JP2018083796A - Skin sticking agent, skin patch, and method for producing skin patch with sheet-like member for release - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a skin sticking agent suitable for a skin patch that is excellent in sticking to a skin surface, peeling from the skin, drug solubility, and drug releasing from the sticking agent.SOLUTION: A skin sticking agent contains: a vinyl polymer (a) that contains a carbobetaine structure and/or sulfobetaine structure with a total content of 1-40 mol%, has a glass transition temperature of -60°C to -10°C, and has a mass average molecular weight of 10000-10000000; and a percutaneous absorbable drug (b).SELECTED DRAWING: None

Description

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

  Conventionally, various adhesives for skin application have been used to fix skin wound coverings and medical devices to the skin. In addition, as a transdermally absorbable preparation for administering a transdermally absorbable drug into the living body through the skin, a transdermal absorption-type external patch such as a plaster, a patch using an adhesive, or a transdermally absorbable adhesive sheet. Agents have been developed. Among them, a transdermal absorbable adhesive sheet containing a transdermally absorbable drug in an adhesive is attracting attention because administration is relatively easy and the dose can be controlled.

  Such a transdermally absorbable pressure-sensitive adhesive sheet is used with a pressure-sensitive adhesive layer containing a transdermally absorbable drug attached to the skin surface, and therefore requires adhesion (adhesion) to the skin surface. In addition, in order to improve the therapeutic effect with more certainty, development of a transdermal patch capable of continuously administering a drug to an affected area for a long time is expected. Therefore, improvement in the drug solubility of the pressure-sensitive adhesive and improvement in the drug release from the pressure-sensitive adhesive are required.

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

For example, rubber-based pressure-sensitive adhesives include styrene-isoprene-styrene block copolymers, polybutenes, polyisobutylenes, polyisoprenes, ethylene-vinyl acetate copolymers, natural rubbers, and the like as tackifiers and softeners. In addition, those with added stabilizers are used.
Patent Document 1 discloses an adhesive containing a styrene-isoprene-styrene block copolymer, a C10-30 paraffin hydrocarbon and / or a naphthene hydrocarbon, and an alicyclic hydrocarbon resin.
Patent Document 2 discloses a thermoplastic sheet made of an ABA type block copolymer, a liquid component compatible with the thermoplastic elastomer, and a patch sheet or tape made of a tackifier.
Patent Document 3 discloses a patch characterized in that the pressure-sensitive adhesive layer contains two kinds of synthetic rubbers having different fluidity.

Further, as silicone-based pressure-sensitive adhesives, those using silicone rubber, dimethylsiloxane base, diphenylsiloxane and 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 polymer and an acrylic polymer mainly composed of (meth) acrylic acid ester.
Patent Document 6 discloses a silicone adhesive for skin that contains a silicone resin and a modified silicone oil that is compatible with the silicone resin and is made into a water-in-oil emulsion.

As an acrylic pressure-sensitive adhesive, Patent Document 7 discloses that a monomer containing a carboxyl group or a hydroxyl group, a copolymer obtained by copolymerizing (meth) acrylic acid ester as an essential component, and a salt in a side chain. Disclosed is a transdermally absorbable preparation comprising a monomer having a nitrogen atom not having a structure and a copolymer obtained by copolymerizing (meth) acrylic acid ester as an essential component.
Patent Document 8 discloses 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.

Patent Documents 9 to 12 disclose a polymer obtained by polymerizing 2-methacryloyloxyethyl phosphoricolin (hereinafter abbreviated as MPC monomer) (hereinafter abbreviated as MPC polymer. Also referred to as a polymer having a phosphobetaine structure). An external preparation for skin comprising
Furthermore, Patent Document 13 describes an external preparation composition for warm feeling and suggests the use of N-methacryloylethyl-N, N-dimethylammonium-α-N-methylcarboxybetaine polymer.

JP-A-5-17346 JP 2004-115774 A JP 2008-127953 A Japanese Patent Laid-Open No. 5-194201 JP 2005-314618 A JP 2008-127953 A JP 2000-44904 A JP-A-9-176604 JP 2003-26608 A JP 2003-73251 A JP 2005-170887 A JP 2014-28783 A JP 2003-250829 A

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 drug solubility is insufficient, and the selection range of the drug composition is wide. There was a drawback of being narrow.
Acrylic pressure-sensitive adhesives such as Patent Documents 7 and 8 are copolymerized with a monomer having a carboxyl group or a hydroxyl group in order to ensure cohesive strength of the pressure-sensitive adhesive. In response, there was a problem that the amount of drug released decreased. Also, drug solubility is not sufficient.
The copolymers disclosed in Patent Documents 9 to 12 have a problem in productivity, such as requiring a plurality of reactions and purification accompanying the synthesis of MPC monomer as a raw material. Moreover, the external preparation disclosed by patent documents 9-12 aims at the usability which is not sticky after apply | coating to skin. In addition, the MPC monomer is limited to a copolymerizable monomer, and it is difficult to use the obtained MPC polymer for an adhesive.
Patent Document 13 suggests the use of a polymer having a carbobetaine structure in a patch. However, it did not satisfy the requirements for adhesion to the skin surface, peelability from the skin, drug solubility, and drug release from the adhesive.

  In view of the above circumstances, the present invention provides an adhesive for skin patch that is suitable for a skin patch excellent in adhesiveness to the skin surface, peelability from the skin, drug solubility, and drug release from the adhesive. The purpose is to provide.

In general, 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. This is not appropriate in terms of drug release.
Therefore, the present inventors use a polymer containing a specific amount of a hydrophilic carbobetaine structure and / or sulfobetaine structure, and having a glass transition temperature and a weight average molecular weight within a specific range, to thereby apply to the skin surface. The present inventors have found that it is possible to provide a patch excellent in adhesiveness, peelability when peeled from the skin, drug solubility, and drug release properties, and have reached the present invention.
That is, the present invention includes at least one repeating structure represented by the following general formulas 1 to 3 in a total repeating structure of 100 mol% in an amount of 1 to 40 mol%, and a glass transition temperature of -60 ° C to -10 ° C. In addition, the present invention relates to a pressure-sensitive adhesive for skin application, comprising a vinyl polymer (a) having a mass average molecular weight of 10,000 to 10,000,000 and a transdermally absorbable drug (b).

（式中、
Ｒ_２は炭素数１〜６のアルキレン基、
Ｒ_３、Ｒ_４はそれぞれ独立して炭素数１〜４のアルキル基、
Ｒ_５は炭素数１〜４のアルキレン基
Ｘは酸素原子または−ＮＨ−、
Ｙは−ＣＯＯ⁻または−ＳＯ_３ ⁻、
Ｒ_７は水素原子またはメチル基、
Ｒ_８は炭素数１〜６のアルキレン基または炭素数１〜６のヒドロキシアルキレン基、
Ｒ_１０〜Ｒ_１４のうち４つは、水素原子、炭素数１〜６のアルキル基を表し、Ｒ_１０〜Ｒ_１4のうちの１つはビニル系重合体の主鎖との結合位置を表し、
Ｒ_１５は炭素数１〜６のアルキレン基または炭素数１〜６のヒドロキシアルキレン基を表し、
＊はビニル系重合体の主鎖との結合位置を表す。）

(Where
R ₂ is an alkylene group having 1 to 6 carbon atoms,
R ₃ and R ₄ are each independently an alkyl group having 1 to 4 carbon atoms,
R ₅ represents an alkylene group having 1 to 4 carbon atoms, X represents an oxygen atom or —NH—,
Y is -COO ^- or -SO ₃ ^-,
R ₇ is a hydrogen atom or a methyl group,
R ₈ is an alkylene group having 1 to 6 carbon atoms or a hydroxyalkylene group having 1 to 6 carbon atoms,
4 of R _{10 to} R ₁₄ represent a hydrogen atom and an alkyl group having 1 to 6 carbon atoms, and one of R _{10 to} R ₁₄ represents a bonding position with the main chain of the vinyl polymer,
R ₁₅ represents an alkylene group having 1 to 6 carbon atoms or a hydroxyalkylene group having 1 to 6 carbon atoms,
* Represents the bonding position with the main chain of the vinyl polymer. )

The vinyl polymer (a) is preferably the following (a1) or (a2).
(A1) At least one of the monomers (A1) to (A3) represented by the following general formulas 4 to 6, and one ethylenically unsaturated group and an alkyl group having 1 to 12 carbon atoms in one molecule. It is a copolymer with the monomer (B) it has.
(A2) having at least one monomer (A4) to (A6) represented by the following general formulas 7 to 9 and one ethylenically unsaturated group and an alkyl group having 1 to 12 carbon atoms in one molecule Copolymer with monomer (B), cyclic sulfonic acid ester (D1), ω-halogenated alkylsulfonic acid metal salt (D2), cyclic carboxylic acid ester (D3) and ω-halogenated alkylcarboxylic acid metal It is a reaction product with one or more betaine agents (D) selected from the group consisting of salts (D4).

（式中、
Ｒ_１は水素原子またはメチル基、
Ｒ_２は炭素数１〜６のアルキレン基、
Ｒ_３、Ｒ_４はそれぞれ独立して炭素数１〜４のアルキル基、
Ｒ_５は炭素数１〜４のアルキレン基
Ｘは酸素原子または−ＮＨ−、
Ｙは−ＣＯＯ⁻または−ＳＯ３⁻、
Ｒ_６は水素原子またはメチル基、
Ｒ_７は水素原子またはメチル基、
Ｒ_８は炭素数１〜６のアルキレン基または炭素数１〜６のヒドロキシアルキレン基、
Ｒ_１６〜Ｒ_２０のうち４つは、水素原子、炭素数１〜６のアルキル基を表し、Ｒ_１６〜Ｒ_２０のうちの１つはＣＨ_２＝Ｃ（Ｒ_２１）を表し、
Ｒ_１５は炭素数１〜６のアルキレン基または炭素数１〜６のヒドロキシアルキレン基を表し、
Ｒ_２１は水素原子またはメチル基を表し、
＊＊はベタイン化剤（Ｄ）との反応部位を表す。）

(Where
R ₁ is a hydrogen atom or a methyl group,
R ₂ is an alkylene group having 1 to 6 carbon atoms,
R ₃ and R ₄ are each independently an alkyl group having 1 to 4 carbon atoms,
R ₅ represents an alkylene group having 1 to 4 carbon atoms, X represents an oxygen atom or —NH—,
Y is -COO ^- or -SO3 ^-,
R ₆ is a hydrogen atom or a methyl group,
R ₇ is a hydrogen atom or a methyl group,
R ₈ is an alkylene group having 1 to 6 carbon atoms or a hydroxyalkylene group having 1 to 6 carbon atoms,
4 of R _{16 to} R ₂₀ represent a hydrogen atom and an alkyl group having 1 to 6 carbon atoms, and one of R _{16 to} R ₂₀ represents CH ₂ = C (R ₂₁ ),
R ₁₅ represents an alkylene group having 1 to 6 carbon atoms or a hydroxyalkylene group having 1 to 6 carbon atoms,
R ₂₁ represents a hydrogen atom or a methyl group,
** represents a reaction site with the betaine agent (D). )

The vinyl polymer (a) is a total of 100 mol% of the monomers (A1) to (A3), the monomer (B), and other monomers (C) used as necessary. The total of the monomers (A1) to (A3) is 1 to 40 mol%, the monomer (B) is 20 to 99 mol%, and the other monomer (C) is 0 to 79 mol%, Or
Monomers (A4) to (A6), monomers (B), and other monomers (C) used as needed, in a total of 100 mol%, monomers (A4) to (A6) The part which is reacting with the betaine agent (D) in the derived structure is 1 to 40 mol%, the monomer (B) is derived from 20 to 99 mol%, and the monomers (A4) to (A6). It is preferable that the total of the part which has not reacted with the betaine agent (D) in the structure and the other monomer (C) is 0 to 78 mol%.

  Moreover, it is preferable that the vinyl polymer (a) contained in 100 mass% of adhesives for skin sticking is 20-99 mass%.

  The present invention also relates to a skin patch having a sheet-like substrate and the above-mentioned adhesive layer for skin patch.

  Furthermore, the present invention applies the adhesive coating liquid containing the adhesive for skin application and a liquid medium to a sheet-like substrate or a peeling sheet-like member, removes the liquid medium, Forming an adhesive layer for skin application containing a transdermally absorbable drug on the sheet-like substrate or the peeling sheet-like member, and laminating the peeling sheet-like member or sheet-like substrate on the adhesive layer; The present invention relates to a method for producing a skin patch with a release sheet member.

  By using a vinyl polymer (a) containing a specific amount of at least one of the structures represented by the general formulas 1 to 3 and having a glass transition temperature and a weight average molecular weight within a specific range, adhesiveness to the skin surface In addition, it was possible to provide a pressure-sensitive adhesive for skin application excellent in peelability when peeled from the skin, drug solubility, and drug release from the pressure-sensitive adhesive.

The adhesive for skin application of the present invention is characterized by containing a vinyl polymer (a). The vinyl polymer (a) is sometimes referred to as betaine resin (a).
<Vinyl polymer (a), betaine resin (a)>
A betaine structure refers to a structure in which a positive charge and a negative charge are not adjacent to each other in the same molecule, and a dissociable hydrogen atom is not bonded to a positively charged atom. The vinyl polymer (a) indicates a vinyl polymer having a betaine structure in the molecular structure. By having a betaine structure in the molecule, it was possible to impart cohesive force to the resin and to impart excellent drug solubility and drug release properties.

  The vinyl polymer (a) has at least one structure represented by the following general formulas 1 to 3 in the side chain. The repeating structure is contained in a total of 100 mol% of the repeating structure in an amount of 1 to 40 mol%, preferably 2 to 35 mol%.

(Where
R ₂ is an alkylene group having 1 to 6 carbon atoms,
R ₃ and R ₄ are each independently an alkyl group having 1 to 4 carbon atoms,
R ₅ represents an alkylene group having 1 to 4 carbon atoms, X represents an oxygen atom or —NH—,
Y is -COO ^- or -SO ₃ ^-,
R ₇ is a hydrogen atom or a methyl group,
R ₈ is an alkylene group having 1 to 6 carbon atoms or a hydroxyalkylene group having 1 to 6 carbon atoms,
4 of R _{10 to} R ₁₄ represent a hydrogen atom and an alkyl group having 1 to 6 carbon atoms, and one of R _{10 to} R ₁₄ represents a bonding position with the main chain of the vinyl polymer,
R ₁₅ represents an alkylene group having 1 to 6 carbon atoms or a hydroxyalkylene group having 1 to 6 carbon atoms,
* Represents the bonding position with the main chain of the vinyl polymer. )

Such a vinyl polymer (a) is preferably obtained by the following method.
That is,
(1) At least one of the monomers (A1) to (A3) represented by the following general formulas 4 to 6, and one ethylenically unsaturated group and an alkyl group having 1 to 12 carbon atoms in one molecule. The monomer (B) is copolymerized. The resulting copolymer is referred to as vinyl polymer (a1).
Or
(2) At least one of the monomers (A4) to (A6) represented by the following general formulas 7 to 9, and one ethylenically unsaturated group and an alkyl group having 1 to 12 carbon atoms in one molecule A monomer (B) is copolymerized, and a betaine agent (D) described later is reacted with a portion derived from the monomers (A4) to (A6) in the obtained copolymer. The obtained reaction product has a betaine structure similarly to the copolymer using the monomer (A1), and is referred to as a vinyl polymer (a2).

(Where
R ₁ is a hydrogen atom or a methyl group,
R ₆ is a hydrogen atom or a methyl group,
R ₉ is a hydrogen atom or a methyl group,
4 of R _{16 to} R ₂₀ represent a hydrogen atom and an alkyl group having 1 to 6 carbon atoms, and one of R _{16 to} R ₂₀ represents CH ₂ = C (R ₂₁ ),
R ₂₁ represents a hydrogen atom or a methyl group,
** represents a reaction site with the betaine agent (D). )
Other symbols are the same as those in general formulas 1 to 3. )

<Vinyl polymer (a1)>
As described above, the vinyl polymer (a1) includes at least one of the monomers (A1) to (A3) selected from the group represented by the general formulas 4 to 6 as a constituent unit of the copolymer. To do. By utilizing the monomers (A1) to (A3), a betaine structure can be introduced into the side chain of the vinyl polymer. Therefore, the monomers (A1) to (A3) can also be referred to as betaine monomers.

<Monomer (A1)>
The monomer (A1) has one ethylenically unsaturated group and a betaine structure in one molecule as shown in the general formula 4.
Examples of such a monomer include N- (meth) acryloyloxymethyl-N, N-dimethylammonium methyl-α-carboxybetaine, N- (meth) acryloyloxyethyl-N, N-dimethylammonium methyl- α-carboxybetaine, N- (meth) acryloyloxypropyl-N, N-dimethylammoniummethyl-α-carboxybetaine, N- (meth) acryloyloxybutyl-N, N-dimethylammoniummethyl-α-carboxybetaine, N -(Meth) acryloyloxymethyl-N, N-diethylammonium methyl-α-carboxybetaine, N- (meth) acryloyloxyethyl-N, N-diethylammoniummethyl-α-carboxybetaine, N- (meth) acryloyloxy Propyl-N, N N- (meth) acryloyloxyalkyl-N, N-dialkylammoniumalkyl- such as diethylammoniummethyl-α-carboxybetaine, N- (meth) acryloyloxybutyl-N, N-diethylammoniummethyl-α-carboxybetaine, etc. N- such as α-carboxybetaine; N- (meth) acrylamidopropyl-N, N-dimethylammonium methyl-α-carboxybetaine, N- (meth) acrylamidopropyl-N, N-diethylammoniummethyl-α-carboxybetaine -(Meth) acrylamide alkyl-N, N-dialkylammonium alkyl-α-carboxybetaine; N- (meth) acrylamidopropyl-N, N-dimethylammonium methyl-α-carboxybetaine, N- (meth) acrylic N- (meth) acrylamidoalkyl-N, N-dialkylammoniumalkyl-α-carboxybetaines such as midpropyl-N, N-diethylammoniummethyl-α-carboxybetaine; N- (meth) acryloyloxymethyl-N, N -Dimethylammonium methyl-α-sulfobetaine, N- (meth) acryloyloxymethyl-N, N-dimethylammoniumethyl-α-sulfobetaine, N- (meth) acryloyloxymethyl-N, N-dimethylammoniumpropyl-α -Sulfobetaine, N- (meth) acryloyloxymethyl-N, N-dimethylammoniumbutyl-α-sulfobetaine, N- (meth) acryloyloxyethyl-N, N-dimethylammoniummethyl-α-sulfobetaine, N- (Meta) acrylo Ruoxyethyl-N, N-dimethylammoniumethyl-α-sulfobetaine, N- (meth) acryloyloxyethyl-N, N-dimethylammoniumpropyl-α-sulfobetaine, N- (meth) acryloyloxyethyl-N, N- Dimethylammoniumbutyl-α-sulfobetaine, N- (meth) acryloyloxypropyl-N, N-dimethylammoniummethyl-α-sulfobetaine, N- (meth) acryloyloxypropyl-N, N-dimethylammoniumethyl-α- Sulfobetaine, N- (meth) acryloyloxypropyl-N, N-dimethylammoniumpropyl-α-sulfobetaine, N- (meth) acryloyloxypropyl-N, N-dimethylammoniumbutyl-α-sulfobetaine, N- ( Meta) Acrylloy Oxybutyl-N, N-dimethylammonium methyl-α-sulfobetaine, N- (meth) acryloyloxybutyl-N, N-dimethylammoniumethyl-α-sulfobetaine, N- (meth) acryloyloxybutyl-N, N- N- (meth) acryloyloxyalkyl-N, N-dimethylammoniumalkyl- such as dimethylammoniumpropyl-α-sulfobetaine, N- (meth) acryloyloxybutyl-N, N-dimethylammoniumbutyl-α-sulfobetaine α-sulfobetaine; N- (meth) acryloyloxymethoxymethoxy-N, N-dimethylammonium methyl-α-sulfobetaine, N- (meth) acryloyloxymethoxymethoxy-N, N-dimethylammoniumethyl-α-sulfobetaine , N- ( T) Acryloyloxymethoxymethoxy-N, N-dimethylammoniumpropyl-α-sulfobetaine, N- (meth) acryloyloxymethoxymethoxy-N, N-dimethylammoniumbutyl-α-sulfobetaine, N- (meth) acryloyloxy Ethoxyethoxy-N, N-dimethylammonium methyl-α-sulfobetaine, N- (meth) acryloyloxyethoxyethoxy-N, N-dimethylammoniumethyl-α-sulfobetaine, N- (meth) acryloyloxyethoxyethoxy-N , N-dimethylammoniumpropyl-α-sulfobetaine, N- (meth) acryloyloxyethoxyethoxy-N, N-dimethylammoniumbutyl-α-sulfobetaine, N- (meth) acryloyloxypropoxypropoxy -N, N-dimethylammonium methyl-α-sulfobetaine, N- (meth) acryloyloxypropoxypropoxy-N, N-dimethylammoniumethyl-α-sulfobetaine, N- (meth) acryloyloxypropoxypropoxy-N, N -Dimethylammoniumpropyl-α-sulfobetaine, N- (meth) acryloyloxypropoxypropoxy-N, N-dimethylammoniumbutyl-α-sulfobetaine, N- (meth) acryloyloxybutoxybutoxy-N, N-dimethylammonium methyl -Α-sulfobetaine, N- (meth) acryloyloxybutoxybutoxy-N, N-dimethylammoniumethyl-α-sulfobetaine, N- (meth) acryloyloxybutoxybutoxy-N, N-dimethylammonium pro N- (meth) acryloyloxyalkoxyanalkoxy-N, N-dimethylammonium such as pill-α-sulfobetaine, N- (meth) acryloyloxybutoxybutoxy-N, N-dimethylammoniumbutyl-α-sulfobetaine Alkyl-α-sulfobetaine; N- (meth) acrylamidopropyl-N, N-dimethylammoniumpropyl-α-sulfobetaine, N- (meth) acrylamidopropyl-N, N-dimethylammoniumbutyl-α-sulfobetaine, etc. N- (meth) acrylamide alkyl-N, N-dialkylammonium alkyl-α-sulfobetaine and the like can be mentioned. In the present invention, the expression (meth) acryl indicates methacryl or acryl.

<Monomer (A2)>
The monomer (A2) also has one ethylenically unsaturated group and a betaine structure in one molecule as shown in the general formula 5.
Examples of such monomers include 1-vinyl-3- (3-sulfopropyl) imidazolium inner salt, 1-vinyl-3- (3-sulfobutyl) imidazolium inner salt, 1-vinyl-2- 1-vinyl-2-alkyl-3- (4-sulfo) such as methyl-3- (3-sulfopropyl) imidazolium inner salt, 1-vinyl-2-methyl-3- (4-sulfobutyl) imidazolium inner salt Alkyl) imidazolium inner salt and the like.

<Monomer (A3)>
The monomer (A3) also has one ethylenically unsaturated group and a betaine structure in one molecule as shown in the general formula 6.
Examples of such a monomer include 2-vinyl-1- (3-sulfopropyl) pyridinium inner salt, 2-vinyl-1- (3-sulfobutyl) pyridinium inner salt, and the like. 4-vinyl-1-((3-sulfoalkyl) pyridinium inner salt; 4-vinyl-1- (3-sulfopropyl) pyridinium inner salt, 4-vinyl-1- (3-sulfobutyl) pyridinium inner salt, etc. 3-sulfoalkyl) pyridinium inner salt.

<Vinyl polymer (a2)>
As described above, the vinyl polymer (a) in the present invention does not need to be a copolymer obtained by copolymerizing the monomers (A1) to (A3) itself, and can be obtained through the following steps. it can.
That is, at least one of the monomers (A4) to (A6) represented by the general formulas 7 to 9, which should be called precursors of the monomers (A1) to (A3), and a monomer that can be copolymerized therewith The body can be copolymerized, and at least a part of the nitrogen indicated by ** in the obtained copolymer can be reacted with the betaine agent (D). The obtained water-soluble vinyl polymer (a2) has a betaine structure in the side chain as in the copolymer using the monomers (A4) to (A6).

As such a monomer (A4), for example,
N- (meth) acryloyloxymethyl-N, N-dimethylamine,
N- (meth) acryloyloxyethyl-N, N-dimethylamine,
N- (meth) acryloyloxypropyl-N, N-dimethylamine,
N- (meth) acryloyloxybutyl-N, N-dimethylamine,
N- (meth) acryloyloxymethyl-N, N-diethylamine,
N- (meth) acryloyloxyethyl-N, N-diethylamine,
N- (meth) acryloyloxypropyl-N, N-diethylamine,
N- (meth) acryloyloxybutyl-N, N-diethylamine,
N- (meth) acryloyloxyalkyl-N, N-dialkylamine such as;
N- (meth) acrylamidopropyl-N, N-dimethylamine,
N- (meth) acrylamidopropyl-N, N-diethylamine,
N- (meth) acrylamide alkyl-N, N-dialkylamines such as;
N- (meth) acryloyloxymethoxymethoxy-N, N-dimethylamine,
N- (meth) acryloyloxyethoxyethoxy-N, N-dimethylamine,
N- (meth) acryloyloxypropoxypropoxy-N, N-dimethylamine,
N- (meth) acryloyloxybutoxybutoxy-N, N-dimethylamine,
N- (meth) acryloyloxyalkoxyanalkoxy-N, N-dimethylamine and the like.

As such a monomer (A5), for example,
1-vinylimidazole, 1-vinyl-2-methyl-imidazole,
1-vinyl-2-alkyl-imidazole.

  Examples of such a monomer (A6) include vinylpyridines such as 4-vinyl-pyridine and 2-vinyl-pyridine.

<Betaine group (D)>
The group of betaine agents (D) includes cyclic sulfonic acid ester (D1), ω-halogenated alkylsulfonic acid metal salt (D2), cyclic carboxylic acid ester (D3) and ω-halogenated alkylcarboxylic acid metal salt (D4). Selected from the group consisting of It is a compound group used for the polymerization of the nitrogen represented by ** of the monomers (A4) to (A6) represented by the general formulas 7 to 9 after polymerization to sulfobetaine or carbobetaine.

  Examples of the cyclic sulfonate ester (D1) include 1,2-ethane sultone, 1,3-propane sultone, and 1,4-butane sultone.

  Examples of such ω-halogenated alkylsulfonic acid metal salt (D2) include sodium 2-chloroethanesulfonate, sodium 2-bromoethanesulfonate, sodium 3-chloropropanesulfonate, sodium 3-bromopropanesulfonate, Examples include sodium 4-chlorobutanesulfonate, sodium 4-bromobutanesulfonate, and the like.

  Examples of such cyclic carboxylic acid ester (D3) include β-propiolactone, γ-butyrolactone, δ-valerolactone, and the like.

  Examples of such ω-halogenated alkylcarboxylic acid metal salt (D4) include sodium 2-chloroacetate, sodium 2-bromoacetate, sodium 3-chloropropionate, sodium 3-bromopropionate, 4-chlorobutyric acid. Examples thereof include sodium, sodium 4-bromobutyrate, sodium 5-chloropentanoate, sodium 5-bromopentanoate and the like.

<Monomer (B)>
When obtaining the vinyl polymers (a1) and (a2), in addition to the monomers (A1) to (A3) and (A4) to (A6), one ethylenically unsaturated group per molecule A monomer (B) having an alkyl group having 1 to 12 carbon atoms can be used. By introducing the structural unit based on the monomer (B), the polarity and Tg are appropriately controlled, and it can have excellent adhesiveness, drug solubility and drug release.

  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 (meta ) 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) ) Alkyl (meth) acrylates such as acrylates; α-olefinic ethylenically unsaturated monomers such as 1-propylene, 1-butene, 1-pentene, 1-hexene, 1-octene, 1-nonene, 1-decene Etc.

<Monomer (C)>
When obtaining the vinyl polymers (a1) and (a2), other monomers (C) other than the monomers (A1) to (A3), (A4) to (A6), and (B) are also used. can do.

<Monomer (C1)>
Among monomers (C), it has a hydroxyl group, a carboxylic acid group, a carboxylic anhydride group, a phosphoric acid group, a sulfonic acid group, a primary to tertiary amide group, a primary to quaternary amine group, and a polyether chain in the molecular structure. This is monomer (C1). Betaine resin (a) can have a polar functional group by having the structural unit based on the monomer (C1) which has a polar functional group.

  Although it does not specifically limit as this monomer (C1), For example, 2-hydroxyethyl (meth) acrylate, 2-hydroxypropyl (meth) acrylate, 4-hydroxybutyl (meth) acrylate, 2- (meth) acrylic Monomers having a hydroxyl group such as leuoxyethyl-2-hydroxyethylphthalic acid, glycerol mono (meth) acrylate, 4-hydroxyvinylbenzene, 1-ethynyl-1-cyclohexanol, allyl alcohol; maleic acid, fumaric acid, Itaconic acid, citraconic acid or their alkyl or alkenyl monoesters, phthalic acid β- (meth) acryloxyethyl monoester, isophthalic acid β- (meth) acryloxyethyl monoester, terephthalic acid β- (meth) acrylic acid Roxyethyl monoester, Monomers having carboxylic acid groups such as succinic acid β- (meth) acryloxyethyl monoester, acrylic acid, methacrylic acid, crotonic acid, cinnamic acid, or anhydrides thereof; vinyl sulfonic acid, styrene sulfonic acid, etc. Monomer having a sulfonic acid group; Monomer having a phosphoric acid group such as (2-hydroxyethyl) methacrylate acid phosphate; (meth) acrylamide, 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-ethoxy Methyl-N-methoxymethylmethacrylamide, N, N- Di (ethoxymethyl) acrylamide, N-ethoxymethyl-N-propoxymethylmethacrylamide, N, N-di (propoxymethyl) acrylamide, N-butoxymethyl-N- (propoxymethyl) methacrylamide, N, N-di ( Butoxymethyl) acrylamide, N-butoxymethyl-N- (methoxymethyl) methacrylamide, N, N-di (pentoxymethyl) acrylamide, N-methoxymethyl-N- (pentoxymethyl) methacrylamide, N, N- Monomers having primary to tertiary amide groups such as dimethylaminopropylacrylamide, N, N-diethylaminopropylacrylamide, N, N-dimethylacrylamide, N, N-diethylacrylamide, diacetone (meth) acrylamide; acrylic Dimethylaminoethyl methyl chloride salt, trimethyl-3- (1- (meth) acrylamide-1,1-dimethylpropyl) ammonium chloride, trimethyl-3- (1- (meth) acrylamidopropyl) ammonium chloride, and trimethyl-3- Monomers having a primary to quaternary amine group such as (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, methoxypolypropylene glycol (meth) acrylate, ethoxypolypropylene glycol (meth) acrylate, propoxypolypropylene glycol (meth) acrylate, n-butoxypolypropylene glycol (meth) acrylate, n -Pentoxypolypropylene glycol (meth) acrylate, phenoxypolypropylene glycol (meth) acrylate, polytetramethylene glycol (meth) acrylate, methoxypolytetramethylene glycol (meth) acrylate, phenoxytetraethylene glycol (meth) acrylate, hexaethylene glycol ( (Meth) acrylate, methoxyhexaeth Examples thereof include monomers having a polyether chain such as lenglycol (meth) acrylate.

<Monomer (C2)>
In addition to the monomers (A1) to (A3), (A4), (B) and (C1), the betaine resin (a) of the present invention includes other monomers having an ethylenically unsaturated group (C2 You may further have a structural unit based on.

  As the monomer (C2), stearyl (meth) acrylate, cetyl (meth) acrylate, cyclohexyl (meth) acrylate, isobornyl (meth) acrylate, methoxyethyl (meth) acrylate, ethoxyethyl (meth) acrylate, propoxyethyl ( Acrylic esters (meth) acrylates such as meth) acrylate, butoxyethyl (meth) acrylate, ethoxypropyl (meth) acrylate; aromatic esters such as phenyl (meth) acrylate, benzyl (meth) acrylate, phenoxyethyl (meth) acrylate ( (Meth) acrylate; allyl (meth) acrylate, 1-methylallyl (meth) acrylate, 2-methylallyl (meth) acrylate, 1-butenyl (meth) acrylate, 2-butyl (meth) acrylate Nyl, 3-butenyl (meth) acrylate, 1,3-methyl-3-butenyl (meth) acrylate, 2-chloroallyl (meth) acrylate, 3-chloroallyl (meth) acrylate, (meth) acrylic acid o -Allylphenyl, 2- (allyloxy) ethyl (meth) acrylate, allyl lactyl (meth) acrylate, citronellyl (meth) acrylate, geranyl (meth) acrylate, rosinyl (meth) acrylate, cinnamyl (meth) acrylate , Ethylenic unsaturation such as, diallyl maleate, diallyl itaconic acid, vinyl (meth) acrylate, vinyl crotonate, vinyl oleate, vinyl linolenate, 2- (2′-vinyloxyethoxy) ethyl (meth) acrylate Group-containing (meth) acrylic acid esters; perfluoromethylmethyl (meth) acrylate Rate, perfluoroethylmethyl (meth) acrylate, 2-perfluorobutylethyl (meth) acrylate, 2-perfluorohexylethyl (meth) acrylate, 2-perfluorooctylethyl (meth) acrylate, 2-perfluoroisononyl Ethyl (meth) acrylate, 2-perfluorononylethyl (meth) acrylate, 2-perfluorodecylethyl (meth) acrylate, perfluoropropylpropyl (meth) acrylate, perfluorooctylpropyl (meth) acrylate, perfluorooctyl amyl Perfluoroalkyl group-containing ethylenically unsaturated monomers having a C1-C20 perfluoroalkyl group such as (meth) acrylate and perfluorooctylundecyl (meth) acrylate (Meth) acrylate monomers may be mentioned.

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

  Examples of the monomer (C2) include aromatic vinyl monomers such as styrene, α-methylstyrene, 2-methylstyrene, chlorostyrene, allylbenzene, and ethynylbenzene; nitrile groups such as (meth) acrylonitrile Ethylenically unsaturated monomers; vinyl acetate, vinyl butyrate, vinyl propionate, vinyl hexanoate, vinyl caprylate, vinyl laurate, vinyl palmitate, vinyl stearate, etc .; butyl vinyl ether, ethyl vinyl ether, etc. Vinyl ether-based ethylenically unsaturated monomers; allyl monomers such as allyl acetate and allyl cyanide; vinyl monomers such as vinyl cyanide, vinylcyclohexane and vinylmethylketone; ethynyl monomers such as acetylene and ethynyltoluene Perfluorobutyl Ethylenically unsaturated bonds that are not (meth) acrylates, such as perfluoroalkyl group-containing ethylenically unsaturated compounds such as tylene, perfluorohexylethylene, perfluorooctylethylene, perfluorodecylethylene, and other alkylenes. The monomer which has is mentioned.

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

In the case of the vinyl polymer (a1), a total of 100 mol% of the monomers (A1) to (A3), the monomer (B), and other monomers (C) used as needed, The sum total of the monomers (A1) to (A3) is 1 to 40 mol%, and preferably 2 to 35 mol%.
Further, in the case of the vinyl polymer (a2), a total of 100 mol% of the monomers (A4) to (A6), the monomer (B) and other monomers (C) used as necessary. Among the structures derived from the monomers (A4) to (A6), the portion reacting with the betaine agent (D) is 1 to 40 mol%, the monomer (B) is 20 to 99 mol%, From the structure derived from the monomers (A4) to (A6), the total of the portion not reacted with the betaine agent (D) and the other monomer (C) is preferably 0 to 79 mol%. preferable.
Adhesiveness suitable by having the part which betaine agent group (D) reacted with the part derived from monomer (A1)-(A3) or monomer (A4)-(A6) in the said range. Can be improved, and drug solubility and drug release can be improved.

  The monomer (B) is composed of the monomer (A1) to (A3) or (A4) to (A6), the monomer (B), and other monomers (C) used as necessary. It is preferable that it is 20-99 mol% in a total of 100 mol%, and it is more preferable that it is 30-98 mol%. By setting it as 99 mol% or less, the hydrophobicity of the vinyl polymer (a) can be suppressed, and the drug solubility can be improved. By being 20 mol% or more, it is easy to impart adhesiveness by lowering the Tg of the resin, and the amount of the monomers (A1) to (A3) or (A4) to (A6) is relatively reduced, The water resistance of the vinyl polymer (a) can be improved.

When other monomer (C) is used, a total of 100 mol of monomers (A1) to (A3) or (A4) to (A6), monomer (B) and other monomer (C) %, The other monomer (C), or the betaine group (D) does not react with the part derived from the other monomer (C) and the monomers (A4) to (A6). The portion is preferably 0 to 79 mol%, more preferably 0 to 68 mol%.
When the monomer (C1) having a polar functional group is used as the other monomer (C), the monomers (A1) to (A3) or (A4), the monomer (B), and other monomers The monomer (C1) having a polar functional group is preferably 0 to 20 mol% in a total of 100 mol% with the monomer (C).
Since the drug is adsorbed on the polar functional group of the monomer (C1) and the drug release may be reduced, it is preferable that the amount of the monomer (C1) is small.

  The vinyl polymer (a) contained in 100% by mass of the adhesive for skin application is preferably 20 to 99% by mass, and more preferably 25 to 99% by mass. By setting the proportion of the vinyl polymer (a) to 20% by mass or more, desired performance such as drug solubility and drug release can be exhibited.

  The vinyl polymer (a) is preferably water-insoluble. In the present invention, water-insoluble means 1 mass of polymer in 99 g of ion-exchanged water at 25 ° C., and after stirring for 24 hours at 25 ° C., the water is removed and the mass is reduced after the polymer is dried under reduced pressure. Is 5% or less. When the vinyl 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.

<Glass transition temperature>
The glass transition temperature (hereinafter also referred to as Tg) of the vinyl polymer (a) is −60 ° C. to −10 ° C., preferably −55 to −15 ° C. When Tg is −60 ° C. or higher, a cohesive force can be imparted, and generation of adhesive residue when the adhesive is peeled from the skin can be suppressed. Moreover, since the wettability to skin improves because Tg is -10 degrees C or less, the outstanding skin adhesiveness can be provided.

<Mass average molecular weight (Mw)>
The mass average molecular weight of the vinyl polymer (a) is 10,000 to 10,000,000, preferably 15,000 to 5,000,000. When the molecular weight is 10,000 or more, a cohesive force can be imparted, and the occurrence of adhesive residue when the adhesive is peeled from the skin can be suppressed. Moreover, since it is 10000000 or less, the solvent solubility of resin improves and it becomes a suitable viscosity, Therefore Suitability for coating improves.

As the mass average molecular weight of the vinyl polymer (a), a value measured in terms of standard polystyrene by gel permeation chromatography (GPC) is adopted. The measurement device and measurement conditions are basically based on the following condition 1 and are allowed to be set to condition 2 depending on the solubility of the sample. However, depending on the polymer type, an appropriate carrier (eluent) and a column suitable for it may be selected and used. For other matters, refer to JISK7252-1-4: 2008. In addition, it is assumed that the hardly soluble polymer compound is measured at a soluble concentration under the following conditions.
(Condition 1)
Column: TOSOHTSKgelSuperHZM-H,
TOSOHTSKgelSuperHZ4000,
TOSOHTSKgelSuperHZ2000
Carrier using tetrahydrofuran-connected column: 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: TosohtskegelSuperAWM-H Two carriers: 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

<Transdermal absorbable drug (b)>
The drug that can be added in the present invention is not particularly limited. For example, a general anesthetic, a sleeping agent, an analgesic, an anti-inflammatory analgesic, a steroid hormone agent, a stimulant / wakeful agent, a neuropsychiatric agent, a local anesthetic, Skeletal muscle relaxant, autonomic agent, antiallergic agent, antihistamine, cardiotonic agent, arrhythmia agent, diuretic, antihypertensive agent, vasoconstrictor, vasodilator, calcium antagonist, antibacterial agent, for parasitic skin diseases Agents, emollients, antibiotics, antidotes, antitussives, antitussives, hypnotics, psychoactive agents, asthma agents, hormone secretagogues, antiulcer agents, anticancer agents, vitamins, skin whitening effects, etc. Etc.

Further, when the use of the skin patch of the present invention is a topical patch, examples of the drug contained in this patch include indomethacin, ketoprofen, flurbiprofen, loxoprofen, loxoprofen sodium, piroxicam, meloxicam, Anti-inflammatory analgesics such as ketorolac, felbinac, diclofenac, diclofenac sodium and the like. Although content of a chemical | medical agent is not specifically limited, Usually, it may be about 0.1-20 mass% with respect to the whole adhesion layer. Any drug for wound treatment, local administration, systemic administration, etc. may be added. Specifically, anti-inflammatory analgesics, steroidal anti-inflammatory agents, vasodilators, antihypertensive diuretics, anesthetics, antihistamines, antitumor agents, antihypertensive / arrhythmic agents, antidepressants / anti-anxiety agents, local anesthetics, Hormonal agents, asthma / nasal allergy treatment agents, anticoagulants, antispasmodic agents, fat-soluble vitamins and the like.
Although the compounding quantity of a chemical | medical agent changes with the kind of chemical | medical agent and the intended purpose of a patch, it is normally used in the range of 0.1 mass%-30 mass% with respect to the total mass of the adhesive for skin patches.

<Tackifier>
The adhesive for skin application of the present invention can further contain a tackifier. Examples of the tackifier include rosin, hydrogenated rosin, rosin ester, terpene resin, modified terpene resin, hydrogenated terpene resin, terpene phenol resin, petroleum resin, coumarone / indene resin, phenol resin, xylene resin, alicyclic Saturated hydrocarbon resin etc. are mentioned.
When these tackifiers are blended, the tack, adhesive and holding power can be easily adjusted. Moreover, these can also be used 1 type or in combination of 2 or more types. Although the compounding quantity of a tackifier changes with the kinds, polarity, etc., it is normally used in 1 mass%-50 mass% with respect to the total mass of the adhesive for skin sticking.

<Transdermal absorption enhancer>
In the present invention, in order to improve the solubility and diffusibility of the drug in the pressure-sensitive adhesive layer, a percutaneous absorption enhancer can be further added.
Specific examples of transdermal absorption enhancers include silicones such as dimethylpolysiloxane, animal and vegetable oils such as olive oil, carboxylic acids such as lactic acid, hydrocarbons such as liquid paraffin and wax, lauric acid, myristic acid, and olein. Higher fatty acids such as acids, higher alcohols such as hexyldecanol, octyldodecanol, isostearyl alcohol, monohydric alcohol fatty acid esters such as isopropyl myristate, hexyl laurate, octyldodecyl myristate, butyl stearate, decyl oleate, 2 -Hexyldecanol, 2-octyldecanol, alcohols such as glycerin, polyoxyethylene nonylphenyl ether, fatty acid glycerin ester, fatty acid polyethylene glycol, polyglycerin fatty acid ester, sucrose fat Nonionic surfactants such as esters, polybutenes, polyisoprene, polyacrylic acid, liquid resin such as polymethacrylic acid, retinol, retinol palmitate, tocopherol, include oily vitamins acetate tocopherol and the like.
When these transdermal absorption promoters are blended, the viscosity of the adhesive layer for skin application can be adjusted. In particular, when a highly hydrophobic compound such as isopropyl myristate is used in combination with a polyhydric alcohol such as glycerin, there is an effect of promoting percutaneous absorption of the drug. The blending amount of the transdermal absorption enhancer varies depending on the type and polarity, the type of adhesive, the polarity and molecular weight, and is usually 0.5% by mass to 50% by mass with respect to the total mass of the adhesive for skin application. It is used in the range.

  Furthermore, the adhesive for skin application of the present invention may further include additives such as thickeners, antioxidants, moisturizers, pH adjusters and the like as appropriate components as long as the purpose is not impaired. In particular, it is preferable to use a moisturizing agent in combination when the skin adhesive is used for an application that directly contacts the skin.

The skin patch of the present invention can be obtained by directly or indirectly laminating a pressure-sensitive adhesive layer containing a vinyl polymer (a) and a transdermally absorbable drug (b) on a sheet-like substrate.
For example, on a sheet-like substrate, a pressure sensitive adhesive coating solution containing a vinyl polymer (a) and a transdermally absorbable drug (b) and a liquid medium is applied and dried. A skin patch with a release sheet member can be obtained by forming an adhesive layer and laminating a release sheet-like member (also referred to as a liner) on the adhesive layer. Alternatively, a skin with a release sheet member is formed by applying and drying an adhesive coating liquid on the release sheet member to form an adhesive layer, and laminating a sheet-like substrate on the adhesive layer. An adhesive patch can be obtained.

  As the sheet-like substrate used in the present invention, a flexible substrate 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 / knitted / nonwoven fabric made of polyester, polyolefin, cellulose ester, polyurethane, polyamide, or the like; or paper can be used. The thickness of these supports is usually 50 μm to 300 μm, preferably 70 μm to 200 μm in the case of a substrate although it depends on the type of patch.

  Among the sheet-like base materials, those having a coarse and porous structure such as a non-woven fabric may be dissolved in the liquid medium, and the dissolved product may fall out. The manufacturing method of laminating the pressure-sensitive adhesive layer formed by applying and drying the pressure-sensitive adhesive coating solution on another substrate in advance is preferable.

  It does not restrict | limit especially as a sheet | seat member for peeling, A well-known peeling film can be used. For example, films such as polyester, polyvinyl chloride, polyvinylidene chloride, polyethylene terephthalate, etc. that have been subjected to release treatment by applying silicone resin, fluororesin, etc. to the contact surface with the adhesive layer, fine paper, glassine paper A laminated film of polyolefin such as high-quality paper or glassine paper and polyolefin is used. The thickness of the release film is usually 10 to 200 μm, preferably 25 to 100 μm.

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

  The following examples further illustrate the present invention, but the following examples do not limit the scope of the present invention in any way. In the examples, “parts” and “%” represent “parts by mass” and “mass%”, respectively, and Tg represents a glass transition temperature.

<Measuring method of glass transition temperature>
The measurement of the glass transition temperature by DSC (differential scanning calorimeter) can be performed as follows. The solution of the vinyl polymer (a) is dried and about 2 mg of the obtained resin is weighed on an aluminum pan, the test container is set on a DSC measurement holder, and obtained at a temperature rising condition of 10 ° C./min. Read the endothermic peak of the chart. The peak temperature at this time is defined as the glass transition temperature of the present invention.

<Synthesis of various betaine monomers>
N-methacryloyloxyethyl-N, N-dimethylammoniumbutyl-α-sulfobetaine and N-acrylamidopropyl-N, N-dimethylammoniumpropyl-α-sulfobetaine used for the synthesis of vinyl polymer (a) are , Synthesized with reference to Patent No. 5690645. Similarly, N-methacryloyloxyethyl-N, N-dimethylammoniummethyl-α-carbobetaine is disclosed in US Pat. No. 3,873,315, 1-vinyl-3- (3-sulfopropyl) imidazolium inner salt and 2-vinyl-1- ( The 3-sulfopropyl) pyridinium inner salt was synthesized with reference to Patent 3584998.

[Production Example 1]
<Preparation of vinyl polymer (a)>
In a reaction vessel equipped with a stirrer, a thermometer, a dropping funnel, and a refluxing vessel, 60 parts of ethyl acetate and 60 parts of ethanol were charged, the internal temperature was raised to 75 ° C., and the atmosphere was sufficiently replaced with nitrogen. 0.4 parts of 2,2′-azodiisobutyronitrile prepared separately and 15 parts of N-methacryloyloxyethyl-N, N-dimethylammoniumbutyl-α-sulfobetaine as monomer (A1) (8.0 mol%), 50 parts (44.9 mol%) of normal octyl acrylate as monomer (B), 30 parts (38.8 mol%) of butyl acrylate, 5 parts (8.3 mol%) of methyl methacrylate 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 product was cooled and taken out. Thereafter, the solvent was completely volatilized in an oven to obtain a vinyl polymer (a). When Tg of the obtained vinyl polymer (a) was measured by DSC, it was 110,000 when the mass average molecular weight was measured by -44.8 ° C. and GPC.

[Production Examples 2 to 21], [Comparative Production Examples 1 to 7]
A vinyl polymer (a) was synthesized in the same manner as in Production Example 1 with the composition shown in Table 1.

The symbols in the table are as follows.
DMBS: N-methacryloyloxyethyl-N, N-dimethylammoniumbutyl-α-sulfobetaine DMPS: N-acrylamidopropyl-N, N-dimethylammoniumpropyl-α-sulfobetaine DMMC: N-methacryloyloxyethyl-N, N -Dimethylammonium methyl-α-carbobetaine VSPI: 1-vinyl-3- (3-sulfopropyl) imidazolium inner salt VSPB: 2-vinyl-1- (3-sulfopropyl) pyridinium inner salt OA: normal octyl acrylate BA : Butyl acrylate MMA: methyl methacrylate HEA: 2-hydroxyethyl acrylate AA: acrylic acid MEA: 2-methoxyethyl acrylate AIBN: 2,2′-azodiisobutyronitrile

[Production Example 22]
In a reaction vessel equipped with a stirrer, a thermometer, a dropping funnel, and a refluxing vessel, 60 parts of ethyl acetate and 60 parts of ethanol were charged, the internal temperature was raised to 75 ° C., and the atmosphere was sufficiently replaced with nitrogen. 0.42 parts of 2,2′-azodiisobutyronitrile prepared separately, 15 parts (50 mol%) of 2- (dimethylamino) ethyl methacrylate as monomer (A4), monomer ( B) 75 parts of butyl acrylate, 5 parts (40 mol%) of methyl methacrylate, and 5 parts (10 mol%) of 2-methoxyethyl acrylate as the monomer (C2) were maintained at an internal temperature of 75 ° C. Then, dropwise addition was continued for 3 hours, and stirring was further continued for 2 hours to obtain a copolymer.
After confirming that the conversion rate exceeded 98% by solid content measurement, 21.4 parts of 1,4-butane sultone (amount corresponding to 1.5 times the monomer (A4)) was added, and stirring was further performed for 20 hours. Continued.
As shown in the following reaction formula, N-methacryloyloxyethyl-N, N-dimethylammonium butyl-α-sulfobetaine which is a kind of monomer (A1) is used by ring-opening reaction of 1,4-butane sultone. The same structure as that of Production Example 1 etc. can be provided in the side chain of the vinyl polymer.

  It was then cooled and removed and the ethyl acetate and ethanol were completely volatilized in the oven. The dried resin was thoroughly washed with methyl ethyl ketone to remove by-products and remaining raw materials. It was 120,000 when the Tg of the obtained resin was measured by DSC and the mass average molecular weight was measured by GPC at −35.0 ° C.

[Production Examples 23 to 27]
A vinyl polymer (a) was synthesized in the same manner as in Production Example 22 with the composition shown in Table 2.

The symbols in the table are as follows.
DM: N-methacryloyloxyethyl-N, N-dimethylamine VI: 1-vinylimidazole VP: 2-vinylpyridine

[Example], [Comparative Example]
(1) Adhesive strength The vinyl polymer synthesized in the production example and comparative production example was dissolved in ethyl acetate and ethanol mixed solvent (weight ratio 70:30) so that the solid content concentration would be 30%, and the vinyl polymer was dissolved therein. After adding 3 parts of loxoprofen sodium as a transdermally absorbable drug to 100 parts of the polymer-based solid content and dissolving it, it was coated on a polyethylene terephthalate film with an applicator so as to have a dry coating film of 30 μm, at 100 ° C. Dried for 2 minutes.
Next, another peeled polyethylene terephthalate film was laminated on the pressure-sensitive adhesive layer side to prepare a skin patch with a release sheet-like member (hereinafter referred to as a patch sheet).
The patch sheet was cut to a width of 25 mm and a length of 75 mm, and then the peeled polyethylene terephthalate film was removed and affixed to a bakelite plate at 23 ° C. and 65% RH. After pressure bonding with a roll according to JIS and allowing to stand for 20 minutes, the film was peeled in the direction of 180 ° at a speed of 300 mm / min in an environment of 23 ° C. and 65% RH, and a peeling force with a width of 25 mm was measured.
◯: 12N <adhesive strength Δ: 8N <adhesive strength ≦ 12N
×: Adhesive strength ≦ 8N

(2) Adhesive residue Using the same sample as the adhesive strength measured in (1) above, the tactile sensation of the adhesive was evaluated by the thumb test. After releasing the finger, whether or not the adhesive remained on the finger was visually evaluated.
◯: No glue transfer on finger x: No glue transfer on finger

(3) Drug solubility The vinyl polymers synthesized in the production examples and comparative production examples were dissolved in a mixed solvent of ethyl acetate and ethanol (weight ratio 70:30) so that the solid content concentration would be 30%, Loxoprofen sodium as a transdermally absorbable drug was added in a certain amount (3 parts, 5 parts, 7 parts, 9 parts, 13 parts, 17 parts, 21 parts) to 100 parts of the vinyl polymer solids and dissolved. Then, it was coated on a polyethylene terephthalate film with an applicator so as to have a dry coating film thickness of 30 μm, and dried at 100 ° C. for 2 minutes.
Next, another polyethylene terephthalate film that had been peeled was laminated on the pressure-sensitive adhesive layer side to prepare a patch.
After this patch was stored for 1 month in a constant temperature and humidity chamber at 25 ° C.-60%, the presence or absence of crystallization of the drug in the adhesive layer was visually observed and evaluated. The maximum drug addition amount in which crystals were not formed was defined as the maximum drug dissolution amount of the adhesive, and was judged according to the following criteria.
A: 17 parts ≦ maximum drug dissolution amount ○: 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 property The vinyl polymer synthesized in the production example and the comparative production example was dissolved in an ethyl acetate solvent so that the solid content concentration would be 30%, and 100 parts of the resin solid content was transdermally dissolved therein. Loxoprofen sodium as an absorptive drug is added in the amount corresponding to the maximum drug dissolution amount of the vinyl polymer obtained in (3), and 2 parts of lactic acid is added as a transdermal absorption enhancer and dissolved, and then the same as in (3) above. Then, a patch having a laminated structure composed of a polyethylene terephthalate / adhesive layer / peeled polyethylene terephthalate film was prepared, and cut into a circle having a diameter of 2 cm (= 3.14 cm ² ).
The back peeled skin of nude mice was set in a Franz diffusion cell, the polyethylene terephthalate film peel-treated from the above patch was peeled off from this skin, the exposed pressure-sensitive adhesive layer was stuck, and the skin permeability was examined.
A phosphate buffer solution (pH 7.2) was used as the receptor solution, 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 permeation rate of loxoprofen sodium was determined by dividing the amount of loxoprofen sodium in the receptor solution 24 hours later by the amount of loxoprofen sodium in the patch and multiplying by 100.
◯: 6 [%] ≦ skin permeability Δ: 3 [%] ≦ skin permeability <6 [%]
×: Skin permeability <3 [%]

As can be seen from Table 3, since the vinyl polymers used in Comparative Examples 1 and 3 did not have a betaine structure, the drug solubility was poor, the cohesive force was reduced, and adhesive residue was generated. In Comparative Example 2, since the vinyl polymer had a high acid value, the drug was adsorbed on the vinyl polymer, and the drug release property was lowered. In the vinyl polymer used in Comparative Example 4, the amount of betaine structure introduced was small, the drug solubility was lowered, the cohesive force was low, and adhesive residue was generated. Since the vinyl polymer used in Comparative Example 5 has a very large amount of betaine structure introduced, the interaction between the vinyl polymer and the drug occurred, and the drug release property decreased. In Comparative Example 6, since the Tg of the vinyl polymer was high, the wettability to the skin was lowered and the adhesive strength was lowered. In Comparative Example 7, since the molecular weight of the vinyl polymer was low, the cohesive force was reduced and adhesive residue was generated.
On the other hand, the vinyl polymer used in the examples had good results with a good balance in all physical properties.

Claims (7)

The total number of repeating structures represented by the following general formulas 1 to 3 includes 1 to 40 mol% in 100 mol% of all repeating structures, the glass transition temperature is −60 ° C. to −10 ° C., and the mass average molecular weight A pressure-sensitive adhesive for skin application comprising a vinyl polymer (a) having a 10000 to 10000000 and a transdermally absorbable drug (b).

(Where
R ₂ is an alkylene group having 1 to 6 carbon atoms,
R ₃ and R ₄ are each independently an alkyl group having 1 to 4 carbon atoms,
R ₅ represents an alkylene group having 1 to 4 carbon atoms, X represents an oxygen atom or —NH—,
Y is -COO ^- or -SO ₃ ^-,
R ₇ is a hydrogen atom or a methyl group,
R ₈ is an alkylene group having 1 to 6 carbon atoms or a hydroxyalkylene group having 1 to 6 carbon atoms,
4 of R _{10 to} R ₁₄ represent a hydrogen atom and an alkyl group having 1 to 6 carbon atoms, and one of R _{10 to} R ₁₄ represents a bonding position with the main chain of the vinyl polymer,
R ₁₅ represents an alkylene group having 1 to 6 carbon atoms or a hydroxyalkylene group having 1 to 6 carbon atoms,
* Represents the bonding position with the main chain of the vinyl polymer. ) The adhesive for skin application according to claim 1, wherein the vinyl polymer (a) is the following (a1) or (a2).
(A1) At least one of the monomers (A1) to (A3) represented by the following general formulas 4 to 6, and one ethylenically unsaturated group and an alkyl group having 1 to 12 carbon atoms in one molecule. It is a copolymer with the monomer (B) it has.
(A2) having at least one monomer (A4) to (A6) represented by the following general formulas 7 to 9 and one ethylenically unsaturated group and an alkyl group having 1 to 12 carbon atoms in one molecule Copolymer with monomer (B), cyclic sulfonic acid ester (D1), ω-halogenated alkylsulfonic acid metal salt (D2), cyclic carboxylic acid ester (D3) and ω-halogenated alkylcarboxylic acid metal It is a reaction product with one or more betaine agents (D) selected from the group consisting of salts (D4).

(Where
R ₁ is a hydrogen atom or a methyl group,
R ₂ is an alkylene group having 1 to 6 carbon atoms,
R ₃ and R ₄ are each independently an alkyl group having 1 to 4 carbon atoms,
R ₅ represents an alkylene group having 1 to 4 carbon atoms, X represents an oxygen atom or —NH—,
Y is -COO ^- or -SO ₃ ^-,
R ₆ is a hydrogen atom or a methyl group,
R ₇ is a hydrogen atom or a methyl group,
R ₈ is an alkylene group having 1 to 6 carbon atoms or a hydroxyalkylene group having 1 to 6 carbon atoms,
4 of R _{16 to} R ₂₀ represent a hydrogen atom and an alkyl group having 1 to 6 carbon atoms, and one of R _{16 to} R ₂₀ represents CH ₂ = C (R ₂₁ ),
R ₁₅ represents an alkylene group having 1 to 6 carbon atoms or a hydroxyalkylene group having 1 to 6 carbon atoms,
R ₂₁ represents a hydrogen atom or a methyl group,
** represents a reaction site with the betaine agent (D). ) Of the monomers (A1) to (A3), the monomer (B), and other monomers (C) used as needed, the total of 100 mol% of the monomers (A1) to (A3) The total is 1 to 40 mol%, the monomer (B) is 20 to 99 mol%, the other monomer (C) is 0 to 79 mol%, or
Monomers (A4) to (A6), monomers (B), and other monomers (C) used as needed, in a total of 100 mol%, monomers (A4) to (A6) The part which is reacting with the betaine agent (D) in the derived structure is 1 to 40 mol%, the monomer (B) is derived from 20 to 99 mol%, and the monomers (A4) to (A6). The adhesive for skin sticking of Claim 2 whose sum total of the part which is not reacting with a betaine agent (D) among structures, and another monomer (C) is 0-79 mol%.   The adhesive for skin application according to any one of claims 1 to 3, wherein the vinyl polymer (a) contained in 100% by mass of the adhesive for skin application is 20 to 99% by mass. .   The skin patch which has a sheet-like base material and the layer of the adhesive agent for skin patches of any one of Claims 1-4.   An adhesive coating liquid containing the adhesive for skin application according to any one of claims 1 to 4 and a liquid medium is applied to a sheet-like base material, the liquid medium is removed, and the sheet-like base material is applied. A method for producing a skin patch with a release sheet-like member, wherein an adhesive layer containing a transdermally absorbable drug is formed thereon, and a release sheet-like member is laminated on the adhesive layer.   An adhesive coating liquid comprising the adhesive for skin application according to any one of claims 1 to 4 and a liquid medium is applied to a peeling sheet-like member, the liquid medium is removed, and the peeling sheet A method for producing a skin patch with a release sheet-like member, wherein a pressure-sensitive adhesive layer containing a transdermally absorbable drug is formed on a shaped member, and a sheet-like substrate is laminated on the pressure-sensitive adhesive layer.