TWI478998B - Percutaneous absorption type preparation - Google Patents

Description

Percutaneous absorption preparation

BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to a percutaneous absorption type preparation, and more particularly to a percutaneous absorption type preparation which has at least one adhesive layer containing an adhesive on one side of a support and is attached to the skin. use.

A percutaneous absorption type preparation in which a pharmaceutical agent is administered to a living body through a skin surface has been proposed in various strip-shaped or sheet-like preparations in which an adhesive layer containing a pharmaceutical ingredient is formed on one side of a nonwoven fabric or a plastic film. For such a percutaneous absorption type preparation to which the skin is applied, it is required to have a characteristic of a certain blood concentration for a long period of time and to suppress the peeling property from the applied skin surface. The former characteristics can be achieved by including a sufficient amount of the pharmaceutical ingredient in the adhesive layer.

Based on this point of view, various cross-linking adhesives have been discussed as adhesives for percutaneous absorption preparations. For example, Patent Document 1 proposes a crosslinked skin adhesive which comprises a resin obtained by copolymerizing diacetone acrylamide and a primary amine group and/or a carboxyl group (carboxyl). The type of hydrazide resin is mixed and crosslinked.

Further, Patent Document 2 proposes a non-aqueous adhesive for medical percutaneous absorption tape preparation, which is used as an adhesive: a (meth)acrylic monomer having an ethyl acetyl group in the molecule and others The acrylic monomer is copolymerized, and the ethyl oxime group present in the molecule of the copolymer is crosslinked with each other.

Further, Patent Document 3 proposes a medical tape agent in which an adhesive to be used is used in combination with the following: in order to improve the cohesive force and the adhesive force (adhesive force), the following is a combination: 2-ethyl acetyl methacrylate The self-crosslinking adhesive polymer A obtained by copolymerizing oxyethyl ester and other vinyl monomers, and the alkyl (meth)acrylate having 4 to 10 carbon atoms in the alkyl group Adhesive polymer B copolymerized with other vinyl monomers.

[Previous Technical Literature] (Patent Literature)

Patent Document 1: Japanese Patent Laid-Open Publication No. 2005-325101

Patent Document 2: International Publication WO2004/112760

Patent Document 3: International Publication WO2006/064747

By using the crosslinked adhesive described in Patent Documents 1 and 2, a sufficient amount of the chemical component can be contained in the adhesive layer. However, a percutaneous absorption type preparation using such an adhesive may have difficulty in maintaining adhesiveness (adhesion) for a long period of time, and for example, may be unsuitable for use for a few days. situation. On the other hand, as described in Patent Document 3, by combining a cross-linking type adhesive and a non-crosslinking type adhesive, it is possible to improve the adhesiveness. However, since the adhesive has a reduced ratio of the cross-linking adhesive contained in the adhesive layer and can be stabilized for a long period of time, the amount of the chemical component or the plasticizer contained in the adhesive layer is reduced, so that it is not suitable for the pharmaceutical ingredient. The blood concentration is maintained for a long time for several days. Further, the adhesive described in Patent Document 3 has excellent initial adhesion, but the adhesive force after a long period of time is not sufficient. Therefore, as a transdermal absorption type preparation suitable for a long period of time, more improved adhesiveness is still sought.

The present invention has been made in view of the above circumstances, and an object thereof is to provide a percutaneous absorption type preparation which uses a crosslinked type adhesive which can contain a sufficient amount of a chemical and a plasticizer in an adhesive layer, and Can maintain adhesion for a long time.

As a result of intensive studies, the inventors have found that the above problems can be solved by including an adhesive containing the following Acr-A and Acr-B in the adhesive layer, that is, containing two kinds of cross-linking acrylic adhesives. The present invention has been completed. Acr-A is a resin mixture containing a component having a (meth)acrylic acid alkyl ester as a main monomer component and containing 3 to 45% by mass of diacetone acrylamide as an essential monomer component in a certain ratio. Acrylic copolymer (X), and acrylic copolymer (Y) containing (meth)acrylic acid alkyl ester as a main monomer component and containing a primary amine group and/or a carboxyl hydrazide in a side chain . Acr-B is a copolymer formed from the following components: acetoxyethyl (meth) acrylate, and can be co-linked with the ethoxylated alkyl (meth) acrylate. One or two or more kinds of vinyl monomers are polymerized.

In other words, the present invention relates to a (1) percutaneous absorption type preparation comprising at least an adhesive layer containing an adhesive on one side of a support, characterized in that the adhesive contains the following acrylic resin Acr. -A and Acr-B.

(Acr-A)

Acr-A is a resin mixture containing 100 parts by mass of the following acrylic copolymer (X) and 0.1 to 30 parts by mass of the following acrylic copolymer (Y).

The acrylic copolymer (X) is an acrylic acid having a (meth)acrylic acid alkyl ester as a main monomer component and containing 3 to 45% by mass of diacetone acrylamide as an essential monomer component and containing no free carboxyl group. Is a copolymer.

Acrylic copolymer (Y) is an acrylic copolymer containing alkyl (meth)acrylate as a main monomer component and containing a primary amine group and/or a carboxyl group in a side chain, and containing no free carboxyl group .

(Acr-B)

Acr-B is an ethyl ethoxylated alkyl (meth) acrylate and one or more kinds of ethylene copolymerizable with the above-mentioned (meth) acrylate ethoxylated alkyl ester. A base monomer is formed and does not contain a copolymer of a free carboxyl group.

The percutaneous absorption type preparation according to the item (1), wherein the adhesive layer further contains a drug and/or a plasticizer.

The present invention is the percutaneous absorption type preparation according to the item (2), wherein the aforementioned agent is fentanyl and/or a salt thereof.

The present invention is the percutaneous absorption type preparation according to the item (2) or (3), wherein the plasticizer is isopropyl myristate and/or isopropyl palmitate.

The percutaneous absorption type preparation according to any one of the items (1) to (4), wherein the acrylic resin Acr-A and Acr are contained in the adhesive layer. The mass ratio of -B is 90:10 to 50:50.

According to the present invention, there is provided a transdermally absorbable preparation which uses a cross-linking adhesive capable of containing a sufficient amount of a chemical and a plasticizer in an adhesive layer, and which can maintain adhesiveness for a long period of time. .

Hereinafter, an embodiment of the percutaneous absorption type preparation of the present invention will be described, and the present invention is not limited by the following embodiments.

The percutaneous absorption type preparation of the present embodiment is designed such that when the support body has a drug surface and the drug surface is applied to the skin, the active ingredient is absorbed into the body through the skin. Examples of such a preparation include a preparation designed to deliver an active ingredient to the systemic circulating bloodstream through the skin, or a preparation designed to deliver the active ingredient to the skin through the skin. The former is classified as a "percutaneous absorption type preparation" in the Japanese Pharmacopoeia, and the latter is classified as a "patch" in the Japanese Pharmacopoeia, but the percutaneous absorption type preparation of the present invention may be any type of preparation.

The percutaneous absorption type preparation of the present embodiment has at least an adhesive layer on one surface of the support. The adhesive layer contains a pharmaceutical ingredient, and the surface that contacts the skin becomes a pharmaceutical surface. The adhesive layer, the support, and the pharmaceutical composition will be described below.

<Adhesive layer>

The adhesive layer is a layer for imparting adhesiveness for adhering the percutaneous absorption type preparation to the skin. The adhesive layer contains a pharmaceutical ingredient. This pharmaceutical ingredient is absorbed by the skin through the adhesive surface of the adhesive layer which is in contact with the skin. The adhesive layer contains an adhesive, a plasticizer, a pharmaceutical ingredient, and other ingredients. Among these, the pharmaceutical ingredient will be described later, and the adhesive, the plasticizer, and other components contained in the adhesive layer will be described first.

[adhesive]

As the adhesive, at least Acr-A and Acr-B described below are contained. Acr-A and Acr-B are acrylic resins which can be crosslinked to form a mesh structure, and are distributed throughout the entire adhesive layer to form a mesh structure capable of containing a pharmaceutical component and a plasticizer. Therefore, the percutaneous absorption type preparation of the present embodiment can contain a sufficient amount of the drug component and the plasticizer. Therefore, the percutaneous absorption type preparation of the present embodiment can maintain the blood concentration of the active ingredient at a constant level for a long period of time.

Acr-A and Acr-B are acrylic resins which do not contain a free carboxyl group. Therefore, the percutaneous absorption type preparation of the present embodiment can prevent the stability of the drug component from being affected even if the drug component contained in the adhesive layer is a component that reacts or interacts with the acid, in addition to being less irritating to the skin. Loss, or transdermal absorbability is reduced. In addition, the phrase "free of a free carboxyl group" means that all of the carboxyl groups are converted into a substituent such as an ester bond by design. Therefore, even if Acr-A and Acr-B contain a carboxyl group produced by hydrolysis of an ester bond or the like, or a carboxyl group derived from an impurity of a raw material, it is included in the scope of the present invention.

(Acr-A)

First, the acrylic resin Acr-A will be described. Acr-A is a resin mixture containing 100 parts by mass of the following acrylic copolymer (X) and 0.1 to 30 parts by mass of the acrylic copolymer (Y). The acrylic copolymer (X) is an alkylene (meth)acrylate as a main monomer component, and contains 3 to 45% by mass of diacetone acrylamide as an essential monomer component, and does not contain a copolymer of a free carboxyl group. Things. The acrylic copolymer (Y) is a copolymer in which an alkyl (meth)acrylate is used as a main monomer component and a primary amine group and/or a carboxyl group is contained in a side chain, and a free carboxyl group is not contained. When the resin mixture is used as an adhesive, it can be based on a carbonyl group derived from diacetone acrylamide contained in the acrylic copolymer (X) and a primary amine group or carboxy group contained in the acrylic copolymer (Y). In the cross-linking reaction of the thiol group, a fine mesh structure is formed in the entire adhesive layer, and a drug component or the like can be held in the mesh structure. From the above viewpoint, the resin mixture can be suitably used for a percutaneous absorption type preparation.

In the production of the acrylic copolymer (X), a method in which a (meth)acrylic acid alkyl ester is used as a main monomer component, diacetone acrylamide is added, and it is 3 to the entire monomer. 45 mass% and allowed to carry out radical polymerization. As the monomer component, a polymerization initiator such as a peroxide or an azo compound can be used and polymerized by a usual method. When these monomers are polymerized, it is preferred to appropriately add a solvent to adjust the viscosity of the reaction solution.

As the alkyl (meth)acrylate, an alkyl (meth)acrylate having an alkyl group having 1 to 12 carbon atoms is preferably used. Specific examples thereof include methyl (meth)acrylate, ethyl (meth)acrylate, propyl (meth)acrylate, butyl (meth)acrylate, and 2-ethyl (meth)acrylate. Hexyl ester, octyl (meth)acrylate, dodecyl (meth)acrylate, and the like. These (meth)acrylic acid alkyl esters can be used individually or in combination of 2 or more types.

The production of the acrylic copolymer (Y) can be exemplified by using an alkyl (meth)acrylate as a main monomer component, adding a monomer component for introducing a primary amine group, and/or introducing it. The monomer component of the carboxymethyl group is 1 to 30% by mass based on the entire monomer, and is subjected to radical polymerization, and then the side chain derived from the monomer component for introducing the carboxymethyl group is converted. It is a carboxy thiol group. When the monomer component is subjected to radical polymerization, a polymerization initiator such as a peroxide or an azo compound can be used and polymerized by a general method. When the monomer component is subjected to radical polymerization, it is preferred to appropriately add a solvent to adjust the viscosity of the reaction solution. Further, as the alkyl (meth)acrylate used in the production of the copolymer (B), the same ones as those exemplified in the above copolymer (A) can be used.

Further, in order to exhibit appropriate crosslinkability with the acrylic copolymer (X), the primary amine group and/or the carboxy group in the acrylic copolymer (Y) in one molecular chain of the acrylic copolymer (Y) The thiol group is preferably two or more, and more preferably three or more.

Further, the monomer component for introducing the primary amine group and/or the monomer component for introducing the carboxymethyl group and the alkyl (meth)acrylate monomer are preferably mixed to have a molar ratio of 1 : 5 to 1:100 and copolymerized.

The monomer component for introducing a primary amine group into the acrylic copolymer (Y) may, for example, be a compound having a vinyl group polymerizable with an alkyl (meth)acrylate and having a primary amine group. As such a compound, a vinylamine etc. are illustrated, for example.

The monomer component for introducing a carboxy fluorenyl group to the acrylic copolymer (Y) includes a ketone group having a vinyl group polymerizable with an alkyl (meth) acrylate and having a reaction with a thiol group. compound of. Examples of such a compound include diacetone acrylamide, acrolein, acetamethylene methacrylate, and the like.

To convert a side chain derived from a monomer component for introducing a carboxymethyl group into a carboxy fluorenyl group, the polymer obtained by the above radical polymerization is dissolved in a polar solvent and, in the presence of an acid catalyst, It can be reacted with dioxonium dicarboxylate. Examples of the dicarboxylic acid dithizone include dioxane adipate, diammonium glutarate, and diammonium pimelate.

In addition, the "main monomer component" in the present specification means a monomer component contained in an amount of 50% by mass or more based on the copolymer, or a monomer which is contained in the highest ratio among a plurality of monomer components. ingredient.

(Acr-B)

Next, the acrylic resin Acr-B will be described. Acr-B is one or two or more kinds of ethylene copolymerized with (meth)acrylic acid ethoxylated alkyl (meth) acrylate and copolymerizable with the ethoxylated alkyl (meth) acrylate. A base monomer is formed and does not contain a copolymer of a free carboxyl group. When such a copolymer is used as an adhesive, a fine mesh structure can be formed in the entire adhesive layer based on the crosslinking reaction of the ethyl ethoxylated alkyl group contained in the copolymer, and the copolymer can be formed therein. In the mesh structure, a pharmaceutical ingredient or the like is retained, and based on the above viewpoint, such a copolymer is suitably used for a percutaneous absorption type preparation.

Examples of the ethoxylated alkyl (meth) acrylate include a hydroxy group of an alkylene glycol group which is deuterated by an acetamidine group, and an acrylic acid or a methyl group. A compound in which acrylic acid is deuterated by another hydroxyl group. As such a compound, for example, 2-acetic acid ethyl methacrylate or 2-ethyl ethoxyethyl acrylate may be exemplified, and 2-ethyl acetyl methacrylate is preferred. Oxyethyl ester. Further, when the total mass of the copolymer is 100, the content of the ethyl ethoxylated ethyl (meth) acrylate in the copolymer is preferably from about 5 to 50% by mass, preferably from 10 to 45. About % by mass.

The vinyl monomer which can be copolymerized with the ethoxylated alkyl (meth) acrylate may, for example, be a compound having an oxime group in the molecule. Examples of such a compound include alkyl (meth)acrylates having an alkyl group having 1 to 12 carbon atoms, and functional groups having a functional group such as a hydroxyl group, a mercaptoamine group or an alkoxyalkyl group in the molecule. Body; and polyalkylene glycol di(meth)acrylates. These ethyl thiol monomers can be used in combination of one type or two types or more.

Specific examples of the (meth)acrylic acid alkyl ester having an alkyl group having 1 to 12 carbon atoms include methyl (meth)acrylate, ethyl (meth)acrylate, and (meth)acrylic acid. Ester, butyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, octyl (meth)acrylate, dodecyl (meth)acrylate, and the like. In addition, examples of the functional monomer having a functional group in the molecule include 2-methoxyethyl (meth)acrylate, acrylamide of diacetone, and 2-(meth)acrylic acid. Hydroxyethyl ester and the like. Further, specific examples of the polyalkylene glycol di(meth)acrylates include diethylene glycol di(meth)acrylate and triethylene glycol di(meth)acrylate. Tetraethylene glycol di(meth)acrylate or the like.

A copolymer of etidronyl (meth) acrylate and another ethyl thiol monomer, which can be produced by a general method using a polymerization initiator such as a peroxide or an azo compound. .

As described above, the adhesive of the present embodiment contains at least a crosslinked resin, that is, the above-mentioned Acr-A, and a resin which is also a crosslinked type, that is, Acr-B. In general, when such a crosslinked type resin is used as an adhesive, the adhesive strength of the adhesive layer tends to decrease. However, the inventors of the present invention have unexpectedly found that an adhesive comprising the above-mentioned Acr-A and Acr-B exhibits better adhesion than when these resins are used alone, and completed the present invention. In the case where Acr-A or Acr-B was used alone as an adhesive, the adhesiveness of the percutaneous absorption type preparation was almost lost 1 day after application to the skin. On the other hand, in the case where Acr-A and Acr-B are used together as an adhesive, the adhesiveness of the percutaneous absorption type preparation can be maintained for more than 3 days when applied to the skin. Further, in the present invention, it is not necessary to use a non-crosslinking type resin as an adhesive in order to impart adhesiveness, so that a large amount of a chemical component can be added to the adhesive layer. Further, a non-crosslinking type resin may be added to the adhesive containing the above Acr-A and Acr-B as needed.

The mass ratio of Acr-A to Acr-B contained in the adhesive is preferably from 90:10 to 49:51, more preferably from 90:10 to 50:50, still more preferably from 85:15 to 50:50. When the amount of Acr-B contained in the adhesive is 10% by mass or more, the increase in the gel fraction due to the passage of time in the adhesive layer to which the chemical component or the like is added is suppressed, so that the transdermal absorption type can be obtained. The quality of the preparation is relatively stable. In addition, when the Acr-B contained in the adhesive is 51% by mass or less, the gel fraction of the adhesive can be sufficiently made, and the increase in the attachment time to the skin by the percutaneous absorption preparation can be suppressed. The sag or cohesion of the adhesive layer is reduced.

Here, the gel fraction is a ratio of the resin component (adhesive) contained in the adhesive layer to the solvent-insoluble resin component of the entire resin component. As the solvent at this time, for example, ethyl acetate can be exemplified. Here, as the cross-linking of Acr-A or Acr-B increases the gel fraction, the gel fraction is also an index indicating the degree of cross-linking obtained by Acr-A or Acr-B. As previously explained, Acr-A or Acr-B can be separately crosslinked to form a mesh structure, but the degree of gel fraction will vary according to the ratio of Acr-A to Acr-B as described above. Therefore, by mixing Acr-A with Acr-B, some interaction may occur between these components. Thus, sufficient adhesion can be obtained by mixing Acr-A and Acr-B as described above, which may be a result of some interaction between these components.

Further, the gel fraction of the adhesive is preferably from 30 to 70%. When the gel fraction of the adhesive is 30% or more, it is possible to suppress a decrease in the sag or cohesive force of the adhesive layer which is caused by an increase in the adhesion time of the percutaneous absorption preparation to the skin. Since the gel fraction of the adhesive is 70% or less, sufficient skin adhesiveness can be obtained.

[Plasticizer]

A plasticizer may be contained in the adhesive layer. As such a plasticizer, an oil having a high boiling point can be generally used, and examples thereof include isopropyl myristate, diethyl sebacate, diisopropyl adipate, and oleic acid B. Fatty acid ester derivatives such as ester, isopropyl palmitate, ethyl laurate, octyl myristate, isotridecyl myristate, medium chain fatty acid triglyceride; hexyl decyl alcohol, octyldodecanol, etc. Higher alkanol derivatives; polyolefin glycols such as polyethylene glycol and polypropylene glycol; oils such as olive oil and castor oil. Among these, isopropyl myristate, isopropyl palmitate, etc. act as a plasticizer for the adhesive, and have an effect of promoting the diffusion of the drug component in the percutaneous absorption preparation, and promoting the component of the drug. The effect of skin penetration is therefore preferred. These can be used individually or in combination of 2 or more types. The blending amount of the plasticizer is preferably from 1 to 40% by mass, more preferably from 5 to 35% by mass, most preferably from 6 to 30% by mass, based on the total mass of the adhesive layer. The amount of the plasticizer to be added is 1% by mass or more based on the total mass of the pressure-sensitive adhesive layer, and the above effects can be sufficiently obtained. The blending amount of the plasticizer is 40% by mass or less based on the total mass of the adhesive layer, and the occurrence of bleeding of the oily substance from the adhesive layer can be suppressed.

[Other ingredients contained in the adhesive layer]

In the adhesive layer, various additives can be added in order to impart the necessary functions. Examples of such an additive include a solvent for dissolving a drug component, various adhesives, a preservative, a pH adjuster, a chelating agent, a transdermal absorption enhancer, an antioxidant, an excipient, a fragrance, a colorant, and the like.

The solvent for dissolving the drug component is not particularly limited as long as it dissolves the drug, and a solvent having no skin irritation is preferred. Examples of such a solvent include lower alcohols such as ethanol, propanol and isopropanol; intermediate alcohols such as hexanol and octanol; and polyhydric alcohols such as glycerin, ethylene glycol and diethylene glycol; and fatty acid esters. Classes, polyvinyl alcohol, N-methylpyrrolidone, lactic acid, and the like. These can be used individually or in combination of 2 or more types.

In the percutaneous absorption type preparation of the present embodiment, in order to form the pressure-sensitive adhesive layer, for example, an adhesive layer such as Acr-A, Acr-B, a pharmaceutical component or a plasticizer may be used. The component to be contained is dissolved in a solvent to prepare a solution, and after the solution is applied to a support, the solvent is heated and evaporated by a known method. The solvent to be used in the method is not particularly limited as long as it is an organic solvent which is evaded in the heating and drying step in the production step of the percutaneous absorption type preparation, and examples thereof include ketones such as acetone and methyl ethyl ketone. Classes; acetates such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate; aliphatic hydrocarbons such as hexane, heptane, octane, cyclohexane; aromatic hydrocarbons such as benzene, toluene and xylene An organic solvent such as an ether such as isopropyl ether, tetrahydrofuran or dioxane. These can be used individually or in combination of 2 or more types.

<support>

As the support, it is preferred that the agent component is non-penetrating or difficult to penetrate and soft. Specifically, for example, polyethylene, polypropylene, ethylene/vinyl acetate copolymer, ethylene/vinyl acetate/carbon monoxide copolymer, ethylene/butyl acrylate/carbon monoxide copolymer, nylon, polyester (poly pair) A resin film such as ethylene phthalate or polybutylene terephthalate or an aluminum sheet. These may be laminated to form a sheet, or may be laminated together with a woven fabric or a non-woven fabric. Further, in order to improve the adhesion to the adhesive layer, surface treatment such as corona treatment or plasma discharge treatment may be applied, or an anchor coat treatment may be applied by an anchoring agent.

<pharmaceutical ingredients>

The pharmaceutical ingredient is contained in the adhesive layer and is absorbed by the skin through the surface of the drug surface, that is, the adhesive layer. In the percutaneous absorption type preparation of the present embodiment, phenanthrene is used as a pharmaceutical ingredient. Bentham, is a compound known as 1-phenethyl-4-N-propionyl-anilinopiperidine. The fentanyl used in the percutaneous absorption type preparation of the present embodiment is phenanthrene (free state) and/or a salt thereof. Specific examples thereof include phenanthrene (free state), citrate citrate, phenentrene hydrochloride, and phenentrene sulfate. Alternatively, phenanthrene (free state) and a salt thereof may be used in combination. The phenanthrene used is preferably phenanthrene (free state) and/or phenanthryl citrate, preferably phenanthrene (free state).

The content of phenanthrene in the adhesive layer can be appropriately determined depending on the purpose of use, etc., but if it is too small, the pharmacological activity will be insufficient, and if it is too large, the blood concentration will rise rapidly or the adhesiveness will decrease. It is preferably from 0.01 to 50% by mass, and more preferably from 0.5 to 20% by mass, based on the total mass of the pressure-sensitive adhesive layer. In the adhesive layer, phenanthrene may be present in a dissolved state, a supersaturated state, or a crystalline state. Further, in order to maintain the transdermal absorbability of the phenanthrene, a part of the phenanthrene may be in a dissolved state and a part may be in a crystalline state.

In the above, the embodiment of the present invention is not limited to the above-described embodiment, and the present invention is not limited to the above-described embodiment, and can be appropriately modified and implemented within the scope of the present invention.

For example, in the above embodiment, phenanthrene is used as the drug component, but other drug components may be used.

[Examples]

Hereinafter, the examples are shown to further specifically describe the percutaneous absorption type preparation of the present invention, but the present invention is not limited by the following examples.

[Production Example 1; Acrylic Resin Acr-A]

The solution of the acrylic copolymer (X) obtained by the synthesis method shown below and the solution of the acrylic copolymer (Y) are mixed, and the acrylic copolymer (X) contained in the solution is mixed with The mass ratio of the acrylic copolymer (Y) was 100:5, and a solution of the acrylic resin Acr-A was obtained.

‧Acrylic copolymer (X)

200 parts by mass of 2-ethylhexyl acrylate, 100 parts by mass of butyl acrylate, 50 parts by mass of diacetone acrylamide, and 300 parts by mass of ethyl acetate were added and mixed. The mixture was transferred to a separable flask equipped with a stirring device and a circulating cooling device, and the mixture was heated to 75 ° C while stirring and nitrogen substitution. A solution obtained by dissolving 2 parts by mass of benzamidine peroxide in 20 parts by mass of ethyl acetate was divided into 5 portions, and 1 part thereof was added to a separable flask, and polymerization was started. The remaining 4 parts were added 1 part every hour from 2 hours after the start of the polymerization reaction, and after the completion of the addition, the reaction was further carried out for 2 hours. Further, in order to adjust the viscosity, 50 parts by mass of ethyl acetate was added every 2 hours after the start of the reaction, and the total amount was added four times. After completion of the reaction, the mixture was cooled, and then ethyl acetate was added thereto to obtain a solution of the acrylic copolymer (X) having a solid content concentration of 30% by mass.

‧Acrylic copolymer (Y)

660 parts by mass of ethyl acrylate, 70 parts by mass of diacetone acrylamide, 40 parts by mass of dodecylmercaptan as a molecular weight modifier, and 400 parts by mass of ethyl acetate were added and mixed. The mixture was transferred to a separable flask equipped with a stirring device and a circulating cooling device, and the temperature was raised to 70 ° C while stirring and nitrogen substitution. A solution obtained by dissolving 5 parts by mass of azobisisobutyronitrile in 100 parts by mass of ethyl acetate was divided into 5 portions, and 1 part thereof was added to a separable flask, and polymerization was started. The remaining 4 parts were added 1 part every hour from 2 hours after the start of the polymerization reaction, and after the completion of the addition, the reaction was further carried out for 2 hours. Further, in order to adjust the viscosity, 50 parts by mass of ethyl acetate was added every 2 hours after the start of the reaction, and the total amount was added four times. After that, a solution obtained by dissolving 40 parts by mass of dioxane adipate in a mixed solution of 40 parts by mass of purified water, 1600 parts by mass of methanol, and 260 parts by mass of ethyl acetate is added, and 5 mass is further added. After the portion of concentrated hydrochloric acid, the temperature was raised to 70 °C. After completion of the reaction, the mixture was cooled, washed with purified water for 3 times, and then the product was dissolved in a mixed solvent of 700 parts by mass of ethyl acetate, 1400 parts by mass of acetone, and 400 parts by mass of methanol. A solution of an acrylic copolymer (Y) having a solid content concentration of 30% by mass.

[Production Example 2; Acrylic Resin Acr-B]

158 parts by mass of 2-ethylhexyl acrylate, 35.1 parts by mass of 2-ethyl acetoxyethyl methacrylate, 76.2 parts by mass of methyl methacrylate, and 80.3 parts by mass of diacetone acrylamide And 1.0 part by mass of tetraethylene glycol dimethacrylate was uniformly dissolved to prepare a monomer solution. 100 parts by mass of this monomer solution was filled in a 2-liter four-necked flask equipped with a Dimroth condenser, a thermometer, a nitrogen injection tube, and a stirring blade, and 350 parts by mass of ethyl acetate was added thereto. As a solvent. While injecting nitrogen gas at a flow rate of 100 mL/min, the temperature was raised to 75 ° C, and after maintaining at 75 ° C for 30 minutes, 0.35 parts by mass of benzoyl peroxide was dissolved in 5 parts by mass of ethyl acetate. Start the agent and set the external temperature to 85 °C. After confirming the circulation of the solvent, the remaining monomer solution was continuously supplied over 3 hours. After 1 hour from the start of the continuous injection of the monomer solution, 500 parts by mass of ethyl acetate was charged over 3 hours. After the ethyl acetate was added, stirring was continued for 12 hours, and then 0.5 part by mass of benzoyl peroxide was added as an additional catalyst, and heating was continued for 12 hours, followed by cooling to obtain a solution of the acrylic resin Acr-B.

[Comparative Production Example 1; Copolymer Z]

A commercially available acrylic copolymer solution (manufactured by Nippon Carbide Industries Co., Ltd., product name: Nissetsu PE300) was used as the copolymer Z for comparative test. The acrylic copolymer Z is obtained by radical copolymerization of 85 parts by mass of 2-ethylhexyl acrylate monomer, 10 parts by mass of 2-hydroxyethyl acrylate, and 5 parts by mass of vinyl acetate. Made.

[Examples 1 to 8]

The acrylic resin Acr-A solution obtained in Production Example 1 and the acrylic resin Acr-B solution obtained in Production Example 2 were mixed, and in the mixed solution, isopropyl myristate was added as a plasticizer. The ester (IPM) and isopropyl palmitate (IPP), and dibutylhydroxytoluene (BHT) as an additive were uniformly stirred throughout the solution to obtain a mixed solution. The thickness of the adhesive layer after the mixture is applied and the surface of the coating is a corona-treated film of polyethylene (polyethylene terephthalate) having a thickness of 25 μm. The patch for transdermal absorption preparations of Examples 1 to 8 was produced by forming 50 μm and drying it to form an adhesive layer. The blending of the respective components was carried out by setting the mass % after drying to the values shown in Table 1. In addition, each numerical value shown in Table 1 means mass %.

[Comparative Examples 1 and 2]

The patches for the percutaneous absorption type preparations of Comparative Examples 1 and 2 were prepared in the same manner as in the above Examples 1 to 8 except for the components of the unmixed portions. The blending of the respective components was carried out by setting the mass % after drying to the values shown in Table 1.

[Comparative Example 3]

The acrylic copolymer Z obtained in Comparative Preparation Example 1 was used instead of the acrylic resin Acr-A, and the same procedure as in the above Examples 1 to 8 was carried out except that isopropyl palmitate (IPP) was not prepared. The patch for a percutaneous absorption type preparation of Comparative Example 3. The blending of the respective components was carried out by setting the mass % after drying to the values shown in Table 1.

[Examples 9 to 18]

The acrylic resin Acr-A solution obtained in Production Example 1 and the acrylic resin Acr-B solution obtained in Production Example 2 were mixed, and in the mixed solution, phenantani as a pharmaceutical component was added as a plastic. The solution of isopropyl myristate (IPM) and isopropyl palmitate (IPP), and dibutylhydroxytoluene (BHT) as an additive were uniformly stirred throughout the solution to obtain a mixed solution. On the support of a PET (polyethylene terephthalate) film formed by corona treatment and having a thickness of 25 μm, the mixture is applied and dried in an adhesive layer. The fentanyl concentration was 0.42 mg/cm ² and dried to form an adhesive layer, and the percutaneous absorption preparations of Examples 9 to 18 were produced. The blending of the respective components was carried out by setting the mass % after drying to the values shown in Table 2. In addition, each numerical value shown in Table 2 means mass %.

[Comparative Example 4]

The acrylic copolymer Z obtained in Comparative Preparation Example 1 was used instead of the acrylic resin Acr-A, and the same procedure as in the above Examples 9 to 18 was carried out except that isopropyl palmitate (IPP) was not prepared. The percutaneous absorption type preparation of Comparative Example 4. The blending of the respective components was carried out by setting the mass % after drying to the values shown in Table 2.

[Evaluation of skin adhesion]

The patches for the percutaneous absorption type preparations (3.2 cm × 3.2 cm; 10 cm ² ) of Examples 1 to 8 and Comparative Examples 1 to 3 were attached to the right upper arm of 10 subjects, and were pasted 72 after attachment. After the hour, the skin attachment state (peeling condition) of each subject was visually observed. The skin patch of the percutaneous absorption type patch was attached to the skin as "no peeling", and the skin adherence state of each subject was evaluated on the basis of the following criteria, and the test was performed on each evaluation standard. The number of people. The results are shown in Table 3.

◎: no peeling

○: Very slight peeling is recognized

△: It can be recognized that the four corners have a slightly wider peeling

×: A wide range of peeling or a large displacement of the attached portion can be recognized

[Pig Percutaneous Absorption Test 1]

The back of the pig (Laris & keke, 11 months old, female, weighing about 25 kg) was depilated, and after washing the surface, the percutaneous absorption preparation was attached to the non-injured area for 72 hours to carry out the medicine. Transdermal absorption test of the component (Bentani). After attaching, cover the non-permeability oil paper to cover the attached part, fix it with a non-woven adhesive bandage, cover the whole with gauze, and then cover the adhesive stretchable bandage, and then cover it with a stretchable net. The whole body. After 72 hours from the attachment of the percutaneous absorption type preparation, the skin attachment state (peeling condition) of each preparation was visually observed, and the skin adhesion of the pig was evaluated in the same evaluation criteria as the above-mentioned skin adhesion test for humans. Sex. Further, after the 72-hour adhesion test, the percutaneous absorption type preparation used in the test was collected, and the residual amount of the drug component in the preparation was investigated by ultrasonic extraction under ultrasonic irradiation, and based on the residual amount. The amount of the agent absorbed by the skin is calculated.

The above test was carried out on the percutaneous absorption type preparations (the phenanthrene content was 2.1 mg/5 cm ² ) of Examples 9 to 18 and Comparative Example 4. The results are shown in Table 4.

[Pig Percutaneous Absorption Test 2]

The back of the pig (Laris & keke, 11 months old, female, weighing about 25 kg) was depilated, and after washing the surface, the percutaneous absorption preparation was attached to the non-injured area for 72 hours to carry out the medicine. Transdermal absorption test of the component (Bentani). After attaching, cover the non-permeability oil paper to cover the attached part, fix it with a non-woven adhesive bandage, cover the whole with gauze, and then cover the adhesive stretchable bandage, and then cover it with a stretchable net. The whole body. During the percutaneous absorption test, blood was taken at regular intervals after attachment by a cannula inserted from the neck and left in the central vein to determine the concentration of the pharmaceutical ingredient in the plasma.

The above test was carried out on the percutaneous absorption type preparations (the phenanthrene content was 16.8 mg/40 cm ² ) of Example 9 and Comparative Example 4. The results are shown in Table 5. In addition, in Table 5, the AUC refers to the area under the blood concentration-time curve (ng × hr / ml), and the so-called Cmax means the maximum blood concentration (ng / ml).

◎: no peeling

○: Very slight peeling is recognized

△: It can be recognized that the four corners have a slightly wider peeling

×: A wide range of peeling or a large displacement of the attached portion can be recognized

As shown in Table 3, it was found that the patches for percutaneous absorption type preparations of Examples 1 to 8 were compared with the patches for the percutaneous absorption type preparations of Examples 1 to 8, and 72 hours after the attachment to the skin. The peeling is suppressed. It can be understood that Acr-A is used in combination with the two cross-linking adhesives of Acr-A and Acr-B alone or Acr-A and Acr-B alone and other adhesives. In the case of Acr-B, the adhesion can be sustained for a long time, and thus the effectiveness of the present invention can be understood. In addition, in Comparative Example 3 in which Acr-B and a non-crosslinking type adhesive were used together, although the initial adhesiveness (initial adhesiveness) was sufficient, the adhesive strength decreased with time, and after 72 hours, Skin adhesion exhibited inferior results as in Examples 1-8. This tendency was also observed in the percutaneous absorption type preparation containing the pharmaceutical ingredient (Examples 9 to 18 and Comparative Example 4, as shown in Table 4).

Further, as shown in Table 4, the transdermal absorption of the agents of the percutaneous absorption type preparations of Examples 9 to 18 was larger than that of the percutaneous absorption type preparation of Comparative Example 4. Further, as shown in Table 5, it can be understood that the percutaneous absorption type preparation of Example 9 showed higher AUC than the percutaneous absorption type preparation of Comparative Example 4, from the viewpoint of maintaining blood concentration, by way of Examples 9 is better.

From the above results, it can be understood that, according to the percutaneous absorption type preparation of the present invention, a cross-linking type adhesive can be used in the adhesive layer and the adhesiveness can be maintained for a long period of time, and the blood of the pharmaceutical ingredient can be maintained for a long period of time. concentration.

Claims (5)

A percutaneous absorption type preparation comprising at least one adhesive layer containing an adhesive on one side of a support, characterized in that the adhesive contains the following acrylic resins Acr-A and Acr-B, (Acr) -A) The Acr-A is a resin mixture containing 100 parts by mass of the following acrylic copolymer (X) and 0.1 to 30 parts by mass of the acrylic copolymer (Y), the acrylic copolymer (X) An acrylic copolymer containing an alkyl (meth)acrylate as a main monomer component and containing 3 to 45% by mass of diacetone acrylamide as an essential monomer component and containing no free carboxyl group. The copolymer (Y) is an acrylic copolymer having an alkyl (meth) acrylate as a main monomer component and a primary amine group and/or a carboxy fluorenyl group in a side chain, and which does not contain a free carboxyl group. Acr-B) is Acr-B which is an ethyl ethoxylated alkyl (meth) acrylate and one which can be copolymerized with the aforementioned ethoxylated alkyl (meth) acrylate. A copolymer of two or more kinds of vinyl monomers and containing no free carboxyl groups. The percutaneous absorption type preparation according to claim 1, wherein the adhesive layer further contains a drug and/or a plasticizer. The percutaneous absorption type preparation according to claim 2, wherein the aforementioned agent is fentanyl and/or a salt thereof. The percutaneous absorption type preparation according to claim 2, wherein the plasticizer is isopropyl myristate and/or isopropyl palmitate. The percutaneous absorption type preparation according to any one of claims 1 to 3, wherein the mass ratio of the acrylic resin Acr-A and Acr-B contained in the adhesive layer is 90:10 to ～ 49:51.