JP2014051467A - Patch - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a patch containing donepezil in which the stability of donepezil is high and the skin permeability of donepezil is excellent.SOLUTION: The patch comprises a support and an adhesive layer positioned on the support. The adhesive layer contains at least donepezil and/or hydrochloride thereof, two kinds or more of additives selected from the group consisting of isostearic acid, propylene carbonate and octyldodecanol, and an adhesive agent. The patch may be used for treatment or prevention of Alzheimer's disease.

Description

  The present invention relates to a patch.

  Donepezil is known as a progression inhibitor of Alzheimer-type dementia symptoms. As a preparation containing donepezil, a donepezil-containing tablet (trade name; Aricept (registered trademark)) is commercially available. On the other hand, donepezil-containing patches that are easier to handle and administer than tablets have been studied (for example, Patent Documents 1 to 5).

International Publication No. 2003/32960 Pamphlet International Publication No. 2006/82728 Pamphlet JP 2007-217328 A JP 2007-302582 A International Publication No. 2008/66179 Pamphlet

  However, in the conventional donepezil-containing patch, the skin permeability of donepezil in the patch is not sufficient.

  The present invention has been made in view of such circumstances, and an object of the present invention is to provide a donepezil-containing patch having a high stability of donepezil and good skin permeability of donepezil.

  The present inventors have found that the above problems can be solved by blending predetermined additives and adhesives as components of the donepezil-containing patch, and have completed the present invention. Specifically, the present invention provides the following.

(1) A patch comprising a support and a pressure-sensitive adhesive layer located on the support,
The pressure-sensitive adhesive layer is
Donepezil and / or its hydrochloride;
Two or more additives selected from the group consisting of isostearic acid, propylene carbonate and octyldodecanol;
A patch comprising at least an adhesive.

(2) The adhesive patch according to (1), wherein the pressure-sensitive adhesive is an acrylic pressure-sensitive adhesive containing at least the following pressure-sensitive adhesive (I) or pressure-sensitive adhesive (II).
Adhesive (I): A resin mixture comprising 100 parts by mass of the following acrylic copolymer (A) and 0.1 to 30 parts by mass of the following acrylic copolymer (B) or 0.05 to 2 parts by mass of a polyamine compound. .
Acrylic copolymer (A); An acrylic copolymer containing (meth) acrylic acid alkyl ester as a main monomer component, diacetone acrylamide in an amount of 3 to 45% by mass as an essential monomer component, and no free carboxyl group.
Acrylic copolymer (B); (meth) acrylic acid alkyl ester as the main monomer component, side chain containing primary amino group and / or carboxyhydrazide group, and free acrylic group .
Adhesive (II): A copolymer of acetoacetoxyalkyl (meth) acrylate and one or more vinyl monomers copolymerizable with the acetoacetoxyalkyl (meth) acrylate, which has a free carboxyl group Copolymer not containing.

  (3) The patch according to (1) or (2), wherein the additive includes isostearic acid.

  (4) The patch according to (3), wherein the pressure-sensitive adhesive layer contains 6 to 11% by mass of isostearic acid.

  (5) The patch according to any one of (2) to (4), wherein the acrylic pressure-sensitive adhesive includes the pressure-sensitive adhesive (I) and the pressure-sensitive adhesive (II).

  (6) The patch according to any one of (1) to (5), which is used for treatment or prevention of Alzheimer-type dementia.

  According to the present invention, a donepezil-containing patch with high donepezil stability and good skin penetration of donepezil is provided.

It is a figure which shows the cumulative skin permeation amount of donepezil in the patch which concerns on the Example of this invention. It is a figure which shows the skin permeation rate of donepezil in the patch which concerns on the Example of this invention.

  Hereinafter, embodiments of the present invention will be specifically described.

  The present invention provides a patch comprising a support and an adhesive layer located on the support and containing a predetermined component such as donepezil. When the pressure-sensitive adhesive layer provided on the support comes into contact with the skin, donepezil in the pressure-sensitive adhesive layer is absorbed from the pressure-sensitive adhesive layer to the skin, and a desired therapeutic effect is exhibited. Hereinafter, each structure of the patch will be described.

[Adhesive layer]
The pressure-sensitive adhesive layer in the present invention contains at least donepezil and / or its hydrochloride, a predetermined additive, and a pressure-sensitive adhesive.

(Donepezil)
As donepezil in the present invention, donepezil (free form) exhibiting an acetylcholinesterase inhibitory action and / or its hydrochloride can be used. The free form of donepezil is preferable in terms of good skin permeability. The free form of donepezil may be obtained by treating donepezil hydrochloride or the like with sodium hydroxide or the like.

  The content of donepezil in the pressure-sensitive adhesive layer can be appropriately adjusted according to the therapeutic effect to be obtained. For example, donepezil in the pressure-sensitive adhesive layer may be contained in the pressure-sensitive adhesive layer by 0.1% by mass or more, preferably 1% by mass or more, more preferably 5% by mass or more, and most preferably 10% by mass or more. . In the patch of the present invention, since the additive and the adhesive described later are included, even if the content of donepezil in the patch is high, donepezil is sufficiently dispersed in the adhesive layer, and the donepezil skin The release property is good.

  Further, donepezil in the pressure-sensitive adhesive layer may be contained in the pressure-sensitive adhesive layer at 25% by mass or less, preferably 20% by mass or less. Even if donepezil content in the pressure-sensitive adhesive layer in the present invention is low, good donepezil skin permeability can be realized.

(Additive)
The present inventors blended two or more additives selected from the group consisting of isostearic acid, propylene carbonate and octyldodecanol into the adhesive layer, thereby stabilizing the stability and skin permeability of donepezil in the patch. I found out that I can raise it. Isostearic acid has an action as a solubilizing agent and / or crystallization inhibitor of donepezil, and can preferably suppress crystallization of donepezil in the patch. In addition, propylene carbonate and octyldodecanol have a function as a solubilizer, can enhance the compatibility between donepezil and other components in the adhesive layer, and can stably dissolve donepezil in the adhesive layer. .

  Since isostearic acid has a particularly high effect of improving the solubility of donepezil, when isostearic acid is used in combination with propylene carbonate and / or octyldodecanol, a large amount of donepezil (for example, 10% by mass or more) is blended. In addition, skin permeability can be enhanced while suppressing crystallization of donepezil in the patch.

  In particular, when isostearic acid is used in combination with propylene carbonate, the skin permeability of donepezil can be increased. Furthermore, when isostearic acid, propylene carbonate and octyldodecanol are blended in the pressure-sensitive adhesive layer, the stability of donepezil can be particularly enhanced. In addition, when isostearic acid, propylene carbonate and octyldodecanol are used in combination, higher donepezil skin permeability can be realized as compared with the case where isostearic acid is used alone.

  The content of the additive in the pressure-sensitive adhesive layer is not particularly limited, but the total amount of additives in the pressure-sensitive adhesive layer is 5 to 50% by mass, preferably 10 to 50% by mass, more preferably 10 to 45% by mass. There may be. When the additive contains isostearic acid and propylene carbonate and / or octyldodecanol, the proportion of isostearic acid in the pressure-sensitive adhesive layer may be 1 to 30% by mass, and propylene carbonate is in the pressure-sensitive adhesive layer. 1-10 mass% may be sufficient, and 5-20 mass% may be sufficient as the ratio in an adhesive layer of octyldodecanol. When the additive is a combination of propylene carbonate and octyldodecanol, the proportion of propylene carbonate in the pressure-sensitive adhesive layer may be 1 to 10% by mass, and octyldodecanol has a proportion in the pressure-sensitive adhesive layer. 5-20 mass% may be sufficient.

  When isostearic acid is contained in the additive, the proportion of isostearic acid in the pressure-sensitive adhesive layer is 1 to 30% by mass, preferably 5 to 20% by mass, more preferably 6 to 15% by mass, and further preferably 6 to 11%. It may be mass%. It is preferable to set the ratio of isostearic acid in the pressure-sensitive adhesive layer to 6% by mass or more in the pressure-sensitive adhesive layer because crystallization of donepezil can be particularly suppressed. Further, when the proportion of isostearic acid in the pressure-sensitive adhesive layer is 11% by mass or less in the pressure-sensitive adhesive layer, the balance with the effects of other components in the pressure-sensitive adhesive layer is maintained, and the skin permeability of donepezil is effectively enhanced. This is preferable.

(Adhesive)
The pressure-sensitive adhesive in the present invention is not particularly limited as long as it is generally used for patches applied to the skin, and one or more of an acrylic pressure-sensitive adhesive, a rubber-based pressure-sensitive adhesive, or a silicon-based pressure-sensitive adhesive. There may be.

  An acrylic pressure-sensitive adhesive is preferred because of its high adhesiveness to the skin and low irritation. Among the acrylic pressure-sensitive adhesives, an acrylic pressure-sensitive adhesive that substantially does not contain a carboxyl group is preferable in that the reactivity with donepezil is low and the decrease in the transdermal absorbability of donepezil can be suppressed. “Substantially free of free carboxyl groups” means that all carboxyl groups have been converted into substituents such as ester bonds by design, including, for example, a small portion of esters. A case where a bond or the like is converted to a free carboxyl group by hydrolysis or a case where a free carboxyl group is included as an impurity derived from a raw material is also included.

  Although it does not specifically limit as an acrylic adhesive which does not contain a carboxyl group substantially, The acrylic adhesive containing at least the following adhesive (I) or adhesive (II) is preferable. These adhesives not only have high adhesiveness to the skin and low skin irritation, but also have low reactivity with donepezil, thus suppressing the decrease in transdermal absorbability while maintaining the stability of donepezil. it can. The acrylic pressure-sensitive adhesive in the present invention preferably contains the following pressure-sensitive adhesive (I) and pressure-sensitive adhesive (II) in that the effect of increasing the skin permeability of donepezil in the patch is high. Hereinafter, the adhesive (I) and the adhesive (II) will be described.

[Adhesive (I)]
The pressure-sensitive adhesive (I) is a resin comprising 100 parts by mass of the following acrylic copolymer (A) and 0.1-30 parts by mass of the following acrylic copolymer (B) or 0.05-2 parts by mass of a polyamine compound. It is a mixture.
Acrylic copolymer (A); An acrylic copolymer containing (meth) acrylic acid alkyl ester as a main monomer component, diacetone acrylamide in an amount of 3 to 45% by mass as an essential monomer component, and no free carboxyl group.
Acrylic copolymer (B); (meth) acrylic acid alkyl ester as the main monomer component, side chain containing primary amino group and / or carboxyhydrazide group, and free acrylic group .

  The pressure-sensitive adhesive (I) is a bridge between a carbonyl group derived from diacetone acrylamide contained in the acrylic copolymer (A) and a primary amino group or carboxyhydrazide group contained in the acrylic copolymer (B). A fine network structure based on the reaction can be formed on the entire pressure-sensitive adhesive layer, and donepezil and the like can be retained in the network structure.

  The pressure-sensitive adhesive (I) can be prepared, for example, according to WO 2011/027786 pamphlet or JP-A-2005-325101.

  Specific methods for preparing the pressure-sensitive adhesive (I) include the following methods. In order to produce an acrylic copolymer (A), (meth) acrylic acid alkyl ester is used as a main monomer component, and diacetone acrylamide, which is also a monomer component, is used in an amount of 3 to 45% by mass based on the whole monomer. The method of adding and carrying out radical polymerization is illustrated. 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, a (meth) acrylic acid alkyl ester having an alkyl group having 1 to 12 carbon atoms is 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 alkyl (meth) acrylates can be used alone or in combination of two or more.

  The acrylic copolymer (A) preferably has a number average molecular weight of 100,000 to 1,500,000 and a weight average molecular weight of 300,000 to 2.5 million. It is preferable that the molecular weight of the acrylic copolymer (A) is in the above range since the adhesive layer of the donepezil-containing patch exhibits appropriate adhesiveness to the skin. The number average molecular weight of the acrylic copolymer (A) is more preferably 300,000 to 1,000,000, and most preferably 500,000 to 800,000 in the above range. Further, the weight average molecular weight of the acrylic copolymer (A) is more preferably 500,000 to 2,000,000, and most preferably 1,000,000 to 1,500,000 in the above range.

  In order to produce the acrylic copolymer (B), a (meth) acrylic acid alkyl ester is used as a main monomer component, and a monomer component for introducing a primary amino group and / or a carboxyhydrazide group is introduced. Illustrated is a method in which a monomer component is added so as to be 1 to 30% by mass with respect to the whole monomer and radical polymerization is performed, and then a side chain derived from the monomer component for introducing a carboxyhydrazide group is converted to a carboxyhydrazide group. Is done. 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 an acrylic copolymer (B), it is possible to use the same thing as what was illustrated by the said acrylic copolymer (A). it can.

  In addition, the primary amino group and / or carboxyhydrazide group in the acrylic copolymer (B) exhibits an appropriate crosslinkability with the acrylic copolymer (A). In one molecular chain of (B), two or more are preferably present, and 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 (B) has a vinyl group that can be polymerized with (meth) acrylic acid alkyl ester, and has a primary amino group. Compounds. Examples of such a compound include vinylamine.

  As a monomer component for introducing a carboxyhydrazide group into the acrylic copolymer (B), there is 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 in the presence of an acid catalyst is added. Dihydrazide may be reacted. Examples of the dicarboxylic acid dihydrazide include adipic acid dihydrazide, glutaric acid dihydrazide, pimelic acid dihydrazide, and the like.

  The number average molecular weight of the acrylic copolymer (B) is preferably 1500 to 50000, and the weight average molecular weight is preferably 2000 to 100,000. When the molecular weight of the acrylic copolymer (B) is not less than the above lower limit value, it is preferable because the mixed solution is prevented from being gelled and the coating property when producing the pressure-sensitive adhesive layer is improved. . Moreover, since the molecular weight of an acrylic copolymer (B) is below the said upper limit, since a moderate crosslinked state can be obtained between acrylic copolymers (A), it is preferable. The number average molecular weight of the acrylic copolymer (B) is more preferably 2000 to 10000, and most preferably 3000 to 8000, in the above range. Moreover, as for the weight average molecular weight of an acryl-type copolymer (B), it is more preferable that it is 5000-20000 among the said range, and it is most preferable that it is 8000-15000.

  As the pressure-sensitive adhesive (I), a resin mixture comprising 100 parts by mass of the acrylic copolymer (A) and 0.05 to 2 parts by mass of the polyamine compound can be used as the pressure-sensitive adhesive. Examples of the polyamine compound include polyhydrazide compounds (such as adipic acid dihydrazide) described in International Publication No. 2011/027786 pamphlet and the like. These compounds can be prepared according to the above pamphlet.

  Although content of the adhesive (I) in an adhesive layer is not specifically limited, 25-75 mass% in an adhesive layer, Preferably it is 35-65 mass%, More preferably, it is 35-60 mass%, More preferably 40-60 mass% may be sufficient.

[Adhesive (II)]
The pressure-sensitive adhesive (II) is a copolymer of acetoacetoxyalkyl (meth) acrylate and one or more vinyl monomers copolymerizable with the acetoacetoxyalkyl (meth) acrylate, which is a free carboxyl group It is a copolymer that does not contain.

  The pressure-sensitive adhesive (II) can form a fine network structure based on a cross-linking reaction between acetoacetoxyalkyl groups contained in the copolymer on the entire pressure-sensitive adhesive, and can retain donepezil and the like in the network structure.

  The pressure-sensitive adhesive (II) can be prepared according to, for example, Japanese Patent No. 3809462. For example, a copolymer of acetoacetoxyalkyl (meth) acrylate and another vinyl monomer is a peroxide compound or an azo compound. It can manufacture by a conventional method using a polymerization initiator.

  Examples of the acetoacetoxyalkyl (meth) acrylate include those 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. As such a compound, for example, 2-acetoacetoxyethyl methacrylate, 2-acetoacetoxyethyl acrylate and the like are preferably used, and 2-acetoacetoxyethyl methacrylate is more preferably used. The content of acetoacetoxyalkyl (meth) acrylate is preferably about 5 to 50% by mass, more preferably about 10 to 45% by mass, when the total mass of the copolymer is 100. .

  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 and the like. These compounds 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. Examples include 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.

  Although content of the adhesive (II) in an adhesive layer is not specifically limited, 5-40 mass% in an adhesive layer, Preferably it is 10-30 mass%, More preferably, it is 10-25 mass%, More preferably 10-20 mass% may be sufficient.

  When a mixture of the pressure-sensitive adhesive (I) and the pressure-sensitive adhesive (II) is used as the acrylic pressure-sensitive adhesive in the pressure-sensitive adhesive layer (that is, the acrylic pressure-sensitive adhesive contains the pressure-sensitive adhesive (I) and the pressure-sensitive adhesive (II). Case), the total amount of the pressure-sensitive adhesive in the pressure-sensitive adhesive layer may be 30 to 95% by mass, preferably 30 to 85% by mass, and more preferably 30 to 80% by mass. Each ratio of adhesive (I) and adhesive (II) may be in the above-mentioned range. If the ratio of the pressure-sensitive adhesive (I) to the pressure-sensitive adhesive (II) is high, the skin permeability of donepezil can be increased more effectively.

(Other ingredients)
The pressure-sensitive adhesive layer in the present invention may contain other components as necessary. Such components include antioxidants (dibutylhydroxytoluene, etc.), tackifiers (rosin esters, etc.), plasticizers, preservatives, pH adjusters, chelating agents, transdermal absorption promoters, excipients, perfumes. , Colorants, fatty acids, fats and oils, cholesterol and the like.

  The content of other components in the pressure-sensitive adhesive layer is not particularly limited, but the total amount of other components in the pressure-sensitive adhesive layer is 0.01 to 20% by mass, preferably 0.05 to 10% by mass, and more preferably. 0.1-5 mass% may be sufficient.

[Support]
The support in the present invention is preferably impermeable or hardly permeable to drug components 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 to the surface of a support body, or an anchor coat process may be given with an anchor agent.

  A release sheet for protecting the surface of the pressure-sensitive adhesive layer may be provided on the surface of the pressure-sensitive adhesive layer opposite to the support. When the patch user peels off the release sheet to expose the surface of the pressure-sensitive adhesive layer, the patch becomes ready for use. The material of the release sheet can be easily removed from the pressure-sensitive adhesive layer, and is preferably impermeable to active ingredients. As such a material, for example, a plastic film such as polyethylene, polyester, polyvinyl chloride, and polypropylene, a single layer film selected from materials such as a metal film, or a laminated film obtained by laminating two or more kinds of materials can be given. Those obtained by treating the surface of these films with silicon can also be used.

[Method for preparing patch]
The method for preparing the patch of the present invention is not particularly limited, and can be prepared by a known method for preparing patches. For example, the patch of the present invention can be obtained after uniformly stirring the components constituting the pressure-sensitive adhesive layer and coating and drying the obtained composition on the surface of the support using a coating machine.

[Patch of the present invention]
The patch of the present invention is excellent in skin penetration of donepezil. The skin permeability of donepezil is evaluated by conducting a known skin permeability test and measuring the (cumulative) skin penetration amount and / or skin penetration rate of donepezil.

  The patch of the present invention is excellent in the stability of donepezil in the patch. The stability of donepezil is determined as follows. First, the patch is placed in a PAN / Al / PET bag (a bag using a film in which PAN (polyacrylonitrile), Al (aluminum), and PET (polyethylene terephthalate) are laminated) and 60 ° C. (humidity 75%). Store in the dark. Next, the donepezil content after 1 week and 2 weeks after storage is measured.

  Since the patch of the present invention contains a predetermined additive, the stability of donepezil in the patch is excellent, and the crystallization of donepezil can be suppressed. In addition, since the patch of the present invention is excellent in the compatibility of the components in the patch, the bleeding of the dissolving agent can be suppressed.

  As described above, since the patch of the present invention is excellent in the skin permeability of donepezil and the like, donepezil can be suitably percutaneously absorbed into the body. Therefore, the patch of the present invention can be conveniently used for the treatment or prevention of Alzheimer-type dementia because it can easily administer donepezil.

  The present invention will be described in detail with reference to the following examples, but these examples illustrate the present invention and do not limit the scope of the present invention.

  The acrylic pressure-sensitive adhesive used in this example is the following pressure-sensitive adhesive (I) or pressure-sensitive adhesive (II).

<Adhesive (I)>
The copolymer (A) solution obtained by the synthesis method shown below and the copolymer (B) solution are in a mass ratio of 100: 5 (copolymer (A): copolymer (B)). The pressure-sensitive adhesive (I) was obtained.

[Copolymer (A) of adhesive (I)]
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 stirring device and a reflux cooling device, and the temperature was raised 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 by one at intervals of 1 hour from the 2nd hour after the start of the reaction, and after the addition was completed, the reaction was continued 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 copolymer (A) used for the pressure-sensitive adhesive (I) having a solid content concentration of 30% by mass.

[Copolymer of pressure-sensitive adhesive (I) (B)]
660 parts by mass of ethyl acrylate, 70 parts by mass of diacetone acrylamide, 40 parts by mass of dodecyl mercaptan and 400 parts by mass of ethyl acetate as a molecular weight regulator 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 by one at intervals of 1 hour from the 2nd hour after the start of the reaction, and after the addition was completed, the reaction was continued for another 2 hours. In order to adjust the viscosity, 50 parts by mass of ethyl acetate was added three times every 2 hours after the start of the reaction. Thereafter, 40 parts by mass of adipic acid dihydrazide dissolved 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 was added, and further 5 parts by mass of concentrated hydrochloric acid was 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 copolymer (B) used for the pressure-sensitive adhesive (I) was obtained.

<Adhesive (II)>
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 To prepare a monomer solution. 100 parts by mass of this monomer solution was charged into a 2-liter four-necked flask equipped with a Dimro 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. From the start of continuous addition of monomer solution, 500 parts by mass of ethyl acetate was added 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, heat-treated for 12 hours, and then cooled to obtain an adhesive (II).

<Comparative example 1 and Examples 1-6>
A composition was prepared according to the formulation shown in Table 1, and coated and dried (60 ° C., 15 minutes) on a support (using a PET film) to obtain a patch, which was used for each of the following tests. Note that KE-311 (Pine Crystal, manufactured by Arakawa Chemical Industries, Ltd.) is a tackifier containing a rosin ester, and BHT (official name: dibutylhydroxytoluene, manufactured by JGC Universal Co., Ltd.) is an antioxidant. Hereinafter, “%” in the table represents mass%.

(Investigation of skin penetration and skin permeation rate of donepezil)
Using the obtained patch, a skin permeability test using the skin of a hairless mouse was performed, and the skin permeation amount and skin permeation rate of donepezil per skin area were calculated. Cut the skin of hairless mice (7 weeks old, male) to 24 mmΦ, and put the obtained skin pieces on a 6-well cell culture plate (each well was filled with 1.3 mL of PBS as a receiver solution). It was installed so as to be on the side. An adhesive layer of a patch punched out to a size of 10 mmΦ was affixed to the stratum corneum side of the skin. The temperature condition was maintained at 32 ° C., and the receiver solution was collected multiple times over time for 30 hours from the placement of the skin. The concentration of donepezil in the collected receiver solution is measured by HPLC, and the cumulative skin permeation amount of donepezil per skin area and skin permeation rate (average rate in steady state) at 30 hours after application based on the obtained numerical values. Calculated.

  The evaluation results of the cumulative skin permeation amount of donepezil are shown in FIG. 1 (mean value ± SD, n = 3). As shown in FIG. 1, the patch of the present invention had good skin penetration of donepezil. Moreover, the evaluation result of the skin penetration rate of donepezil is shown in FIG. 2 (mean value ± SD, n = 3). As shown in FIG. 2, the patch of the present invention had a high skin penetration rate of donepezil.

  From the results of Example 4 and the like, it was confirmed that the patch containing isostearic acid as an additive had high skin permeability. In particular, from the results of Example 3 and the like, it was confirmed that isostearic acid has high skin permeability when used in combination with propylene carbonate. From the results of Examples 1 and 2, it was confirmed that the skin permeability was particularly good when 6 to 11% by mass of isostearic acid was contained. Moreover, from the results of Examples 2 and 6, it was confirmed that the skin permeability was high when the adhesive (I) and the adhesive (II) were included as the acrylic adhesive.

(Evaluation of the stability of donepezil)
The obtained patch was placed in a PAN / Al / PET bag and stored at 60 ° C. (humidity 75%). After storage, the donepezil content after 1 week and 2 weeks was measured by HPLC (UV271 nm). The evaluation results are shown in Table 2.

  As shown in Table 2, in the patch of the present invention, donepezil in the patch was stable. In particular, when isostearic acid, propylene carbonate and octyldodecanol were blended in the adhesive layer, the stability of donepezil was particularly high (Examples 1 and 2).

Claims (6)

A patch comprising a support and an adhesive layer located on the support,
The pressure-sensitive adhesive layer is
Donepezil and / or its hydrochloride;
Two or more additives selected from the group consisting of isostearic acid, propylene carbonate and octyldodecanol;
A patch comprising at least an adhesive. The patch according to claim 1, wherein the pressure-sensitive adhesive is an acrylic pressure-sensitive adhesive containing at least the following pressure-sensitive adhesive (I) or pressure-sensitive adhesive (II).
Adhesive (I): A resin mixture comprising 100 parts by mass of the following acrylic copolymer (A) and 0.1 to 30 parts by mass of the following acrylic copolymer (B) or 0.05 to 2 parts by mass of a polyamine compound. .
Acrylic copolymer (A); An acrylic copolymer containing (meth) acrylic acid alkyl ester as a main monomer component, diacetone acrylamide in an amount of 3 to 45% by mass as an essential monomer component, and no free carboxyl group.
Acrylic copolymer (B); (meth) acrylic acid alkyl ester as the main monomer component, side chain containing primary amino group and / or carboxyhydrazide group, and free acrylic group .
Adhesive (II): A copolymer of acetoacetoxyalkyl (meth) acrylate and one or more vinyl monomers copolymerizable with the acetoacetoxyalkyl (meth) acrylate, which has a free carboxyl group Copolymer not containing.   The patch according to claim 1 or 2, wherein the additive comprises isostearic acid.   The patch according to claim 3, comprising 6 to 11% by mass of isostearic acid in the pressure-sensitive adhesive layer.   The patch according to any one of claims 2 to 4, wherein the acrylic pressure-sensitive adhesive includes the pressure-sensitive adhesive (I) and the pressure-sensitive adhesive (II).   The patch according to any one of claims 1 to 5, which is used for treatment or prevention of Alzheimer-type dementia.

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