperature (hereinafter, also referred to as Tg) of the polymer (a) is −60 ° C. to −5 ° C., preferably −55 to −15 ° C. When the Tg is −60 ° C. or higher, cohesive force can be imparted, and the generation of adhesive residue when the adhesive is peeled from the skin can be suppressed. Further, when the Tg is −5 ° C. or lower, the wettability to the skin is improved, so that excellent skin adhesiveness can be imparted.
The glass transition temperature is a value obtained by DSC (Differential Scanning Calorimetry).

<Mass average molecular weight (Mw)>
The mass average molecular weight of the polymer (a) is 10,000 to 10,000,000, preferably 15,000 to 6,000,000. When the molecular weight is 10,000 or more, cohesive force can be imparted, and the generation of adhesive residue when the adhesive is peeled from the skin can be suppressed. Further, when the content is 10,000,000 or less, the solvent solubility of the resin is improved, and the viscosity is appropriate, so that the coating suitability is improved.

For the mass average molecular weight of the polymer (a), a value measured by gel permeation chromatography (GPC) in terms of standard polystyrene is adopted. The measuring device and measuring conditions are basically based on the following condition 1, and it is allowed to be set to condition 2 depending on the solubility of the sample and the like. However, depending on the polymer species, an appropriate carrier (eluent) and a column suitable for the carrier may be selected and used as appropriate. For other matters, JIS K7252-1 to 4: 2008 will be referred to. The poorly soluble polymer compound shall be measured at a soluble concentration under the following conditions.
When it is difficult to measure the molecular weight of the polymer (a), the mass average molecular weight of the amine oxide precursor polymer can be used as the mass average molecular weight of the polymer (a). The mass average molecular weight of the amine oxide precursor polymer is a value measured by gel permeation chromatography (GPC) in terms of standard polystyrene, and the measuring device and measuring conditions are basically based on the following condition 3.
(Condition 1)
Column: TOSOHTSKgelSuperHZM-H,
TOSOHTSKgelSuperHZ4000,
TOSOHTSKgelSuperHZ2000
Carrier using a column connected to: tetrahydrofuran Measurement temperature: 40 ° C
Carrier flow rate: 1.0 ml / min
Sample concentration: 0.1% by mass
Detector: RI (refractive index) detector Injection amount: 0.1 ml
(Condition 2)
Column: Carrier that connects two TOSOHTSKgelSuperAWM-H: 10 mM LiBr / N-methylpyrrolidone Measurement temperature: 40 ° C.
Carrier flow rate: 1.0 ml / min
Sample concentration: 0.1% by mass
Detector: RI (refractive index) detector Injection amount: 0.1 ml
(Condition 3)
Column: TOSOHTSKgelSuperAW4000,
TOSOHTSKgelSuperAW3000,
TOSOHTSKgelSuperAW2500
Use a column that connects
Carrier: Mixed solution of N, N-dimethylformamide (1L), triethylamine (3.04g), LiBr (0.87g) Measurement temperature: 40 ° C.
Carrier flow rate: 0.6 ml / min

The pressure-sensitive adhesive for skin application of the present invention preferably contains 20 to 99% by mass of the polymer (a) in 100% by mass of the pressure-sensitive adhesive for skin application, and more preferably 25 to 99% by mass. By setting the proportion of the polymer (a) to 20% by mass or more, desired performances such as drug solubility and drug release can be exhibited.

<Transdermal drug (b)>
The agent that can be added in the present invention is not particularly limited, and for example, a general anesthesia agent, a hypnotic agent, an analgesic agent, an anti-inflammatory analgesic agent, a steroid hormone agent, an excitatory / stimulant agent, a neuropsychiatric agent, a local anesthetic agent, etc. For skeletal muscle relaxants, autonomic nerve agents, antiallergic agents, antihistamine agents, cardiotonic agents, arrhythmia agents, diuretics, antihypertensive agents, vasoconstrictors, vasodilators, calcium channel blockers, antibacterial agents, for parasitic skin diseases Agents, skin softeners, antibiotics, analgesics, antitussives, antipruritic agents, hypnotics, psychostimulants, asthma agents, hormone secretion promoters, anti-ulcer agents, anticancer agents, vitamins, skin-beautifying ingredients, etc. And so on.

When the skin patch of the present invention is used as a topical patch, examples of the drug contained in this patch include indomethacin, ketoprofen, flurbiprofen, loxoprofen, loxoprofen sodium, piroxicam, and meloxicam. Examples thereof include anti-inflammatory analgesics such as ketolorac, ferbinac, diclofenac, and diclofenac sodium. The content of the drug is not particularly limited, but is usually about 0.1 to 20% by mass with respect to the entire adhesive layer. Any drug for wound healing, topical administration, systemic administration, etc. may be added. Specifically, anti-inflammatory analgesics, steroidal anti-inflammatory agents, vasodilators, antihypertensive diuretics, anesthetics, antihistamines, antitumor agents, antihypertensive / arrhythmia agents, antidepressants / antidepressants, local anesthetics, Examples include hormonal agents, asthma / nasal allergy therapeutic agents, anticoagulants, analgesics, and fat-soluble vitamins.
The blending amount of the drug varies depending on the type of the drug and the purpose of use of the patch, but is preferably in the range of 0.1% by mass to 40% by mass in 100% by mass of the adhesive for skin application.

<Adhesive imparting agent>
The pressure-sensitive adhesive for skin application of the present invention may further contain a pressure-imparting agent. Examples of the tackifier include rosin, hydrogenated rosin, rosin ester, terpene resin, modified terpene resin, hydrogenated terpene resin, terpene phenol resin, petroleum resin, kumaron inden resin, phenol resin, xylene resin, and alicyclic group. Saturated hydrocarbon resin and the like can be mentioned.
When these tackifiers are blended, the tack, the adhesive and the holding power can be easily adjusted. In addition, these may be used alone or in combination of two or more. The blending amount of the tackifier varies depending on the type, polarity, etc., but is usually used in the range of 1% by mass to 50% by mass in the mass% of the pressure-sensitive adhesive for skin application.

<Transdermal absorption promoter>
In the present invention, a transdermal absorption promoter can be further added in order to improve the solubility and diffusivity of the drug in the pressure-sensitive adhesive layer.
Specific examples of the transdermal absorption accelerator include silicones such as dimethylpolysiloxane, animal and vegetable oils such as olive oil, carboxylic acids such as lactic acid, liquid paraffins, hydrocarbons such as wax, lauric acid, myristic acid, and olein. Higher fatty acids such as acids, higher alcohols such as hexyldecanol, octyldodecanol, and isostearyl alcohol, monohydric fatty acid esters such as isopropyl myristate, hexyl laurate, octyldodecyl myristate, butyl stearate, and decyl oleate, 2. -Alcohols such as hexyldecanol, 2-octyldecanol, glycerin, nonionic surfactants such as polyoxyethylene nonylphenyl ether, fatty acid glycerin ester, fatty acid polyethylene glycol, polyglycerin fatty acid ester, sucrose fatty acid ester, polybutene, poly Examples thereof include liquid resins such as isoprene, polyacrylic acid and polymethacrylic acid, and oily vitamins such as retinol, retinol palmitate, tocophenol and tocophenol acetate.
When these transdermal absorption promoters are blended, the viscosity of the adhesive layer for skin application can be adjusted. Further, in particular, when a highly hydrophobic compound such as isopropyl myristate and a polyhydric alcohol such as glycerin are used in combination, there is also an effect of promoting transdermal absorption of the drug. The blending amount of the transdermal absorption promoter varies depending on the type and polarity, the type of the pressure-sensitive adhesive, the polarity and the molecular weight, etc., but is usually in the range of 0.5% by mass to 50% by mass in the mass% of the pressure-sensitive adhesive for skin application. Used in.

Further, in the pressure-sensitive adhesive for skin application of the present invention, additives such as a thickener, an antioxidant, a moisturizer, and a pH adjuster can be appropriately used as optional components as long as the purpose is not impaired. In particular, when it is used as an adhesive for skin application and in direct contact with the skin, it is preferable to use a moisturizer together.

The skin patch of the present invention can be obtained by directly or indirectly laminating a pressure-sensitive adhesive layer containing a polymer (a) and a transdermal drug (b) on a sheet-like substrate.
For example, a pressure-sensitive adhesive layer containing a skin-adhesive pressure-sensitive adhesive containing a polymer (a) and a transdermal agent (b) and a pressure-sensitive adhesive coating liquid containing a liquid medium are applied and dried on a sheet-like substrate. By laminating a peeling sheet-like member (also referred to as a liner) on the pressure-sensitive adhesive layer, a skin patch with a peeling sheet member can be obtained. Alternatively, the adhesive coating liquid is applied and dried on the peeling sheet-like member to form an adhesive layer, and the sheet-like base material is laminated on the adhesive layer to form the skin with the peeling sheet member. A patch for use can be obtained.

As the sheet-like base material used in the present invention, a flexible base material usually used for a skin patch can be used, and is not particularly limited. Specifically, for example, a polymer film such as polyester, polyolefin, or cellulose ester; a woven fabric, knitted fabric, or non-woven fabric made of polyester, polyolefin, cellulose ester, polyurethane, polyamide, or the like; or paper can be used. The thickness of these supports is usually set to 50 μm to 300 μm, preferably 70 μm to 200 μm in the case of a base material, although it depends on the type of patch.

Of the sheet-like base materials, those with coarse mesh and porous materials such as non-woven fabrics may come off by the method of applying the one dissolved in a liquid medium to the support, and the dissolved material may come off inside even if it does not come off. Since it permeates to the extent that the dissolved material is consumed excessively, the manufacturing method of laminating the pressure-sensitive adhesive layer formed by applying and drying the pressure-sensitive adhesive coating liquid on another base material in advance is preferable.

The release sheet member is not particularly limited, and a known release film can be used. For example, films such as polyester, polyvinyl chloride, polyvinylidene chloride, and polyethylene terephthalate, which have been peeled by applying silicone resin, fluororesin, etc. to the contact surface with the adhesive layer, high-quality paper, glassin paper, etc. Papers such as, high-quality paper, glassin paper, etc., and a laminated film of polyolefin are used. The thickness of the release film is usually 10 to 200 μm, preferably 25 to 100 μm.

Further, as the patch, in addition to the support layer and the pressure-sensitive adhesive layer, other commonly used functional layers such as a liner and a surface protective layer can be laminated.

The present invention will be described in more detail with reference to the following examples, but the following examples do not limit the scope of rights of the present invention in any way. In the examples, "parts" and "%" represent "parts by mass" and "% by mass", respectively, and Tg means the glass transition temperature.

<Measurement method of glass transition temperature>
The glass transition temperature can be measured by DSC (Differential Scanning Calorimetry) as follows. The solution of the polymer (a) was dried, about 2 mg of the obtained polymer was weighed on an aluminum pan, the test container was set in the DSC measurement holder, and the chart obtained under the heating condition of 10 ° C./min. Read the endothermic peak. The peak temperature at this time is defined as the glass transition temperature of the present invention.

<Measurement method of hydroxyl value>
It was measured by the method described in JISK-1557.

[Manufacturing Example 1]
<Preparation of polymer (a)>
In a reaction vessel equipped with a stirrer, a thermometer, a dropping funnel, and a refluxer, 100 parts of ethyl acetate was charged, the internal temperature was raised to 75 ° C., and nitrogen was sufficiently substituted. 0.4 parts of 2,2'-azodiisobutyronitrile, 15 parts of N, N-dimethylaminoethyl methacrylate as monomer (A), and 50 parts of normal octyl acrylate as monomer (B), which were prepared separately. , 30 parts of butyl acrylate and 5 parts of methyl methacrylate were mixed, and the mixture was added dropwise for 3 hours while maintaining the internal temperature at 75 ° C., and further stirred for 2 hours. After confirming that the conversion rate exceeded 98% by solid content measurement, the mixture was cooled to obtain a solution of a polymer having a tertiary amino group.
Next, 9.3 parts (equal molar amount of N, N-dimethylaminoethyl methacrylate used) of 35% hydrogen peroxide solution as an oxidizing agent was added to the obtained polymer solution having a tertiary amino group. The amino group was oxidized by reacting at 70 ° C. for 16 hours. After confirming that the amine oxide conversion rate exceeded 98%, the mixture was cooled and taken out, and then the solvent was completely volatilized in an oven to obtain a polymer (a).
The amine oxide conversion rate described above was determined according to the method disclosed in JP-A-10-182589.
The amine oxide group content of the obtained polymer was the amount of N, N-dimethylaminoethyl methacrylate added and 0.94 mmol / g from the above formula 1.
The Tg of the obtained polymer (a) was measured by DSC at −39.8 ° C., and the mass average molecular weight was measured by GPC to be 150,000.

[Production Examples 2 to 21], [Comparative Production Examples 1 to 7]
The polymer (a) was synthesized by the same method as in Production Example 1 with the compounding composition shown in Table 1.

The symbols in the table are as follows.
DMAEMA: N, N-dimethylaminoethyl methacrylate DEAEMA: N, N-diethylaminoethyl methacrylate DMAPAA: N, N-dimethylaminopropylacrylamide VP: 2-vinylpyridine VI: 1-vinylimidazole OA: normal octyl acrylate BA: butyl acrylate MMA: Methyl methacrylate HEA: 2-Hydroxyethyl acrylate AA: NVP acrylate: N-vinyl-2-pyrrolidone MEA: 2-Methoxyethyl acrylate AIBN: 2,2'-azodiisobutyronitrile HPO: 35% hydrogen peroxide solution

[Comparative Manufacturing Example 8]
In a reaction vessel equipped with a stirrer, a thermometer, a dropping funnel, and a refluxer, 100 parts of ethyl acetate was charged, the internal temperature was raised to 75 ° C., and nitrogen was sufficiently substituted. A separately prepared mixture of 0.2 parts of 2,2'-azodiisobutyronitrile, 75 parts of 2-ethylhexyl acrylate, 22 parts of N-vinyl-2-pyrrolidone, and 3 parts of acrylic acid was prepared. The dropping was continued for 3 hours while keeping the internal temperature at 75 ° C., and stirring was continued for another 2 hours. After confirming that the conversion rate exceeded 98% by solid content measurement, the mixture was cooled at 40 ° C. to obtain a polymer having a Tg of −26.8 ° C. and a mass average molecular weight of 1,500,000.
Then, 5 parts of lauryldimethylamine oxide was added, and the mixture was uniformly dissolved, cooled and taken out, and then only the solvent was completely volatilized in an oven to obtain a mixture of low molecular weight amine oxide and polymer.
The amine oxide group content in the obtained mixture is 0.21 mmol / g from the amount of lauryldimethylamine oxide added.

[Comparative Manufacturing Example 9]
A mixture of a low molecular weight amine oxide and a polymer was obtained in the same manner as in Comparative Production Example 8 except that the amount of lauryldimethylamine oxide was 18 parts.
The amine oxide group content in the obtained mixture is 0.66 mmol / g from the amount of lauryldimethylamine oxide added.

[Manufacturing Example 22]
In a 4-neck flask equipped with a stirrer, a reflux condenser, a nitrogen introduction tube, an introduction tube, and a thermometer, 10 parts of N-methyldiethanolamine as a monomer having a tertiary amino group and Sanniks PP4000 as a polyol component (hydroxyl value: 87.9 parts of 26.8 KOHmg / g (manufactured by Sanyo Kasei Co., Ltd.) and 19.6 parts of hexamethylene diisocyanate as a polyisocyanate component were charged, and the temperature was raised to 60 ° C. with stirring under a nitrogen stream to uniformly dissolve the mixture. It was. Subsequently, 0.002 part of dibutyltin dilaurate was added as a catalyst and reacted at 110 ° C. for 3 hours.
Then, the temperature was lowered to 40 ° C., and 13.8 parts of isophorone diamine was added dropwise as a polyamine component over 2 hours to carry out a chain extension reaction. Further, 0.38 parts of hexylamine was added as a terminal terminator and reacted at 40 ° C. for 30 minutes to obtain a solution of an amine oxide precursor polymer, that is, a polymer having a tertiary amino group.
Next, 8.2 parts (equal molar amount of N-methyldiethanolamine used) of 35% hydrogen peroxide solution as an oxidizing agent was added to the obtained polymer solution having a tertiary amino group, and 16 at 70 ° C. The amino group was oxidized by reacting for a time. After confirming that the amine oxide conversion rate exceeded 98%, the mixture was cooled and taken out, and then the solvent was completely volatilized in an oven to obtain a polymer (a).
The amine oxide group content of the obtained polymer was the amount of N-methyldiethanolamine added and 0.63 mmol / g from the above formula 1.
The Tg of the obtained polymer (a) was measured by DSC and found to be 136000 when the mass average molecular weight was measured by GPC at -19 ° C.

[Production Examples 23 to 27], [Comparative Production Examples 10 to 12]
The polymer (a) was synthesized by the same method as in Production Example 22 with the compounding composition shown in Table 2.

The symbols in the table are as follows.
MDEA: N-Methyldiethanolamine EEDA: N-Ethyldiethanolamine DMAP: 3-Dimethylaminopropane-1,2-diol PP4000: Sanniks PP4000 (polyoxypropylene glycol, hydroxyl value: 26.8KOHmg / g, Sanyo Kasei Kogyo Co., Ltd. Made)
P4010: Kuraray polyol P4010 (aliphatic polyester polyol, hydroxyl value 28KOHmg / g, manufactured by Kuraray Co., Ltd.)
GI-3000: Hydroxyl hydrogenated polybutadiene at both ends (hydroxyl value: 27.7 KOHmg / g, manufactured by Nippon Soda Corporation)
HDI: Hexamethylene diisocyanate IPDI: Isophorone diisocyanate IPDA: Isophorone diamine BDA: 1,4-butanediamine HA: Hexylamine HPO: 35% hydrogen peroxide solution

[Example], [Comparative example]
The polymer (a) synthesized in the production example and the comparative production example was dissolved in a mixed solvent of ethyl acetate and ethanol (mass ratio 70:30) so as to have a solid content concentration of 30%, and the solid content of the polymer (a) was dissolved therein. After adding 3 parts of sodium loxoprofen as a transdermal absorbable agent to 100 parts and dissolving the mixture, the mixture was coated on a polyethylene terephthalate film with an applicator so as to have a dry coating film of 30 μm, and dried at 100 ° C. for 2 minutes.
Next, another peel-treated polyethylene terephthalate film was laminated on the pressure-sensitive adhesive layer side to prepare a skin patch with a peel-off sheet-like member (hereinafter referred to as a patch sheet).

(1) Adhesive Strength After cutting this patch sheet to a width of 25 mm and a length of 75 mm, the peeled polyethylene terephthalate film was removed, and the patch was attached to a bakelite plate under the conditions of 23 ° C. and 65% RH. After roll crimping according to JIS and allowing it to stand for 20 minutes, it was peeled in the 180 degree direction at a speed of 300 mm / min in an environment of 23 ° C. and 65% RH, and a peeling force having a width of 25 mm was measured.
〇: 12N <Adhesive strength Δ: 8N <Adhesive strength ≤12N
X: Adhesive strength ≤ 8N

(2) Adhesive residue Using the same sample as the one whose adhesive strength was measured in (1) above, the tactile sensation of the adhesive was evaluated by a thumb test. After releasing the finger, it was visually evaluated whether the adhesive remained on the finger.
〇: No glue transfer on the finger ×: No glue transfer on the finger

(3) Drug Solubility The polymer (a) synthesized in Production Examples and Comparative Production Examples was dissolved in a mixed solvent of ethyl acetate and ethanol (weight ratio 70:30) so that the solid content concentration was 30%, and the above-mentioned To 100 parts of the solid content of the polymer (a), sodium loxoprofen as a transdermal absorbable agent was added in a fixed amount (3 parts, 5 parts, 7 parts, 9 parts, 13 parts, 17 parts, 21 parts) and dissolved. Then, it was coated on a polyethylene terephthalate film with an applicator so as to have a dry coating film of 30 μm, and dried at 100 ° C. for 2 minutes.
Next, another stripped polyethylene terephthalate film was laminated on the pressure-sensitive adhesive layer side to prepare a patch.
After storing this patch in a constant temperature and humidity chamber at 25 ° C.-60% for 1 month, the presence or absence of crystal precipitation of the drug in the pressure-sensitive adhesive layer was visually observed and evaluated. The maximum amount of drug added that did not form crystals was defined as the maximum amount of drug dissolved in the pressure-sensitive adhesive, and the determination was made according to the following criteria.
⊚: 17 parts ≤ maximum drug dissolution amount 〇: 9 parts ≤ maximum drug dissolution amount <17 parts Δ: 5 parts ≤ maximum drug dissolution amount <9 parts ×: maximum drug dissolution amount <5 parts

(4) Drug Release The polymer (a) synthesized in the production example and the comparative production example was dissolved in an ethyl acetate solvent so that the solid content concentration was 30%, and the resin solid content was percutaneously charged therein with respect to 100 parts of the resin solid content. Loxoprofen sodium as an absorbable agent is added in the maximum amount of the polymer (a) obtained in (3), and two parts of lactic acid are added and dissolved as a transdermal absorption accelerator, and then the same as in (3) above. Then, a laminated patch made of polyethylene terephthalate / adhesive layer / peeled polyethylene terephthalate film was prepared, and cut into a circular shape (= 3.14 cm ² ) having a diameter of 2 cm.
The peeled skin on the back of the nude mouse was set in a Franz-type diffusion cell, and the polyethylene terephthalate film peeled from the patch was peeled off from the patch, and an exposed adhesive layer was attached to the skin to examine the skin permeability.
As the receptor solution, a phosphate buffer solution (pH 7.2) was used, and the amount of loxoprofen sodium transferred from the patch to the receptor solution through the skin was measured by HPLC after 24 hours. The skin permeability of loxoprofen sodium was determined by dividing the amount of loxoprofen sodium in the receptor solution after 24 hours by the amount of loxoprofen sodium in the patch and then multiplying by 100.
〇: 6 [%] ≤ skin permeability Δ: 3 [%] ≤ skin permeability <6 [%]
X: Skin permeability <3 [%]

(5) Skin irritation The polymer (a) synthesized in Production Examples and Comparative Production Examples was dissolved in a mixed solvent of ethyl acetate and ethanol (weight ratio 70:30) so that the solid content concentration was 30%, and the above-mentioned To 100 parts of the solid content of the polymer (a), 3 parts of sodium loxoprofen as a transdermal absorbent agent was added and dissolved, and then coated on a polyethylene terephthalate film with an applicator so as to have a dry coating film of 30 μm at 100 ° C. It was dried for 2 minutes.
Next, another peel-treated polyethylene terephthalate film was laminated on the pressure-sensitive adhesive layer side to prepare a skin patch with a peel-off sheet-like member (hereinafter referred to as a patch sheet).
A square planar test piece with a side of 2 cm was cut out from this patch sheet, the peeled polyethylene terephthalate film was removed, and these test pieces were applied to the back skin of a rabbit pretreated with a clipper and a shaver for 24 hours. After being applied over and over, it was peeled off, and 30 minutes and 24 hours after the peeling, the erythema state of the skin was visually observed and judged according to the following criteria. 〇: No erythema ×: With erythema

As can be seen from Table 3, the polymers (a) used in Comparative Examples 1 to 3 and 10 do not have an amine oxide group, and therefore have poor drug solubility, poor drug release, or poor drug release. The cohesive force is low, and adhesive residue may occur. In the polymer (a) used in Comparative Example 4, since the amount of amine oxide groups introduced was small, the drug solubility was lowered, the cohesive force was low, and adhesive residue was generated.
Since the polymer (a) used in Comparative Example 5 had a very large amount of amine oxide groups introduced, the interaction between the polymer (a) and the drug became strong, and the drug release property decreased.
In Comparative Examples 6 and 11, since the Tg of the polymer (a) was high, the wettability to the skin was lowered and the adhesive strength was lowered. In Comparative Examples 7 and 12, since the molecular weight of the polymer (a) was low, the cohesive force was lowered and adhesive residue was generated.
In Comparative Example 8, lauryldimethylamine oxide was added as a low molecular weight amine oxide, but the result was that the amount of the drug dissolved was insufficient. Further, in Comparative Example 9, a large amount of lauryldimethylamine oxide was added in order to improve the amount of the drug dissolved, but skin irritation was observed due to the influence of the low molecular weight amine oxide, and the adhesive strength was also lowered.
On the other hand, the polymer (a) used in the examples obtained well-balanced and good results in all physical properties.

Claims (9)

A polymer (a) containing an amine oxide group of 0.25 to 3 mmol / g, a glass transition temperature of -60 ° C to -5 ° C, and a mass average molecular weight of 10,000 to 1,000,000.
With the transdermal drug (b),
Adhesive for skin application, characterized by containing. The pressure-sensitive adhesive for skin application according to claim 1, wherein the polymer (a) is selected from the group consisting of a vinyl-based polymer and a urethane-based polymer. Whether the polymer (a) is a reaction product of a polymer having a tertiary amino group and an oxidizing agent,
Or
A polymer obtained by polymerizing a monomer having an amine oxide group with another monomer.
The adhesive for skin application according to claim 1 or 2. The pressure-sensitive adhesive for skin application according to claim 2 or 3, wherein the vinyl-based polymer has at least one structure represented by the following general formulas (1) to (3).

(During the ceremony,
X is a divalent binding group or a direct bond,
y is 0 or 1,
R ¹ is an alkylene group having 1 to 6 carbon atoms,
R ² and R ³ are independently alkyl groups having 1 to 4 carbon atoms, respectively.
R ⁴ is a hydrogen atom or a methyl group,
Four of R ^{5 to} R ⁹ represent a hydrogen atom and an alkyl group having 1 to 6 carbon atoms, and one of R ^{5 to} R ⁹ represents a bonding position with the main chain of a vinyl polymer.
* Indicates the bonding position of the vinyl polymer with the main chain. ) The pressure-sensitive adhesive for skin application according to claim 2 or 3, wherein the urethane-based polymer has at least one structure represented by the following general formulas (4) to (6).

(During the ceremony,
R ¹⁰ , R ¹² , and R ¹⁵ each independently have an alkylene group having 1 to 6 carbon atoms.
R ¹¹ _, R ¹³ , R ¹⁴ , R ¹⁶ and R ¹⁷ independently have an alkyl group, an aryl group, an aralkyl group, and a pyridyl group.
Y represents O or N
** represents the bonding position of the urethane polymer with the main chain. ) The pressure-sensitive adhesive for skin application according to any one of claims 1 to 5, wherein the polymer (a) contained in 100% by mass of the pressure-sensitive adhesive for skin application is 20 to 99% by mass. A skin patch having a sheet-like substrate and a layer of the skin patch adhesive according to any one of claims 1 to 6. The pressure-sensitive adhesive coating solution containing the skin-sticking pressure-sensitive adhesive and the liquid medium according to any one of claims 1 to 6 is applied to a sheet-like base material, the liquid medium is removed, and the sheet-like base material is removed. A method for producing a skin patch with a peeling sheet-like member, wherein a pressure-sensitive adhesive layer containing a transdermal absorbable agent is formed on the pressure-sensitive adhesive layer, and a peeling sheet-like member is laminated on the pressure-sensitive adhesive layer. The adhesive coating liquid containing the skin-sticking adhesive and the liquid medium according to any one of claims 1 to 6 is applied to a peeling sheet-like member, the liquid medium is removed, and the peeling sheet is removed. A method for producing a skin patch with a sheet-like member for peeling, wherein a pressure-sensitive adhesive layer containing a transdermal absorbable agent is formed on the shape member, and a sheet-like base material is laminated on the pressure-sensitive adhesive layer.