JPWO2011010556A1 - Transdermal preparation - Google Patents

Abstract

The present invention provides a transdermally absorbable preparation capable of maintaining sticking properties for a long time while using a cross-linking type pressure-sensitive adhesive that can contain a sufficient amount of a drug in the pressure-sensitive adhesive layer. The percutaneous absorption-type preparation of the present invention comprises a pressure-sensitive adhesive layer containing at least a pressure-sensitive adhesive on one side of a support, and two types of acrylics obtained by copolymerizing a specific monomer in combination as the pressure-sensitive adhesive. System resin Acr-A and Acr-B are included.

Description

  The present invention relates to a transdermally absorbable preparation, and more particularly, to a transdermally absorbable preparation that is provided with a pressure-sensitive adhesive layer containing at least an adhesive on one side of a support and is used by being attached to the skin.

  Various transdermal preparations that administer drugs to the living body through the skin surface have been proposed in the form of tapes or sheets in which an adhesive layer containing drug components is formed on one side of a nonwoven fabric or plastic film. ing. As described above, the transdermal preparation of the type that is applied to the skin is required to have a characteristic of maintaining a predetermined blood concentration over a long period of time and a characteristic of suppressing dropout from the applied skin surface. . The former property is achieved by containing a sufficient amount of drug component in the pressure-sensitive adhesive layer.

  From this point of view, various types of cross-linkable pressure-sensitive adhesives have been studied as pressure-sensitive adhesives for transdermal absorption preparations. For example, Patent Document 1 discloses a type of cross-linked skin adhesive in which a resin obtained by copolymerizing diacetone acrylamide and a resin containing a primary amino group and / or a carboxyhydrazide group are mixed and cross-linked. Agents have been proposed.

  In Patent Document 2, a (meth) acrylic monomer having an acetoacetyl group in the molecule and another acrylic monomer are copolymerized, and the acetoacetyl groups present in the copolymer molecule are cross-linked. There has been proposed a non-aqueous pressure-sensitive adhesive for medical transdermal absorption tape preparations using the above-mentioned as a pressure-sensitive adhesive.

  Patent Document 3 discloses a self-crosslinkable adhesive obtained by copolymerizing methacrylic acid-2-acetoacetoxyethyl ester and other vinyl monomers in order to improve cohesion and adhesion (adhesive strength). Using a pressure-sensitive adhesive in which an adhesive polymer A and an adhesive polymer B obtained by copolymerizing an alkyl (meth) acrylic acid alkyl ester having 4 to 10 carbon atoms in an alkyl group and other vinyl monomers are combined Tapes have been proposed.

JP-A-2005-325101 International Publication No. WO2004 / 112760 International Publication WO2006 / 064747

  By using a crosslinking type pressure-sensitive adhesive as described in Patent Documents 1 and 2, it is possible to contain a sufficient amount of drug component in the pressure-sensitive adhesive layer. However, transdermal preparations using these pressure-sensitive adhesives may be difficult to maintain the sticking property (stickiness) for a long time, and are not suitable for applications that are applied to the skin for several days, for example. There is a case. On the other hand, as described in Patent Document 3, the adhesiveness can be improved by combining a cross-linking type pressure-sensitive adhesive and a non-cross-linking type pressure-sensitive adhesive. However, this pressure-sensitive adhesive has a reduced proportion of the cross-linking type pressure-sensitive adhesive contained in the pressure-sensitive adhesive layer, and the amount of drug components and plasticizers that can be stably contained in the pressure-sensitive adhesive layer for a long time is reduced. It is not suitable for applications in which the blood concentration of the drug component is maintained for a long period of several days. Furthermore, the pressure-sensitive adhesive described in Patent Document 3 has good initial sticking property, but the sticking power after a long time is still not sufficient. Therefore, more improved sticking properties have been demanded for long-term use for transdermal preparations.

  The present invention has been made in view of the above situation, and is capable of sticking over a long period of time while using a cross-linking type pressure-sensitive adhesive that can contain a sufficient amount of a drug and a plasticizer in the pressure-sensitive adhesive layer. An object of the present invention is to provide a percutaneous absorption preparation capable of maintaining the above.

  As a result of intensive studies, the present inventors have included the above-mentioned problems by including a pressure-sensitive adhesive containing the following Acr-A and Acr-B, which are two types of cross-linked acrylic pressure-sensitive adhesives, in the pressure-sensitive adhesive layer. The inventors have found that this can be solved, and have completed the present invention. Acr-A is an acrylic copolymer (X) containing (meth) acrylic acid alkyl ester as a main monomer component and diacetone acrylamide acrylamide as an essential monomer component, and (meth) acrylic acid alkyl ester. Is a resin mixture containing, as a main monomer component, an acrylic copolymer (Y) containing a primary amino group and / or a carboxyhydrazide group in the side chain in a predetermined ratio. Acr-B is a copolymer of acetoacetoxyalkyl (meth) acrylate and one or more vinyl monomers copolymerizable with the acetoacetoxyalkyl (meth) acrylate.

That is, the present invention is (1) a transdermal preparation having a pressure-sensitive adhesive layer containing at least a pressure-sensitive adhesive on one side of a support, and the following acrylic resins Acr-A and Acr-B are used as the pressure-sensitive adhesive. Is a transdermally absorbable preparation characterized by comprising
(Acr-A)
A resin mixture comprising 100 parts by mass of the following acrylic copolymer (X) and 0.1 to 30 parts by mass of the following acrylic copolymer (Y).
Acrylic copolymer (X); An acrylic copolymer containing (meth) acrylic acid alkyl ester as a main monomer component, 3 to 45% by mass of diacetone acrylamide as an essential monomer component, and no free carboxyl group.
Acrylic copolymer (Y); Acrylic copolymer containing (meth) acrylic acid alkyl ester as the main monomer component, containing a primary amino group and / or carboxyhydrazide group in the side chain, and no free carboxyl group .
(Acr-B)
A copolymer of acetoacetoxyalkyl (meth) acrylate and one or more vinyl monomers copolymerizable with the acetoacetoxyalkyl (meth) acrylate, which does not contain a free carboxyl group.

  The present invention is also (2) the percutaneous absorption preparation according to (1), wherein the pressure-sensitive adhesive layer further contains a drug and / or a plasticizer.

  The present invention also relates to (3) the percutaneous absorption preparation according to (2), wherein the drug is fentanyl and / or a salt thereof.

  The present invention is also (4) the percutaneous absorption preparation according to (2) or (3), wherein the plasticizer is isopropyl myristate and / or isopropyl palmitate.

  In the present invention, (5) the mass ratio of the acrylic resins Acr-A and Acr-B contained in the pressure-sensitive adhesive is 90:10 to 50:50. (1) to (4) The transdermally absorbable preparation according to any one of the items.

  ADVANTAGE OF THE INVENTION According to this invention, the transdermal absorption type which can maintain adhesiveness over a long time, using the bridge | crosslinking type adhesive which can contain sufficient quantity of chemical | medical agents and a plasticizer for an adhesive layer. A formulation is provided.

  Hereinafter, one embodiment of the transdermally absorbable preparation of the present invention will be described, but the present invention is not limited to the following embodiment.

  The transdermally absorbable preparation of the present embodiment has a drug surface on a support and is a drug designed to be absorbed into the body through the skin when applied while the drug surface is in contact with the skin. It is. Such formulations include formulations designed to deliver the active ingredient through the skin to the systemic bloodstream and formulations designed to deliver the active ingredient locally through the skin. The former is classified as “percutaneous absorption preparation” in the Japanese Pharmacopoeia, and the latter is classified as “patch” in Japanese Pharmacopoeia. It may be a type of formulation.

  The transdermally absorbable preparation of this embodiment includes at least an adhesive layer on one side of a support. This pressure-sensitive adhesive layer contains a drug component, and the surface that contacts the skin is the drug surface. Hereinafter, an adhesive layer, a support body, and a chemical | medical agent component are demonstrated.

<Adhesive layer>
The pressure-sensitive adhesive layer is a layer for imparting adhesive properties for adhering to the skin to the percutaneous absorption preparation. The adhesive layer contains a drug component. This drug component is absorbed into the skin through the drug surface where the adhesive layer contacts the skin. The pressure-sensitive adhesive layer contains a pressure-sensitive adhesive, a plasticizer, a drug component, and other components. Among these, a chemical | medical agent component is mentioned later, and the other component contained in an adhesive, a plasticizer, and an adhesive layer is demonstrated here.

[Adhesive]
The pressure-sensitive adhesive includes at least Acr-A and Acr-B described below. Acr-A and Acr-B are acrylic resins that can be crosslinked to form a network structure, and form a network structure that can contain a drug component and a plasticizer in the entire pressure-sensitive adhesive layer. For this reason, the percutaneous absorption type preparation of the present embodiment can contain a sufficient amount of a drug component and a plasticizer. Therefore, the transdermal preparation of this embodiment can maintain the blood concentration of the active ingredient at a predetermined level for a long time.

  Acr-A and Acr-B are acrylic resins that do not contain a free carboxyl group. For this reason, the percutaneous absorption-type preparation of the present embodiment has little irritation to the skin, and the drug component contained in the pressure-sensitive adhesive layer may react with or interact with an acid. It is possible to prevent the stability of the drug component from being impaired or the percutaneous absorbability from being lowered. Note that “does not contain a free carboxyl group” means that all carboxyl groups are converted into substituents such as ester bonds by design. For this reason, even if Acr-A or Acr-B contains, for example, a carboxyl group generated by hydrolysis of an ester bond or the like, or a carboxyl group as an impurity derived from raw materials, it is included in the scope of the present invention.

(Acr-A)
First, Acr-A which is an acrylic resin will be described. Acr-A is a resin mixture containing 100 parts by mass of the acrylic copolymer (X) described below and 0.1 to 30 parts by mass of the acrylic copolymer (Y). The acrylic copolymer (X) is a copolymer containing (meth) acrylic acid alkyl ester as a main monomer component, 3 to 45% by mass of diacetone acrylamide as an essential monomer component, and no free carboxyl group. The acrylic copolymer (Y) is a copolymer containing (meth) acrylic acid alkyl ester as a main monomer component, a primary amino group and / or carboxyhydrazide group in the side chain, and no free carboxyl group. . When such a resin mixture is used as an adhesive, the carbonyl group derived from diacetone acrylamide contained in the acrylic copolymer (X) and the primary amino contained in the acrylic copolymer (Y). Use for transdermal preparations in that a fine network structure based on a cross-linking reaction with a group or a carboxyhydrazide group can be formed on the entire pressure-sensitive adhesive layer, and drug components can be retained in the network structure. Are preferably used.

  In order to produce the acrylic copolymer (X), there is exemplified a method in which (meth) acrylic acid alkyl ester is a main monomer component and diacetone acrylamide is added in an amount of 3 to 45% by mass with respect to the whole monomer and radical polymerization is performed. Is done. These monomer components can be polymerized by a conventional method using a polymerization initiator such as a peroxide compound or an azo compound. In polymerizing these monomers, it is preferable to add a solvent as appropriate in order to adjust the viscosity of the reaction solution.

  As the (meth) acrylic acid alkyl ester, those having 1 to 12 carbon atoms in the alkyl group are preferably used. Specifically, methyl (meth) acrylate, ethyl (meth) acrylate, propyl (meth) acrylate, butyl (meth) acrylate, (meth) acrylate-2-ethylhexyl, octyl (meth) acrylate, (Meth) acrylic acid dodecyl etc. are mentioned. These (meth) acrylic acid alkyl esters can be used alone or in combination of two or more.

In order to produce the acrylic copolymer (Y), a (meth) acrylic acid alkyl ester is a main monomer component, and a monomer component for introducing a primary amino group and / or a carboxyhydrazide group is introduced. Examples thereof include a method in which the monomer component is added in an amount of 1 to 30% by mass with respect to the whole monomer for radical polymerization, and then the side chain derived from the monomer component for introducing a carboxyhydrazide group is converted to a carboxyhydrazide group. When the monomer component is radically polymerized, it may be polymerized by a conventional method using a polymerization initiator such as a peroxide compound or an azo compound. In radical polymerization of the monomer component, it is preferable to add a solvent as appropriate in order to adjust the viscosity of the reaction solution. In addition, as (meth) acrylic-acid alkylester used when manufacturing a copolymer (B), the thing similar to what was illustrated by the said copolymer (A) can be used.
In addition, the primary amino group and / or carboxyhydrazide group in the acrylic copolymer (Y) exhibits an appropriate crosslinkability with the acrylic copolymer (X). Two or more are preferably present in one molecular chain of (Y), more preferably three or more.
Further, the monomer component for introducing the primary amino group and / or the monomer component for introducing the carboxyhydrazide group and the (meth) acrylic acid alkyl ester monomer have a molar ratio of 1: 5 to 1. : It is preferable to mix and copolymerize so that it may become 100.

  The monomer component for introducing the primary amino group into the acrylic copolymer (Y) has a vinyl group that can be polymerized with (meth) acrylic acid alkyl ester, and has a primary amino group. The compound which has is mentioned. Examples of such a compound include vinylamine.

  As a monomer component for introducing a carboxyhydrazide group into the acrylic copolymer (Y), a keto group having a vinyl group polymerizable with an alkyl (meth) acrylate and capable of reacting with a hydrazide compound The compound which has is mentioned. Examples of such compounds include diacetone acrylamide, acrolein, acetoacetoxyethyl methacrylate, and the like.

  In order to convert a side chain derived from a monomer component for introducing a carboxyhydrazide group into a carboxyhydrazide group, the polymer obtained by the above radical polymerization is dissolved in a polar solvent, and the dicarboxylic acid is dissolved in the presence of an acid catalyst. What is necessary is just to make it react with dihydrazide. Examples of the dicarboxylic acid dihydrazide include adipic acid dihydrazide, glutaric acid dihydrazide, pimelic acid dihydrazide, and the like.

  In addition, the “main monomer component” in the present specification is a monomer component that is contained in an amount of 50% by mass or more with respect to the copolymer, or a monomer component that is contained in the highest proportion among a plurality of monomer components. Means.

(Acr-B)
Next, Acr-B, which is an acrylic resin, will be described. Acr-B is a copolymer of acetoacetoxyalkyl (meth) acrylate and one or more vinyl monomers copolymerizable with the acetoacetoxyalkyl (meth) acrylate, and contains a free carboxyl group It is a copolymer that does not. When such a copolymer is used as a pressure-sensitive adhesive, a fine network structure based on a crosslinking reaction between acetoacetoxyalkyl groups contained in the copolymer can be formed on the whole pressure-sensitive adhesive layer. It is preferably used as a percutaneous absorption-type preparation because it can retain a drug component or the like in its structure.

  Examples of the acetoacetoxyalkyl (meth) acrylate include compounds in which one hydroxyl group of an alkylene glycol is acylated with an acetoacetyl group and the other hydroxyl group is acylated with acrylic acid or methacrylic acid. Examples of such compounds include 2-acetoacetoxyethyl methacrylate and 2-acetoacetoxyethyl acrylate, and 2-acetoacetoxyethyl methacrylate is more preferable. The content of acetoacetoxyalkyl (meth) acrylate in the copolymer is preferably about 5 to 50% by mass, and about 10 to 45% by mass when the total mass of the copolymer is 100. It is more preferable.

  Examples of the vinyl monomer copolymerizable with acetoacetoxyalkyl (meth) acrylate include compounds having a vinyl group in the molecule. Examples of such compounds include (meth) acrylic acid alkyl esters having 1 to 12 carbon atoms in the alkyl group, functional monomers having a functional group such as a hydroxyl group, an amide group, and an alkoxylalkyl group in the molecule, And polyalkylene glycol di (meth) acrylates. These vinyl monomers can be used alone or in combination of two or more.

Specific examples of (meth) acrylic acid alkyl esters having 1 to 12 carbon atoms in the alkyl group include methyl (meth) acrylate, ethyl (meth) acrylate, propyl (meth) acrylate, and (meth) acrylic. Butyl acid, 2-ethylhexyl (meth) acrylate, octyl (meth) acrylate, dodecyl (meth) acrylate, and the like. Specific examples of functional monomers having a functional group in the molecule include (2-methoxyethyl (meth) acrylate, diacetone acrylamide, and 2-hydroxyethyl (meth) acrylate). . Specific examples of polyalkylene glycol di (meth) acrylates include diethylene glycol di (meth) acrylate, triethylene glycol di (meth) acrylate, triethylene glycol di (meth) acrylate, and tetraethylene glycol di (meth) acrylate. ) Acrylate and the like.

  A copolymer of acetoacetoxyalkyl (meth) acrylate and another vinyl monomer is produced by a conventional method using a polymerization initiator such as a peroxide compound or an azo compound.

  As already described, the pressure-sensitive adhesive of this embodiment includes at least the above-mentioned Acr-A that is a cross-linking type resin and Acr-B that is also a cross-linking type resin. In general, when such a cross-linked resin is used as an adhesive, the adhesive strength of the adhesive layer tends to decrease. However, the present inventors have surprisingly found that the pressure-sensitive adhesive using the above Acr-A and Acr-B together exhibits better adhesion than when these resins are used alone, The present invention has been completed. When Acr-A or Acr-B is used alone as an adhesive, the sticking property of the transdermal preparation is almost lost in one day after application to the skin. On the other hand, when Acr-A and Acr-B are used in combination as an adhesive, the sticking property of the transdermal preparation is maintained for 3 days or more after application to the skin. Furthermore, in the present invention, it is not necessary to use a non-crosslinked resin as a pressure-sensitive adhesive in order to impart sticking properties. Therefore, it is possible to add a large amount of drug components to the pressure-sensitive adhesive layer. In addition, it is also possible to add resin which is not a crosslinking type to the adhesive containing said Acr-A and Acr-B as needed.

  The mass ratio of Acr-A and Acr-B contained in the pressure-sensitive adhesive is preferably 90:10 to 49:51, more preferably 90:10 to 50:50, and 85:15 to 50: More preferably, it is 50. Since the Acr-B contained in the pressure-sensitive adhesive is 10% by mass or more, the increase in gel fraction over time is suppressed in the pressure-sensitive adhesive layer to which the drug component or the like is added. Can be made stable. Moreover, when Acr-B contained in an adhesive is 51 mass% or less, the gel fraction of an adhesive can be made sufficient and the sticking time to the skin of a percutaneous absorption type preparation will become long. It is possible to suppress sagging of the pressure-sensitive adhesive layer and a decrease in cohesive force.

  Here, the gel fraction represents the ratio of the solvent-insoluble resin component to the entire resin component in the resin component (adhesive) contained in the adhesive layer. Examples of the solvent in this case include ethyl acetate. Here, since the gel fraction increases as the crosslinking of Acr-A and Acr-B proceeds, the gel fraction is also an index representing the degree of crosslinking by Acr-A and Acr-B. As described above, Acr-A and Acr-B can each be crosslinked independently to form a network structure, but as described above, depending on the ratio of Acr-A and Acr-B, the gel The degree of the fraction changes. Therefore, there is a possibility that some interaction occurs between Acr-A and Acr-B by mixing them. Therefore, by mixing Acr-A and Acr-B, sufficient sticking property as described above can be obtained as a result of some interaction between them.

  In addition, it is preferable that the gel fraction of an adhesive is 30 to 70%. When the gel fraction of the pressure-sensitive adhesive is 30% or more, it is possible to suppress sagging of the pressure-sensitive adhesive layer and a decrease in cohesive force due to an increase in the time for applying the transdermal preparation to the skin. When the gel fraction of the pressure-sensitive adhesive is 70% or less, sufficient skin adhesion can be obtained.

[Plasticizer]
The pressure-sensitive adhesive layer can contain a plasticizer. As such a plasticizer, generally an oily substance having a high boiling point can be used. For example, isopropyl myristate, diethyl sebacate, diisopropyl adipate, ethyl oleate, isopropyl palmitate, ethyl laurate, palmitic Fatty acid ester derivatives such as octyl acid, isotridecyl myristate, medium chain fatty acid triglycerides, higher alcohol derivatives such as hexyl decanol, octyldodecanol, polyalkylene glycols such as polyethylene glycol, polypropylene glycol, olive oil, castor oil, etc. And the like. Among these, isopropyl myristate, isopropyl palmitate, etc. act as a plasticizer for adhesives, and have the effect of promoting the diffusion of the drug component in the percutaneous absorption preparation and the effect of promoting the skin permeation of the drug component. Yes, it is preferable. These can be used alone or in combination of two or more. It is preferable that the compounding quantity of a plasticizer is 1-40 mass% with respect to the whole mass of an adhesive layer, It is more preferable that it is 5-35 mass%, It is most 6-30 mass% preferable. The said effect can fully be acquired because the compounding quantity of a plasticizer is 1 mass% or more with respect to the whole mass of an adhesive layer. When the blending amount of the plasticizer is 40% by mass or less with respect to the total mass of the pressure-sensitive adhesive layer, it is possible to suppress bleeding that causes oily substances to leak from the pressure-sensitive adhesive layer.

[Other components contained in the adhesive layer]
Various additives can be added to the pressure-sensitive adhesive layer in order to impart a required function. Examples of such additives include solvents for dissolving drug components, various pressure-sensitive adhesives, preservatives, pH adjusters, chelating agents, percutaneous absorption accelerators, antioxidants, excipients, fragrances, colorants, and the like. Is exemplified.

  The solvent for dissolving the drug component is not particularly limited as long as it is a solvent capable of dissolving the drug, but is preferably a solvent having no skin irritation. Examples of such solvents include lower alcohols such as ethanol, propanol, and isopropanol, intermediate alcohols such as hexanol and octanol, polyhydric alcohols such as glycerin, ethylene glycol, and diethylene glycol, fatty acid esters, polyvinyl alcohol, and N-methyl. Examples include pyrrolidone and lactic acid. These can be used alone or in combination of two or more.

  In the transdermal preparation of this embodiment, in order to form the pressure-sensitive adhesive layer, as an example, the components to be contained in the pressure-sensitive adhesive layer such as the Acr-A, Acr-B, the drug component, and the plasticizer are solvents. There is a method in which a solution is prepared by dissolving in a solution, and the solution is applied to a support, followed by heat evaporation of the solvent by a known method. The solvent used in such a method is not particularly limited as long as it is an organic solvent that evaporates in the heat-drying step in the manufacturing process of the transdermal preparation, and examples thereof include ketones such as acetone and methyl ethyl ketone, and methyl acetate. , Acetates such as ethyl acetate, propyl acetate, butyl acetate, aliphatic hydrocarbons such as hexane, heptane, octane, cyclohexane, aromatic hydrocarbons such as benzene, toluene, xylene, isopropyl ether, tetrahydrofuran, dioxane, etc. And organic solvents such as ethers. These can be used alone or in combination of two or more.

<Support>
The support is preferably impermeable or impermeable to the drug component and flexible. Specifically, polyethylene, polypropylene, ethylene-vinyl acetate copolymer, ethylene-vinyl acetate-carbon monoxide copolymer, ethylene-butyl acrylate-carbon monoxide copolymer, nylon, polyester (polyethylene terephthalate), poly Examples thereof include a resin film such as butylene terephthalate and an aluminum sheet. These may be laminated | stacked and formed in a sheet form, and may be laminated | stacked with a woven fabric and a nonwoven fabric. Moreover, in order to improve adhesiveness with an adhesive layer, surface treatments, such as a corona treatment and a plasma discharge treatment, may be given, or an anchor coat treatment may be given with an anchor agent.

<Drug component>
The drug component is contained in the pressure-sensitive adhesive layer and is absorbed into the skin through the drug surface which is the surface of the pressure-sensitive adhesive layer. In the transdermally absorbable preparation of this embodiment, fentanyl is used as a drug component. Fentanyl is a compound called 1-phenethyl-4-N-propionylanilinopiperidine. The fentanyl used in the transdermally absorbable preparation of the present embodiment is fentanyl (free form) and / or a salt thereof. Specific examples include fentanyl (free form), fentanyl citrate, fentanyl hydrochloride, fentanyl sulfate, and the like, and fentanyl (free form) and a salt thereof may be used in combination. As the fentanyl used, fentanyl (free form) and / or fentanyl citrate is preferable, and fentanyl (free form) is more preferable.

  The content of fentanyl in the pressure-sensitive adhesive layer can be appropriately determined according to the purpose of use, etc., but if it is too small, the pharmacological activity becomes insufficient, and if it is too much, the blood concentration rapidly increases or the adhesiveness is increased. It is preferable that it is 0.01-50 mass% with respect to the whole mass of an adhesive layer, and it is more preferable that it is 0.5-20 mass%. Fentanyl may be present in the adhesive layer in a dissolved state, a supersaturated state, or a crystalline state. Further, in order to maintain the transdermal absorbability of fentanyl, part of fentanyl may be in a dissolved state and part of it may be in a crystalline state.

  The percutaneous absorption preparation of the present invention has been specifically described with reference to the embodiment. However, the present invention is not limited to the above-described embodiment, and appropriate modifications are made within the scope of the configuration of the present invention. Can be implemented.

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

  Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to the following examples.

[Production Example 1; Acrylic Resin Acr-A]
A solution of acrylic copolymer (X) obtained by the synthesis method shown below and a solution of acrylic copolymer (Y) are combined with acrylic copolymer (X) and acrylic copolymer contained in the solution. It mixed so that mass ratio with a polymer (Y) might be set to 100: 5, and the solution of 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. This mixture was supplied to a separable flask equipped with a stirrer and a reflux cooling device, and heated to 75 ° C. while stirring and purging with nitrogen. A solution in which 2 parts by mass of benzoyl peroxide was dissolved in 20 parts by mass of ethyl acetate was divided into 5 parts, and 1 part thereof was added to a separable flask to initiate polymerization. The remaining 4 parts were added one part at a time interval from 2 hours after the start of the reaction, and after the addition was completed, the reaction was allowed to proceed for another 2 hours. In order to adjust the viscosity, 50 parts by mass of ethyl acetate was added 4 times every 2 hours after the start of the reaction. After completion of the reaction, the mixture was cooled and then ethyl acetate was added to obtain a solution of 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 dodecyl mercaptan as a molecular weight regulator, and 400 parts by mass of ethyl acetate were added and mixed. This mixture was supplied to a separable flask equipped with a stirring device and a reflux cooling device, and the temperature was raised to 70 ° C. while stirring and purging with nitrogen. A solution in which 5 parts by mass of azobisisobutyronitrile was dissolved in 100 parts by mass of ethyl acetate was divided into 5 parts, and 1 part thereof was added to a separable flask to initiate polymerization. The remaining 4 parts were added one part at a time interval from 2 hours after the start of the reaction, and after the addition was completed, the reaction was allowed to proceed for another 2 hours. In order to adjust the viscosity, 50 parts by mass of ethyl acetate was added 4 times every 2 hours after the start of the reaction. Thereafter, 40 parts by weight of adipic acid dihydrazide dissolved in a mixed solution of 40 parts by weight of purified water, 1600 parts by weight of methanol and 260 parts by weight of ethyl acetate was added, and 5 parts by weight of concentrated hydrochloric acid was further added. The temperature was raised to. After completion of the reaction, the mixture is cooled and washed three times with purified water, and then the product is 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, so that the solid content concentration is 30% by mass. A solution of an acrylic copolymer (Y) was obtained.

[Production Example 2: Acrylic resin Acr-B]
Uniformly 158 parts by weight of 2-ethylhexyl acrylate, 35.1 parts by weight of 2-acetoacetoxyethyl methacrylate, 76.2 parts by weight of methyl methacrylate, 80.3 parts by weight of diacetone acrylamide, and 1.0 part by weight of tetraethylene glycol dimethacrylate The monomer solution was prepared. 100 parts by mass of this monomer solution was charged into a 2-liter four-necked flask equipped with a Dimroth cooler, thermometer, nitrogen gas blowing tube, and stirring blade, and 350 parts by mass of ethyl acetate was added as a solvent. The temperature was raised to 75 ° C. while blowing nitrogen gas at a flow rate of 100 mL / min. After maintaining at 75 ° C. for 30 minutes, 0.35 parts by mass of benzoyl peroxide as an initiator was dissolved in 5 parts by mass of ethyl acetate and added. The external temperature was set to 85 ° C. After confirming the reflux of the solvent, the remaining monomer solution was continuously added over 3 hours. One hour after the start of continuous charging of the monomer liquid, 500 parts by mass of ethyl acetate was charged over 3 hours. After stirring for 12 hours after adding ethyl acetate, 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 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 copolymer Z for comparison test. This acrylic copolymer Z was prepared by radical copolymerization of 85 parts by mass of acrylic acid-2-ethylhexyl monomer, 10 parts by mass of acrylic acid-2-hydroxyethyl ester, and 5 parts by mass of vinyl acetate. is there.

[Examples 1 to 8]
The solution of acrylic resin Acr-A obtained in Production Example 1 and the solution of acrylic resin Acr-B obtained in Production Example 2 were mixed, and this mixed solution was mixed with isopropyl myristate (IPM) as a plasticizer. And isopropyl palmitate (IPP) and dibutylhydroxytoluene (BHT) as an additive were added, and the whole liquid was stirred uniformly, and the liquid mixture was obtained. By applying and drying this mixed solution on a support of a PET (polyethylene terephthalate) film having a thickness of 25 μm whose corona treatment has been applied to the coating surface, the thickness of the pressure-sensitive adhesive layer after drying is 50 μm. A pressure-sensitive adhesive layer was formed, and patches for transdermal preparations of Examples 1 to 8 were produced. The blending of each component was performed so that the mass% after drying became a value shown in Table 1. In addition, each numerical value shown in Table 1 means mass%.

[Comparative Examples 1 and 2]
The patches for transdermal absorption type preparations of Comparative Examples 1 and 2 were prepared in the same procedure as in Examples 1 to 8 except that some components were not blended. The blending of each component was performed so that the mass% after drying became a value shown in Table 1.

[Comparative Example 3]
Examples 1 to 8 above, except that instead of the acrylic resin Acr-A, the acrylic copolymer Z obtained in Comparative Preparation Example 1 was used and isopropyl palmitate (IPP) was not blended. A patch for a percutaneous absorption-type preparation of Comparative Example 3 was prepared in the same procedure as described above. The blending of each component was performed so that the mass% after drying became a value shown in Table 1.

[Examples 9 to 18]
The solution of the acrylic resin Acr-A obtained in Production Example 1 and the solution of the acrylic resin Acr-B obtained in Production Example 2 were mixed, and fentanyl as the drug component and myristic as the plasticizer were mixed in this mixed solution. Isopropyl (IPM) and isopropyl palmitate (IPP) and dibutylhydroxytoluene (BHT) as additives were added, and the whole liquid was uniformly stirred to obtain a mixed liquid. This mixed solution was applied on a 25 μm thick PET (polyethylene terephthalate) film support having a corona-treated coating surface so that the fentanyl concentration in the pressure-sensitive adhesive layer after drying was 0.42 mg / cm ^2. The pressure-sensitive adhesive layer was formed by processing and drying, and the percutaneous absorption type preparations of Examples 9 to 18 were produced. The blending of each component was performed so that the mass% after drying became a value shown in Table 2. In addition, each numerical value shown in Table 2 means mass%.

[Comparative Example 4]
Examples 9 to 18 above, except that instead of the acrylic resin Acr-A, the acrylic copolymer Z obtained in Comparative Production Example 1 was used and isopropyl palmitate (IPP) was not blended. The percutaneous absorption type preparation of Comparative Example 4 was prepared in the same procedure as described above. The blending of each component was performed so that the mass% after drying became a value shown in Table 2.

[Evaluation of skin adhesion]
72 hours after applying the patches for transdermal absorption preparations of Examples 1 to 8 and Comparative Examples 1 to 3 (3.2 cm × 3.2 cm; 10 cm ² ) to the upper right arm of 10 monitors. After the lapse of time, the skin application state (peeling state) of each monitor was visually observed. The skin patch condition of each monitor was evaluated according to the following criteria, and the number of monitors corresponding to each evaluation criterion was examined. . The results are shown in Table 3.
◎: No peeling ○: Very slight peeling was observed △: Slightly wide peeling was observed at the four corners, etc. ×: Peeling was recognized in a wide range, or a large shift in the applied site was observed

[Pig transdermal absorption test 1]
After removing the hair from the back of a pig (Landlace & Large Yorkshire, 11 months old, female, weight approximately 25 kg) and washing the surface, a percutaneous absorption preparation was affixed to the site without injury for 72 hours, and the drug component (fentanyl) ) Percutaneous absorption test. After sticking, put impervious oil paper to cover the sticking part, fix with non-woven adhesive bandage, cover the whole with gauze, further cover with adhesive cloth elastic bandage, and then stretch the whole body with elastic net Covered. After 72 hours from the application of the transdermal absorption preparation, the skin application state (peeling state) of each preparation was visually observed, and the pig skin was evaluated according to the same evaluation criteria as the above-mentioned human skin adhesion test. The sticking property was evaluated. In addition, after the 72-hour sticking test, the percutaneous absorption-type preparation used in the test was collected and extracted with methanol under ultrasonic irradiation to examine the remaining amount of the drug component in the preparation. Based on this remaining amount, The amount of drug absorbed through the skin was calculated.
The said test was done with respect to the transdermal absorption type preparation (fentanyl content 2.1 mg / 5cm < ² >) of Examples 9-18 and the comparative example 4. FIG. The results are shown in Table 4.

[Pig transdermal absorption test 2]
After removing the hair from the back of a pig (Landlace & Large Yorkshire, 11 months old, female, weight approximately 25 kg) and washing the surface, a percutaneous absorption preparation was affixed to the site without injury for 72 hours, and the drug component (fentanyl) ) Percutaneous absorption test. After sticking, put impervious oil paper to cover the sticking part, fix with non-woven adhesive bandage, cover the whole with gauze, further cover with adhesive cloth elastic bandage, and then stretch the whole body with elastic net Covered. During the percutaneous absorption test, blood was collected at regular intervals from the cannula inserted from the neck and placed in the central vein, and the concentration of the drug component in the plasma was measured.
The said test was done with respect to the transdermal formulation (fentanyl content 16.8 mg / 40 cm < ² >) of Example 9 and Comparative Example 4. The results are shown in Table 5. In Table 5, AUC is the area under the blood concentration-time curve (ng × hr / ml), and Cmax is the maximum blood concentration (ng / ml).

◎：剥離なし
○：ごく軽度の剥離が認められた
△：四隅等にやや広い剥離が認められた
×：広い範囲に剥離が認められた、又は貼付部位の大幅なずれが認められた

◎: No peeling ○: Very slight peeling was observed △: Slightly wide peeling was observed at the four corners, etc. ×: Peeling was recognized in a wide range, or a large shift in the applied site was observed

  As shown in Table 3, the patches for transdermal absorption preparations of Examples 1 to 8 were peeled after 72 hours from application to the skin, compared with the patches for transdermal absorption preparations of Comparative Examples 1 to 3. It turns out that it is suppressed. From this, when two types of cross-linking type pressure sensitive adhesives, Acr-A and Acr-B, are used in combination, compared to the case where these are used alone or when other pressure sensitive adhesives are used together while using them alone. Thus, it is understood that the adhesive strength lasts for a long time, and the effectiveness of the present invention is understood. In addition, Comparative Example 3 in which Acr-B and a non-crosslinking type adhesive were used in combination had sufficient initial sticking property (initial tack), but the adhesive strength tends to decrease with time, and 72 hours. The later skin adhesion was inferior to Examples 1-8. Such a tendency was also observed in the percutaneous absorption preparations actually containing the drug component (Examples 9 to 18 and Comparative Example 4, Table 4).

  Further, as shown in Table 4, it can be seen that the percutaneous absorption preparations of Examples 9 to 18 have a larger amount of drug percutaneous absorption than the percutaneous absorption preparation of Comparative Example 4. Furthermore, as shown in Table 5, it is understood that the percutaneous absorption preparation of Example 9 shows higher AUC than the percutaneous absorption preparation of Comparative Example 4, and is preferable from the viewpoint of maintaining the blood concentration.

  From the above, according to the transdermally absorbable preparation of the present invention, it is understood that the adhesiveness can be maintained for a long time while using the cross-linking type pressure-sensitive adhesive in the pressure-sensitive adhesive layer, and the drug can be used for a long time. It will be understood that blood concentrations of the components can be maintained.

Claims (5)

A transdermal absorption-type preparation comprising a pressure-sensitive adhesive layer containing at least a pressure-sensitive adhesive on one side of a support,
A transdermal preparation containing the following acrylic resins Acr-A and Acr-B as the adhesive.
(Acr-A)
A resin mixture comprising 100 parts by mass of the following acrylic copolymer (X) and 0.1 to 30 parts by mass of the following acrylic copolymer (Y).
Acrylic copolymer (X); An acrylic copolymer containing (meth) acrylic acid alkyl ester as a main monomer component, 3 to 45% by mass of diacetone acrylamide as an essential monomer component, and no free carboxyl group.
Acrylic copolymer (Y); Acrylic copolymer containing (meth) acrylic acid alkyl ester as the main monomer component, containing a primary amino group and / or carboxyhydrazide group in the side chain, and no free carboxyl group .
(Acr-B)
A copolymer of acetoacetoxyalkyl (meth) acrylate and one or more vinyl monomers copolymerizable with the acetoacetoxyalkyl (meth) acrylate, which does not contain a free carboxyl group.   The transdermal preparation according to claim 1, wherein the pressure-sensitive adhesive layer further contains a drug and / or a plasticizer.   The transdermal preparation according to claim 2, wherein the drug is fentanyl and / or a salt thereof.   The transdermal preparation according to claim 2 or 3, wherein the plasticizer is isopropyl myristate and / or isopropyl palmitate.   The transdermal absorption type according to any one of claims 1 to 4, wherein the mass ratio of the acrylic resins Acr-A and Acr-B contained in the adhesive is 90:10 to 49:51. Formulation.