JP6551202B2 - Adhesive for skin application, transdermal absorbable adhesive, and transdermal absorbable adhesive sheet - Google Patents

Description

The present invention relates to an adhesive for skin application, and a transdermally absorbable adhesive using the adhesive for skin application,
The present invention also relates to a transdermally absorbable pressure-sensitive adhesive sheet using the transdermally absorbable adhesive.

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 are being 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.

Since such a transdermal absorbable adhesive sheet is used by attaching an adhesive layer containing a transdermally absorbable drug to the skin surface, the adhesiveness to the skin surface (adhesion), the follow-up to the skin surface Properties (flexibility), drug stability in the adhesive, drug release from the adhesive, skin irritation due to steaming and adhesive components during application, adhesive residue on the skin when the adhesive is peeled off Various characteristics such as skin irritation due to exfoliation are required.

In order to meet such demands, many design methods have been studied as adhesives for skin application.

For example, Patent Document 1 discloses a monomer containing a carboxyl group or a hydroxyl group,
A copolymer formed by copolymerizing (meth) acrylic acid ester as an essential component, a monomer having a nitrogen atom having no salt structure in the side chain, and (meth) acrylic acid ester as an essential component Disclosed is a transdermally absorbable preparation using a copolymer obtained by polymerization.
Patent Document 2 discloses a pressure-sensitive adhesive composition comprising a water-insoluble copolymer comprising N-vinyl-2-pyrrolidone as a constituent and a polymer comprising a monoalkyl ester of maleic anhydride as a constituent. Disclose.
Patent Document 3 discloses an acrylic gel material in which a crosslinked gel layer containing an acrylate polymer and a liquid component is formed on at least one surface of a support.
Patent Document 4 discloses a pressure-sensitive adhesive for skin application comprising an acrylic polymer and a paste-like component.
Patent Document 5 discloses an acrylic adhesive microsphere obtained by suspension polymerization of an acrylic monomer mixture containing a (meth) acrylate having a branched alkyl group having 14 to 22 carbon atoms and a polar monomer, and crosslinked. Disclosed is a pressure-sensitive adhesive for skin application comprising a water-absorbing polymer.
Patent Document 6 discloses an acrylic copolymer prepared by using, as an essential component, a (meth) acrylic acid alkyl ester monomer having an alkyl group having 4 to 12 carbon atoms and a highly polar vinyl monomer containing a hydroxyl group, and an adhesive. Disclosed is a strong adhesion re-peelable pressure-sensitive adhesive comprising an imparting agent and an isocyanate compound.
Patent Document 7 discloses a (meth) acrylic acid ester copolymer having a crosslinkable functional group,
Disclosed is a pressure-sensitive adhesive composition for skin application, comprising a long-chain isocyanate-based crosslinking agent having two or more isocyanate groups in a molecule added to a pressure-sensitive adhesive component containing a (meth) acrylic oligomer.

Next, Patent Document 8 discloses a pressure-sensitive adhesive composition for skin application containing a water-absorbing polyalkylene oxide-modified product and a thermoplastic resin as in the present invention, and shows excellent adhesion to the skin. It is done.

Furthermore, Patent Document 9 discloses an acrylic resin in which polyethylene oxide (hereinafter sometimes abbreviated as PEG) is incorporated in the main chain as in the present invention, but a description of the adhesive for skin application taken up in the present invention. There is no

Japanese Patent Laid-Open No. 2000-44904 JP-A-9-176604 JP-A-3-220120 Unexamined-Japanese-Patent No. 6-319793 JP, 2011-182847, A Unexamined-Japanese-Patent No. 11-269439 gazette Unexamined-Japanese-Patent No. 2006-213603 JP 2012-240937 A Patent Document 9 JP 2007-77292 A

Acrylic pressure-sensitive adhesives such as Patent Documents 1 to 7 are copolymerized with a monomer having a carboxyl group or a hydroxyl group in order to ensure the cohesive strength of the pressure-sensitive adhesive. As a result, there has been a problem in that the amount of drug released is reduced, or plasticization by various additives and drugs, and the reaction of a crosslinking agent added to supplement cohesive failure are hindered.
The water-absorbing polyalkylene oxide modified product disclosed in Patent Document 8 is a polyurethane obtained by reacting polyethylene oxide, a diol compound and a diisocyanate compound, and due to the high cohesive strength of the urethane bond, depending on the drug used, the drug release amount There has been a problem of causing a decrease in the number.
In view of the above circumstances, the present invention is based on adhesiveness (adhesiveness) to the skin surface, irritating skin due to stuffiness and adhesive components at the time of application, adhesive residue and exfoliation on the skin when the adhesive is peeled off An object of the present invention is to provide a pressure-sensitive adhesive for skin application that is excellent in skin irritation, drug stability in a pressure-sensitive adhesive, and drug release from the pressure-sensitive adhesive.

Generally, in order to increase the hydrophilicity of a polymer, a method of introducing a highly polar group such as a carboxyl group or a hydroxyl group, or introducing a bond having a high cohesive force such as a urethane bond, a urea bond, or an amide bond. Is known, but is not appropriate in terms of drug interaction.
Therefore, as a result of intensive studies to solve the above-mentioned problems, the present inventors incorporated hydrophilic polyethylene oxide into the main chain of the acrylic resin, thereby maintaining hydrophilicity while maintaining the inherent flexibility of the acrylic resin. The polymer which expressed was examined.
As a result, when a block copolymer having an acrylic polymer part (A1) and a polyethylene oxide part (A2) is formed, the block copolymer maintains good properties of an acrylic resin and has good drug solubility and chemicals. The present inventors have found that it is possible to develop release properties and further improve the workability during coating, and have reached the present invention.
That is, in the present invention, a block weight formed by combining an acrylic polymer portion (A1) and a polyethylene oxide portion (A2) via a structure of any of the following general formulas (I-1) to (I-3) The adhesive for skin sticking containing the united body (A).

Mass of polyethylene oxide part (A2) contained in the block polymer (A) /
[Total mass of acrylic polymer portion (A1) and polyethylene oxide portion (A2)] = 0.01 to 0.5 is preferable.
In addition, the block polymer (A) has a polyethylene oxide portion (A2), and has a mass average molecular weight of 5,000 to 100,000, and is a polymer azo having a portion represented by the following general formula (II) It is preferable that it is a block polymer which polymerizes an acryl-type monomer using a type | system | group polymerization initiator. In formula, m and n show an integer greater than or equal to 1.
The glass transition temperature of the block copolymer (A) is preferably −70 to 50 ° C.
It is preferable that the adhesive for skin application further contains a crosslinking agent.

The present invention relates to a transdermally absorbable pressure-sensitive adhesive containing a transdermally absorbable drug and the aforementioned adhesive for skin application.

The present invention also relates to a percutaneously absorbable pressure-sensitive adhesive sheet having a sheet-like support and a percutaneously absorbable pressure-sensitive adhesive layer formed of the above-mentioned percutaneously absorbable pressure-sensitive adhesive.

By using the block polymer (A) in which the acrylic polymer part (A1) and the polyethylene oxide part (A2) are bonded with a specific structure, the adhesion (adhesion) to the skin surface and stuffiness at the time of application Excellent skin non-irritating property due to skin and adhesive components, non-stimulating skin due to adhesive residue on skin and exfoliation when peeling adhesive, drug stability in adhesive, and drug release from adhesive It was possible to provide a pressure sensitive adhesive for skin application.

<Block polymer (A)>
The block polymer (A) in the present invention has an acrylic polymer portion (A1) and a polyethylene oxide portion (A2).
The polyethylene oxide portion of the block polymer (A) is located in the main chain of the conventional acrylic resin. Therefore, the solubility with respect to water improves, As a result, when it applies to the adhesive for skin sticking, the chemical | medical agent solubility in an adhesive and the chemical | medical agent release | release property from an adhesive improve. Furthermore, since the polyethylene oxide part is arranged in the main chain instead of the side chain of the acrylic resin, the decrease in the glass transition temperature can be suppressed, and when cutting the coating film after applying the adhesive for skin application Moreover, the workability that the adhesive layer hardly adheres to the blade is also improved.
Moreover, a crosslinked coating film can also be formed by forming the acrylic polymer part (A1) in the block polymer (A) using a monomer having a functional group capable of reacting with a crosslinking agent described later. By forming a crosslinked coating film, it is possible to suppress skin irritation due to adhesive residue on the skin and exfoliation when exfoliating the pressure-sensitive adhesive. Examples of the functional group that the acrylic polymer portion (A1) may have include a carboxyl group, a hydroxyl group, an epoxy group, an amino group, and an isocyanate group.

Due to the balance between the highly hydrophilic polyethylene oxide part (A2) constituting the block polymer (A) and the hydrophobic acrylic polymer part (A1), drug stability in the adhesive and drug release from the adhesive Sex and the like can be effectively controlled. The block polymer (A) has a mass of polyethylene oxide part (A2) / [total mass of acrylic polymer part (A1) and polyethylene oxide part (A2)] = 0.01 to 0.5. Preferably
It is more preferable that (A2) / [(A1) + (A2)] = 0.1 to 0.4. That is,
In the total mass of 100% by mass of the acrylic polymer part (A1) and the polyethylene oxide part (A2), the polyethylene oxide part (A2) is preferably 1 to 50% by mass, and 10 to 40% by mass. Is more preferred.

In the present invention, the block polymer (A) has an acrylic polymer part (A1) and a polyethylene oxide part (A2) via any one of the following formulas (I-1) to (I-3). There is no particular limitation on the synthesis method as long as they are bonded.

The block polymer (A) formed by the above formula (I-1) will be described.
When an acrylic polymer is synthesized using 4,4′-azobis (4-cyanovaleric acid) (for example, a commercial product “V-501” manufactured by Wako Pure Chemical Industries, Ltd.) as a radical polymerization initiator,
An acrylic resin having a carboxyl group at the end is obtained. To this, polyethylene glycol is added as a raw material constituting the polyethylene oxide portion, and an esterification reaction is performed, whereby the acrylic polymer portion (A1) and the polyethylene oxide portion (A2) are represented by the formula (I).
(A) can be obtained as a block polymer formed by bonding according to -1).

Alternatively, a site represented by the following general formula (II) having a polyethylene oxide moiety (A2) as a radical polymerization initiator when synthesizing an acrylic polymer and having a mass average molecular weight of 5,000 to 100,000. It can obtain by polymerizing an acryl-type monomer, using the polymer azo-type polymerization initiator which has these. The polymer azo polymerization initiator has a structure in which a polymer segment and an azo group (—N═N—) are repeatedly bonded. In this embodiment, the polymer azo initiator includes a PEG block as the polymer segment. The block polymer (A) can be easily synthesized by using

(In the formula, m and n each represent an integer of 1 or more.)

The mass average molecular weight of the polymer azo polymerization initiator is about 5000 to 100,000, preferably 1
It may be 10,000 to 50,000. The molecular weight of the PEG moiety of the initiator may be about 800 to 10,000, preferably about 1000 to 8000.
The high molecular weight azo polymerization initiator comprises a polyethylene oxide moiety (A2) and an azo group (-N).
= N-) containing repeating moieties.
Since the polymer azo polymerization initiator has a polyethylene oxide part (A2),
It is soluble in water, alcohol, and organic solvent, and the block polymer (A) can be synthesized by solution polymerization, emulsion polymerization, and dispersion polymerization. In addition, since there is a polymerization initiation moiety (radical generation moiety: -N = N-) in the molecular chain skeleton, it is not necessary to separately use a polymerization initiator, and furthermore, compared to the terminal reactive macromonomer It has the features of high reactivity and stability.
The polymer azo polymerization initiator is: C (CH ₃ ) CN— (CH ₂ ) ₂ —COO— (CH ₂ CH
A radical represented by ₂ O) _m —CO— (CH ₂ ) ₂ —C (CH ₃ ) CN · is generated, and an acrylic monomer described later is polymerized. And the main chain which the acrylic polymer part (A1) formed from an acrylic monomer and the part derived from the said radical couple | bonded is formed, and a block polymer (A) is formed. The polyethylene oxide part (A2) is derived from a part of the radical.
As a specific example of the polymeric azo polymerization initiator, a polymeric azo initiator VPE020 manufactured by Wako Pure Chemical Industries, Ltd.
1 (the molecular weight of the part of (CH ₂ CH ₂ O) _m is about 2000, and n is about 6).

In the present invention, 2,2′-azobisisobutyronitrile, 2,2′-azobis (2-methylbutyronitrile), 1,1′- is used in combination with the above-mentioned polymer azo polymerization initiator. Azobis (
Cyclohexane 1-carbonitrile), 2,2'-azobis (2,4-dimethylvaleronitrile), 2,2'-azobis (2,4-dimethyl-4-methoxyvaleronitrile), dimethyl 2,2'-azobis (2-methylpropionate), 4,4′-azobis (4-cyanovaleric acid), 2,2′-azobis (2-hydroxymethylpropionitrile),
Azo initiators such as 2,2'-azobis [2- (2-imidazolin-2-yl) propane], benzoyl peroxide, tert-butyl perbenzoate, cumene hydroperoxide, diisopropyl peroxydicarbonate, -N-propyl peroxydicarbonate or di (2-ethoxyethyl) peroxydicarbonate, tert-butylperoxy-2-ethylhexanoate, tert-butylperoxy neodecanoate or tert
Organic peroxide initiators such as butyl peroxybivalate, (3,5,5-trimethylhexanoyl) peroxide, dipropionyl peroxide, and diacetyl peroxide can be used. By using these initiators in combination, PEG can be incorporated into the acrylic polymer portion (A1) with high initiation efficiency and efficiency, and residual monomers can be reduced.

Moreover, at the time of synthesis, a chain transfer agent such as mercaptans such as lauryl mercaptan and n-dodecyl mercaptan, α-methylstyrene dimer and limonene is used depending on the application,
The molecular weight and terminal structure may be controlled.

Next, a block polymer (A) in which the acrylic polymer portion (A1) and the polyethylene oxide portion (A2) are bonded to each other via the above formula (I-2) will be described.
2,2′-Azobis [N- (2-hydroxyethyl) -2-yl as radical polymerization initiator
Methylpropanamide] (For example, a commercial product “VA-086” of Wako Pure Chemical Industries, Ltd., etc.)
When an acrylic polymer is synthesized using, an acrylic resin having a hydroxyl group at the terminal is obtained. The acrylic polymer part (A1) and the polyethylene oxide part (A2) are bonded to each other by adding polyethylene glycol as a raw material constituting the polyethylene oxide part and performing a urethanization reaction using a bifunctional isocyanate compound. A block polymer (A) can be obtained.

Next, the block polymer (A) formed by bonding according to the above formula (I-3) will be described.
2,2'-azobis [N- (2-carboxyethyl) -2- as radical polymerization initiator
Methylpropionamidine] tetrahydrate (for example, a commercial product “VA-” of Wako Pure Chemical Industries, Ltd.
057 "etc.) to synthesize an acrylic polymer, an acrylic resin having a carboxyl group at the terminal is obtained. To this, polyethylene glycol is added as a raw material constituting the polyethylene oxide part, and an esterification reaction is performed, whereby an acrylic polymer part (A
A block polymer (A) can be obtained in which 1) and a polyethylene oxide moiety (A2) are bonded by formula (I-3).

  The glass transition temperature of the block copolymer (A) will be described. The glass transition temperature of the block copolymer (A) is preferably −70 to 50 ° C., more preferably −60 to 40 ° C. By setting the glass transition temperature to -70 to 50 ° C., the adhesion to the skin surface can be improved, and further, good embeddability to the base material becomes possible, and the processability as an adhesive for skin sticking is improved. Can.

The glass transition temperature can be adjusted by appropriately preparing the type of monomer constituting the acrylic polymer portion (A1). For example, by increasing the ratio of polyalkoxyalkyl (meth) acrylates such as 2-methoxyethyl (meth) acrylate,
Glass transition temperature is -50 ° C because it can impart flexibility specific to side-chain ether bond
Can be prepared in a range close to.

<Monomer>
Next, an acrylic monomer which is a raw material of the acrylic polymer portion (A1) of the block polymer (A) will be described. In the present invention, the acrylic monomer means both an acrylic monomer and a methacrylic monomer.
Examples of the monomer that can be used include a monomer that does not have a functional group that serves as a crosslinking point, and a monomer that includes a functional group that serves as a crosslinking point.
As a monomer which does not have a functional group which becomes a crosslinking point, for example,
An alkyl acrylate having 1 to 20 carbon atoms in the alkyl group;
An alkyl methacrylate having 1 to 20 carbon atoms in the alkyl group;
Methoxymethyl (meth) acrylate, 2-methoxyethyl (meth) acrylate, ethoxymethyl (meth) acrylate, ethoxyethyl (meth) acrylate, propoxymethyl (meth) acrylate, propoxyethyl (meth) acrylate, 2- (2-methoxy Ethoxy) ethyl (meth) acrylate, 2- [2- (2-methoxyethoxy) ethoxy] ethyl (meth) acrylate, 2- (2-ethoxyethoxy) ethyl (meth) acrylate, 2
-An alkoxy group-containing monomer such as-[2- (2-ethoxyethoxy) ethoxy] ethyl (meth) acrylate or tetrahydrofurfuryl (meth) acrylate;
Vinyl group-containing monomers such as (meth) acrylonitrile, vinyl acetate, butadiene, isoprene, styrene;
N-vinylpyrrolidone, N-vinyl-ε-caprolactam, 1-vinylimidazole,
Amide group-containing monomers such as N-isopropylacrylamide and N, N-dimethylacrylamide;
Etc.
These may be used alone or in combination of two or more.

As the monomer having a functional group that becomes a crosslinking point, a carboxyl group-containing monomer, a hydroxyl group-containing monomer, an epoxy group-containing monomer, an amino group-containing monomer, an isocyanate group-containing monomer, and the like can be used.
For example, a copolymer having a carboxyl group introduced therein can be crosslinked with an epoxy compound, an aziridine compound, a carbodiimide compound, a metal chelate compound, or an N-hydroxyethylacrylamide compound. A copolymer having a hydroxyl group introduced can be crosslinked with an isocyanate compound, a carbodiimide compound, or the like. A copolymer having an amino group introduced therein can be crosslinked with an epoxy compound. The copolymer into which the isocyanate group has been introduced can be crosslinked by a hydroxyl group-containing compound. The amount of the monomer having a functional group serving as a crosslinking point is preferably 10% by mass or less in a total of 100% by mass of all monomers. By using it at 10 mass% or less, when a crosslinking agent is used together, a coating film having an appropriate crosslinking density can be obtained.

The carboxyl group-containing monomer is not particularly limited as long as it has a carboxyl group in its structure. For example, (meth) acrylic acid, 2-carboxyethyl (meth) acrylate, or alkylene such as ethylene oxide or propylene oxide Alkylene oxide addition type succinic acid having a carboxyl group at the terminal end of repeated addition of oxide (
Meta) acrylate, maleic acid and the like can be mentioned.

The hydroxyl group-containing monomer is not particularly limited as long as it has a hydroxyl group in the structure, and for example, 2-hydroxyethyl (meth) acrylate, 1-hydroxypropyl (meth) acrylate, (meth) acrylate 2-hydroxypropyl, (meth) acrylic acid 3-
Hydroxypropyl, 1-hydroxybutyl (meth) acrylate, glycerol monofunctional (meth) acrylate, polylactone system having hydroxyl group at the end by ring-opening addition of lactone ring (
(Meth) acrylic acid ester, alkylene oxide addition system (meth) acrylic acid ester having a hydroxyl group at the terminal after repeated addition of alkylene oxide such as ethylene oxide and propylene oxide, glucose ring system (meth) acrylic acid ester, 4-hydroxystyrene, N-hydroxyethyl (meth) acrylamides are mentioned.

The epoxy group-containing monomer is not particularly limited as long as it has an epoxy group in its structure, and examples thereof include glycidyl (meth) acrylate and 3,4-epoxycyclohexylmethyl (meth) acrylate. .

The amino group-containing monomer is not particularly limited as long as it has an amino group in the structure thereof. For example, monomethylaminoethyl (meth) acrylate, monoethylaminoethyl (meth) acrylate, (meth) acrylic Examples thereof include monomethylaminopropyl acid and monoethylaminopropyl (meth) acrylate.

In the present invention, it is preferable to copolymerize a monomer having a functional group to be a crosslinking point from the viewpoint of suppressing the adhesive residue of the block polymer (A) on the skin. Thereby, a functional group capable of reacting with a crosslinking agent described later can be introduced, and a crosslinked coating film can be formed.

Furthermore, in the present invention, a polyfunctional monomer may be further copolymerized to partially introduce a cross-linked structure into the block polymer (A).
In the case of crosslinking while copolymerizing, as the crosslinking ratio increases, the greater the amount of polyfunctional monomer used, the higher the degree of crosslinking, and the possibility of gelation during the reaction also increases. Therefore, the amount of the polyfunctional monomer is preferably in the range of 0.01 to 10% by mass, and more preferably 0.1 to 5% by mass in 100% by mass of all monomers. When the block polymer (A) is crosslinked by a polyfunctional monomer,
Since it becomes hardly water-soluble, the problem of peeling off from the substrate can be reduced as in the case of using a crosslinking agent.

The polyfunctional monomer is not particularly limited as long as it has two or more ethylenically unsaturated groups in its structure. For example, ethylene glycol di (meth) acrylate, diethylene glycol di (meth) acrylate, polyethylene oxide di (Meth) Acrylate, Propylene Glycol Polyethylene Oxide Di (Meth) Acrylate, Dipropylene Glycol Polyethylene Oxide Di (Meth) Acrylate, Polypropylene Glycol Di (Meth) Acrylate, 1,6-Hexanediol Di (Meth) Acrylate, Glycerin Di (Meth) acrylate, dimethylol tricyclodecane di (meth) acrylate, tripropylene glycol di (meth) acrylate, or neopentyl glycol modified trimethylolpropane di (meth) Difunctional (meth) acrylates such as acrylate;
Trifunctional or more polyfunctional compounds such as trimethylolpropane tri (meth) acrylate, pentaerythritol tri (meth) acrylate, pentaerythritol tetra (meth) acrylate, dipentaerythritol hexa (meth) acrylate, or dipentaerythritol penta (meth) acrylate Functional (meth) acrylates; or
(Meth) acrylic acid adduct of 1,6-hexanediol diglycidyl ether, (meth) acrylic acid adduct of neopentyl glycol diglycidyl ether, (meth) acrylic acid adduct of glycerol diglycidyl ether, bisphenol A diglycidyl Examples include (meth) acrylic acid adducts of ether, (meth) acrylic acid adducts of bisphenol F type epoxy, and (meth) acrylic acid adducts of novolac type epoxy. Moreover, what modified | denatured the (meth) acrylate mentioned above further with (poly) alkylene oxide, (poly) caprolactone, etc. can also be used.

In the present invention, the block polymer (A) can be synthesized by a known method. For example, solution polymerization, bulk polymerization, emulsion polymerization, dispersion (precipitation) polymerization and the like are preferable, and solution polymerization and dispersion (precipitation) polymerization are more preferable.

As mentioned above, the block polymer (A) is the mass of the polyethylene oxide moiety (A2) /
[Mass total of acrylic polymer portion (A1) and polyethylene oxide portion (A2)] = 0.01 to 0.5 is preferable, (A2) / [(A1) + (A2)] = 0
. More preferably, it is 1 to 0.4.
The method for obtaining the mass of the polyethylene oxide portion (A2) / [total mass of the acrylic polymer portion (A1) and the polyethylene oxide portion (A2)] in the present invention will be described.
Strictly speaking, when calculating the mass of the polyethylene oxide part (A2), it should be determined by calculating only the weight of the polyethylene oxide in the azo polymerization initiator. In the present invention, the polyethylene oxide part (A2) is calculated. The mass of the polymer azo polymerization initiator having the above is applied as it is. Further, the mass of the acrylic polymer portion (A1) is the total amount of acrylic monomers subjected to polymerization.
That is, when it synthesize | combined using 90 mass parts of monomers, and 10 mass parts of polymeric azo polymerization initiators which have a polyethylene oxide part (A2), a polyethylene oxide part (A2)
) / [Total mass of acrylic polymer portion (A1) and polyethylene oxide portion (A2)] is 0.1.

The mass average molecular weight of the block polymer (A) is preferably 100,000 to 2,000,000 from the viewpoint of handling properties and application to a sheet-like support. When the mass average molecular weight is 100,000 or more, a high cohesive force due to the entanglement of the polymer can be imparted, and an adhesive residue is hardly generated when peeling off after being attached to the skin.
The mass average molecular weight of the block polymer (A) can be prepared, for example, by appropriately changing the ratio of the total number of moles of the acrylic monomer to the number of moles of the azo group contained in the high molecular weight azo polymerization initiator. It becomes possible. For example, if the ratio of the total number of moles of acrylic monomers to the number of moles of azo groups contained in the polymer azo polymerization initiator is 200, a 200-mer acrylic polymer is incorporated between PEG chains. Become.

<Crosslinking agent>
Next, the crosslinking agent which can be used in the present invention will be described. Examples of the crosslinking agent that can be used in the present invention include those having at least one functional group selected from an epoxy group, an isocyanate group, and an aziridinyl group, a metal chelate compound, a carbodiimide group-containing compound, and the like. These crosslinking agents can be used for the purpose of increasing the modulus of elasticity and resistance of the coating film, and can be used to adjust the adhesion.

[Crosslinking agent having an epoxy group]
The crosslinking agent having an epoxy group used in the present invention is not particularly limited as long as it has two or more epoxy groups in one molecule.
As a crosslinking agent having a bifunctional epoxy group, for example, ethylene glycol diglycidyl ether, polyethylene oxide diglycidyl ether, propylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, tetramethylene glycol diglycidyl ether, polytetramethylene glycol diglycidyl Ether, 1
Aliphatic epoxy compounds such as 6, 6-hexanediol diglycidyl ether, neopentyl glycol diglycidyl ether, polybutadiene diglycidyl ether, bisphenol A epoxy resin, bisphenol F epoxy resin, bisphenol S epoxy resin, biphenol epoxy resin Dihydroxy benzophenone diglycidyl ether,
Resorcinol diglycidyl ether, hydroquinone diglycidyl ether, dihydroxyanthracene type epoxy resin, bisphenol fluoro orange glycidyl ether, N,
Examples thereof include aromatic epoxy compounds such as N-diglycidyl aniline, hydrogenated products of the above-mentioned aromatic epoxy compounds, and alicyclic epoxy compounds such as hexahydrophthalic acid diglycidyl ester.
Examples of the crosslinking agent having three or more epoxy groups include triglycidyl isocyanurate, trisphenol type epoxy compound, tetrakisphenol type epoxy compound, phenol novolac type epoxy compound and the like.

[Crosslinking agent having isocyanate group]
The crosslinking agent having an isocyanate group used in the present invention is not particularly limited as long as it is a compound having two or more isocyanate groups in one molecule.
Examples of the bifunctional isocyanate compound include 2,2′-diphenylmethane diisocyanate, 2,4′-diphenylmethane diisocyanate, 4,4′-diphenylmethane diisocyanate, 2,4-tolylene diisocyanate, 2,6-tolylene diisocyanate, hexa Methylene diisocyanate, isophorone diisocyanate, etc. can be mentioned.
As the trifunctional isocyanate compound, trimethylolpropane adduct of diisocyanate described above, a biuret reacted with water, 3 having an isocyanurate ring
There is a mer.
Moreover, the isocyanate group in the crosslinking agent which has an isocyanate group may be blocked, and does not need to be blocked.
The blocked isocyanate crosslinking agent used in the present invention may be a blocked isocyanate compound in which the isocyanate group in the isocyanate compound is blocked with ε-caprolactam, MEK (methyl ethyl ketone) oxime, cyclohexanone oxime, pyrazole, phenol or the like. There is no particular limitation.

[Crosslinking agent having aziridinyl group]
The aziridine compound used in the present invention is not particularly limited as long as it is a compound having two or more aziridine groups in one molecule. As an aziridine compound,
For example, 2,2′-bishydroxymethylbutanol tris [3- (1-aziridinyl)
Propionate], 4,4-bis (ethyleneiminocarbonylamino) diphenylmethane, and the like.

[Metal chelate compound]
Examples of the metal chelate compound used in the present invention include organic chelate compounds such as aluminum chelate compounds, aluminum alkoxide compounds and aluminum acylate compounds, titanium chelate compounds, organic alkoxide compounds such as titanium alkoxide compounds and titanium acylate compounds, and zirconium And organic zirconium compounds such as chelate compounds, zirconium alkoxide compounds, and zirconium acylate compounds.

[Carbodiimide group-containing compound]
As the carbodiimide group-containing compound used in the present invention, carbodilite series of Nisshinbo Co., Ltd. can be used, and water-based types such as V-02, V-04 and V-06, V-01 and V-03. And oily types such as V-05, V-07, and V-09.

[Β-Hydroxyalkylamide group-containing compound]
In the present invention, a β-hydroxyalkylamide group-containing compound can also be used as a crosslinking agent.
The β-hydroxyalkylamide group-containing compound is not particularly limited as long as it is a compound containing a β-hydroxyalkylamide group in the molecule. Examples of the β-hydroxyalkylamide group-containing compound include various compounds including N, N, N ′, N′-tetrakis (hydroxyethyl) adipamide (Primid XL-552 manufactured by Emschemy).

In the present invention, the crosslinking agent may be used alone or in combination. The amount of the crosslinking agent to be used may be determined in consideration of the type and the number of moles of functional groups contained in the block polymer (A), and is not particularly limited, but usually the block polymer (A) 100
It is used in the range of 0.1 parts by mass to 10 parts by mass with respect to parts by mass. By blending in a range smaller than the number of moles of the functional group contained in the block polymer (A), the concern that the unreacted crosslinking agent is percutaneously absorbed into the body can be eliminated. Within this range, the elastic modulus and adhesive strength of the pressure-sensitive adhesive composition can be adjusted.

<Tackifier>
As tackifiers that can be added in the present invention, for example, rosin, hydrogenated rosin, rosin ester, terpene resin, modified terpene resin, hydrogenated terpene resin, terpene phenol resin, petroleum resin, coumarone-indene resin, phenol Examples thereof include resins, xylene resins, and alicyclic saturated hydrocarbon resins.
When these tackifiers are blended, adjustment of tack, adhesive and holding power becomes easy. These may be used alone or in combination of two or more. The compounding amount of the tackifier varies depending on the type and polarity, but is usually 1 with respect to the total weight of the adhesive for skin application.
It is used in the range of wt% to 50 wt%.

The pressure-sensitive adhesive for sticking to the skin according to the present invention can also be used to form a pressure-sensitive adhesive sheet for sticking to the skin without containing a percutaneously absorbable drug as described in the next section. In such a case, the adhesive for skin application of the present invention can further contain a component such as glycerin in order to enhance the affinity with the skin.

[Transdermal absorbable adhesive]
The transdermally absorbable pressure-sensitive adhesive of the present invention includes the above-mentioned pressure-sensitive adhesive for skin application of the present invention and a transdermally absorbable drug.
<Dermal absorbable drug>
The drug that can be added in the present invention is not particularly limited, and any drug for wound treatment, topical administration, or systemic administration may be added. Specifically, anti-inflammatory analgesics, steroidal anti-inflammatory agents, vasodilators, antihypertensive diuretics, anesthetics, antihistamines, antineoplastic agents, antihypertensive / arrhythmic agents, antidepressive / anxiolytics, local anesthetics, Hormonal agents, asthma / nasal allergy therapeutic agents, anticoagulants, anticonvulsants, fat-soluble vitamins and the like.
The compounding amount of the drug varies depending on the type of drug and purpose of use of the patch, but it is usually used in the range of 0.1% by weight to 30% by weight with respect to the total weight of the adhesive for skin sticking.

<Dermal absorption enhancer>
In the present invention, in order to improve the solubility and diffusion 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, hydrocarbons such as liquid paraffin and wax, higher fatty acids such as lauric acid, myristic acid and oleic acid, hexyl decanol, octyldodecanol,
Higher alcohols such as isostearyl alcohol, monohydric alcohol fatty acid esters such as isopropyl myristate, hexyl laurate, octyldodecyl myristate, butyl stearate, decyl oleate, 2-hexyl decanol, 2-octyl decanol,
Non-ionic surfactants such as alcohols such as glycerin, polyoxyethylene nonyl phenyl ether, fatty acid glycerin ester, fatty acid polyethylene glycol, polyglycerin fatty acid ester, sucrose fatty acid ester, polybutene, polyisoprene, polyacrylic acid, polymethacrylic acid Liquid oils 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. 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 compounding amount of the percutaneous absorption enhancer varies depending on the type and polarity, type of adhesive, polarity and molecular weight, etc., but is usually in the range of 1% by weight to 50% by weight based on the total weight of the adhesive for skin application Used in

Furthermore, the pressure-sensitive adhesive for application to the skin according to the present invention may further be added as an optional component as long as the purpose is not impaired.
Additives such as thickeners, antioxidants, humectants, pH adjusters and the like can also be used as appropriate. In particular,
In the case where it is used for an application that directly contacts the skin as an adhesive for skin application, it is preferable to use a moisturizing agent in combination.

The percutaneously absorbable pressure-sensitive adhesive sheet of the present invention comprises a percutaneously absorbable drug and an acrylic polymer portion (A1).
) And a polyethylene oxide part (A2) from a transdermally absorbable pressure-sensitive adhesive containing a block polymer (A) formed by bonding with any of the aforementioned general formulas (I-1) to (I-3) The pressure-sensitive adhesive layer to be formed can be obtained by laminating directly or indirectly on the sheet-like support layer. For example, a pressure-sensitive adhesive layer formed by applying and drying a transdermal absorbable adhesive on a sheet-like support or by applying and drying a transdermal absorbable adhesive on a peelable sheet (also called a liner) in advance. It can be obtained by laminating a sheet-like support on top.

As a sheet-like support used in the present invention, a flexible base generally used for a skin patch can be used, and it 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. Although the thickness of these supports depends on the type of patch, it is usually set to 50 μm to 300 μm, preferably 70 μm to 200 μm in the case of a base material, and 3 μm to 100 μm, preferably 5 μm to 50 μm in the case of a release material. Set to

Of the sheet-like support, those having a coarse and porous structure such as a nonwoven fabric may be dissolved out in the above-described method in which the solution dissolved in the organic solvent is applied to the support. The manufacturing method of laminating the pressure-sensitive adhesive layer formed by applying and drying the adhesive for skin application on the above-mentioned different base material in advance, which also consumes extra dissolved matter because it penetrates into the inside. preferable.

In addition to the support layer and the pressure-sensitive adhesive layer, the skin patch includes, for example, a liner and a surface protective layer,
Other functional layers that are commonly used can be laminated.

The present invention will be more specifically described by the following examples, but the following examples do not in any way limit the scope of the present invention. In the examples, "part" and "%"
"Parts by weight" and "% by weight" are respectively represented, Mw means mass average molecular weight, and Tg means glass transition temperature.

<Measuring method of mass average molecular weight (Mw)>
Mw is measured by Showa Denko GPC (gel permeation chromatography) "GP
C-101 "was used. GPC is liquid chromatography that separates and quantifies substances dissolved in a solvent (THF; tetrahydrofuran) based on the difference in molecular size. The measurement in the present invention is performed using “KF-805L” (made by Showa Denko KK: GPC column: 8 mm ID × 3) on the column.
00 mm size) connected in series, sample concentration 1 wt%, flow rate 1.0 ml / mi
It carried out on the conditions of n, pressure 3.8MPa, and column temperature 40 degreeC, and the determination of the mass mean molecular weight (Mw) was performed in polystyrene conversion. For data analysis, a calibration curve, a molecular weight, and a peak area were calculated using manufacturer's built-in software, and a mass average molecular weight was determined using a range of retention time of 15 to 30 minutes as an analysis target.

<Measuring method of glass transition temperature>
With regard to the block polymer (A) from which the solvent has been removed by drying, “DSC-manufactured by METTLER TOLEDO”
Using “1”, weigh about 5 mg of sample amount into a standard container made of aluminum and measure temperature modulation amplitude ±
It measured to -80-100 degreeC on the conditions of 1 degreeC, temperature-modulation period 60 second, and temperature increase rate 2 degree-C / min, and calculated | required the glass transition temperature from the differential thermal curve of a reversible component.

<Synthesis of block polymer>
Production Example 1
In a reaction vessel equipped with a thermometer, stirrer, nitrogen inlet tube, reflux condenser, and dropping tube, under a nitrogen stream,
100 parts by weight of ethyl acetate was charged as an organic solvent, and heated at 80 ° C. for 30 minutes with stirring. 68 parts by weight of 2-ethylhexyl acrylate, 20 parts by weight of isobutyl acrylate, 2 parts by weight of acrylic acid, and 10 parts by weight of M-90G (manufactured by Shin-Nakamura Chemical Co., Ltd .: methoxypolyethylene glycol # 400 methacrylate) as monomers in the dropping tube Part, VPE0 as polymerization initiator
10 parts by weight of 201 (manufactured by Wako Pure Chemical Industries, Ltd .: polyethylene glycol unit-containing macroazo initiator) and 10 parts by weight of ethyl acetate as a solvent were added dropwise over 2 hours. After completion of the dropwise addition, the mixture was aged for 8 hours and then cooled to room temperature to stop the reaction. Thereafter, ethyl acetate was added for dilution to obtain a block copolymer solution having a solid content of 40% by weight. Mw of the obtained block copolymer was 920,000, the ratio of PEG was 9.1 wt%, and Tg was -58 ° C.

[Production Examples 2 to 7]
Synthesis was performed in the same manner as in Production Example 1 according to the composition and parts by weight of Table 1, and a block copolymer solution was obtained. The characteristic values are shown in Table 1.

[Production Example 8]
A reaction vessel equipped with a thermometer, a stirrer, a nitrogen inlet tube, a reflux condenser, and a dropping tube under a nitrogen stream,
As an organic solvent, 65 parts by weight of MEK was charged, and heated at 80 ° C. for 30 minutes while stirring. In the dropping tube, 30 parts by weight of 2-ethylhexyl acrylate as monomers, 20 parts by weight of isobutyl acrylate, 8.1 parts by weight of V501 (manufactured by Wako Pure Chemical Industries, Ltd .: azo initiator) as a polymerization initiator, and methyl ethyl ketone as a solvent 5 parts by weight (hereinafter referred to as MEK) was charged and dropped over 2 hours. After completion of dropping, the mixture was aged for 5 hours, and then cooled to room temperature to stop the reaction, thereby obtaining an acrylic resin having a terminal carboxylic acid. Thereafter, 20 parts by weight of PEG 2000 (manufactured by NOF Corporation, polyethylene glycol, Mn = 2000, hydroxyl value = 56), 0.05 parts by weight of tetrabutyl orthotitanate as a catalyst are charged, and the temperature is raised to 85 ° C. After confirming the outflow, the temperature was raised to 120 ° C., and then the dehydration reaction was continued while raising the temperature by 10 ° C. every 30 minutes. When the temperature reached 230 ° C., the reaction was continued at that temperature for 3 hours, held under a vacuum of about 2 kPa for 1 hour, and further reacted under a vacuum of about 1 kPa for 2-3 hours to lower the temperature . When the internal temperature dropped to 100 ° C., ethyl acetate was added and diluted to obtain a block polymer solution having a solid content of 40% by weight. Mw of the obtained block copolymer is 102.
And the proportion of PEG were 25.5% by weight, and the Tg was -45 ° C.

[Comparative Production Example 1]
Instead of 10 parts by weight of VPE 0201 (manufactured by Wako Pure Chemical Industries, Ltd .: macro-azo initiator containing polyethylene glycol unit) as a polymerization initiator, V601 (manufactured by Wako Pure Chemical Industries: 2,
An acrylic monomer was polymerized in the same manner as in Production Example 1 except that 0.9 parts by weight of 2′-azobis (isobutyric acid) dimethyl) was used to obtain an acrylic polymer solution having a solid content of 40% by weight. Mw of the obtained acrylic polymer was 760,000, the ratio of PEG was 0% by weight, and Tg was -52 ° C.

[Comparative Production Examples 2-3]
Synthesis was carried out in the same manner as in Comparative Production Example 1 according to the composition and parts by weight of Table 1, and an acrylic polymer solution was obtained. The characteristic values are shown in Table 1.

In Table 1, the symbols are as follows.
2EHA: 2-ethylhexyl acrylate iBA: isobutyl acrylate AA: acrylic acid M-90G: methoxypolyethylene glycol # 400 methacrylate HEA: 2-hydroxyethyl acrylate MEA: methoxyethyl acrylate BA: butyl acrylate EA: ethyl acrylate VPE 0201: polyethylene glycol Unit containing macroazo initiator V601: 2,2'-azobis (isobutyric acid) dimethyl

[Examples 1 to 17], [Comparative Examples 1 to 6]
In the composition shown in Tables 2-3, a block polymer, a crosslinking agent, and a tackifier are blended, dissolved in an ethyl acetate solvent so that the solid content concentration is 30%, and an adhesive for skin application is prepared. The adhesive strength, adhesive residue, skin irritation, transdermal absorption promoter retention, and drug release were evaluated.

In Tables 2-3, symbols are as follows.
ALCH: Kawaken Fine Chemical Co., Aluminum Chelate Compound Chemitite PZ: Nippon Shokubai Co., Ltd., Multifunctional Aziridine Compound EX321L: Nagase ChemteX Corp., Multifunctional Aliphatic Epoxy Compound V05: Nisshinbo Co., Ltd., Oily Carbodiimide Group-containing Compound XL552: Ms Chemie's hydroxyalkylamide group-containing compound TDI-TMP: Tolylene diisocyanate trimethylolpropane adduct Ester gum H: Arakawa Chemical Industries, Ltd., hydrogenated rosin ester compound

<Evaluation>
(1) Adhesive strength The adhesive for skin application prepared in Examples and Comparative Examples 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 polyethylene terephthalate film that had been peeled off was laminated on the pressure-sensitive adhesive layer side to produce a pressure-sensitive adhesive sheet. The adhesive 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 applied to a bakelite plate at 23 ° C.
Affixed under conditions of 5% RH. 300m after roll-bonding according to JIS and allowed to stand for 20 minutes
Peeling was performed in the direction of 180 degrees at a speed of m / min, and the peeling force at that time was measured.
aa: 15 [N / 25 mm] <Adhesive strength a: 12 [N / 25 mm] <Adhesive strength ≦ 15 [N / 25 mm]
b: 8 [N / 25 mm] <Adhesive strength ≦ 12 [N / 25 mm]
c: Adhesive strength ≦ 8 [N / 25 mm]

(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, it was visually evaluated whether the adhesive remained on the finger.
aa: There is nothing after the glue on the finger a: There is only a slight amount b: Some that exists partially c: It is completely glued after

(3) Skin irritation Using a sample similar to the adhesive strength measured in (1) above, a test piece on a plane square having an area of 30 cm ² was cut from the patch, and then a polyethylene terephthalate film that had been peel-treated was removed. After removing and making the pressure-sensitive adhesive layer completely exposed, when the test piece was affixed to the upper arm of the tester and 12 hours had passed, the state of the skin surface was visually observed.
a: no erythema b: very weak erythema c: erythema

(4) Holding power of transdermal absorption enhancer After blending 30 parts by mass of glycerin as a transdermal absorption accelerator with respect to 100 parts by mass of the solid content of the adhesive for skin application prepared in Examples and Comparative Examples, the above (1 In the same manner as in the above, a pressure-sensitive adhesive sheet for skin sticking having a laminated structure comprising polyethylene terephthalate film / pressure-sensitive adhesive layer / peeled-off polyethylene terephthalate film was produced. After the preparation, the adhesive sheet for skin application was allowed to stand at 23 ° C. and 65% RH for one month, and then the surface-peeled polyethylene terephthalate film was peeled off, and the glycerin was transferred to the film surface and visually evaluated. .
aa: not transferred at all a: very slightly transferred b: partially transferred c: completely transferred

(5) Drug releasability After blending 1 part by mass of methyl salicylate as a transdermally absorbable drug with respect to 100 parts by mass of the solid content of the adhesive for skin application prepared in Examples and Comparative Examples, the same as (1) 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 ). Set the peeled skin of nude mice in a Franz-type diffusion cell.
The peeled polyethylene terephthalate film was peeled off from the patch, and the exposed adhesive layer was attached to examine skin permeability. As a receptor solution, phosphate buffer (pH
7.2), the amount of methyl salicylate transferred from the patch to the receptor fluid through the skin was measured by HPLC after 24 hours. The skin permeation rate of methyl salicylate was determined by dividing the amount of methyl salicylate in the receptor solution 24 hours later by the amount of methyl salicylate in the patch and multiplying by 100.
aa: 80 [%] ≦ skin transmittance a: 60 [%] ≦ skin transmittance <80 [%]
b: 40 [%] ≦ skin transmittance <60 [%]
c: Skin permeability <40 [%]

As can be seen from the Examples and Comparative Examples shown in Tables 2 to 3, since the acrylic polymers used in Comparative Examples 1 to 6 do not have a polyethylene glycol moiety in the main chain of the acrylic resin, they promote percutaneous absorption. The physical properties satisfying both the holding power of the agent and the drug releasing property could not be obtained.
On the other hand, the block polymer used in the examples has a polyethylene glycol moiety (A2) in the main chain.
Therefore, good results were obtained with good balance in all physical properties. In addition, it was possible to impart retention of the skin absorption promoter and drug release properties. This is because the block polymer of the present invention has a polyethylene glycol part in the main chain, so that the solubility in water is improved while maintaining the high cohesive force that is the original characteristic of the acrylic polymer part (A1). It is thought that. This makes it possible to control the flexibility that leads to an improvement in adhesive strength and the hydrophilic / hydrophobic balance that leads to the retention of the transdermal absorption enhancer and the drug release properties. It is thought that it became a polymer.

Claims (7)

A pressure-sensitive adhesive for skin application, comprising a block polymer (A) in which an acrylic polymer part (A1) and a polyethylene oxide part (A2) are bonded via a structure of the following general formula (I- 1) .
  The mass of the polyethylene oxide portion (A2) / [the total mass of the acrylic polymer portion (A1) and the polyethylene oxide portion (A2)] contained in the block polymer (A) = 0.01 to 0.5 The pressure-sensitive adhesive for skin application according to claim 1. Block polymer (A) is, have a polyethylene oxide moiety (A2), using the polymer azo polymerization initiator having a site represented by the below Symbol formula (II), by polymerizing an acrylic monomer consisting of block polymers der is,
The polymer azo polymerization initiator has a mass average molecular weight of 5,000 to 100,000.
The adhesive for skin sticking according to any one of claims 1 or 2.
In formula, m and n show an integer greater than or equal to 1.   The adhesive agent for skin sticking of any one of Claims 1-3 whose glass transition temperature of a block copolymer (A) is -70-50 degreeC.   The adhesive for skin sticking of any one of Claims 1-4 which further contains a crosslinking agent.   A transdermally absorbable adhesive comprising a transdermally absorbable drug and the adhesive for skin application according to any one of claims 1 to 5.   A percutaneously absorbable pressure-sensitive adhesive sheet comprising a sheet-like support and a percutaneously absorbable pressure-sensitive adhesive layer formed from the percutaneously absorbable pressure-sensitive adhesive according to claim 6.