JPWO2016190002A1 - Patch - Google Patents

Abstract

An object of the present invention is to provide a donepezil-containing patch with reduced skin irritation. The present invention is a patch comprising a support and an adhesive layer located on the support, wherein the adhesive layer comprises donepezil and / or a pharmaceutically acceptable hydrochloride thereof, and an absorption accelerator. And an adhesive, and a patch that is continuously applied to a patient for 65 hours or more and 96 hours or less.

Description

  The present invention relates to a patch.

  Donepezil is known as a progression inhibitor of Alzheimer-type dementia. 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 developed (for example, Patent Documents 1 to 4).

Special table 2013-529680 gazette JP 2012-236773 A JP 2014-28791 A JP 2014-51467 A

  By the way, it was known that the donepezil-containing patch is likely to cause erythema or the like at the application site of the patch and has high skin irritation. In conventional donepezil-containing patches, the stability and skin permeability of donepezil in the patches have been studied, but the means for reducing skin irritation causing erythema and the like has not been known.

  The present invention has been made in view of such circumstances, and an object thereof is to provide a donepezil-containing patch with reduced skin irritation.

  The present inventors have found that skin irritation is unexpectedly reduced when the donepezil-containing patch is continuously applied to a patient for about 3 to 4 days, that is, 65 hours or more and 96 hours or less, The present invention has been completed. Specifically, the present invention provides the following.

  (1) A patch comprising a support and an adhesive layer positioned on the support, wherein the adhesive layer comprises donepezil and / or a pharmaceutically acceptable hydrochloride thereof, and an absorption accelerator. A patch that is applied to a patient continuously for 65 hours or more and 96 hours or less.

  (2) The patch according to (1), wherein the content of the absorption accelerator is 0.10% by mass or more and 10.0% by mass or less with respect to the pressure-sensitive adhesive layer.

  (3) The patch according to (1) or (2), wherein the pressure-sensitive adhesive layer contains an acrylic pressure-sensitive adhesive.

  (4) The patch according to (3), wherein the content of the acrylic pressure-sensitive adhesive is 20% by mass or more and 90% by mass or less with respect to the pressure-sensitive adhesive layer.

  (5) The patch according to any one of (1) to (4), wherein the pressure-sensitive adhesive layer has a thickness of 40.0 μm to 200 μm.

  (6) The patch according to any one of (1) to (5), wherein the patient is an Alzheimer type dementia patient.

  According to the present invention, a donepezil-containing patch with reduced skin irritation is provided.

It is a figure which shows the skin permeation amount of donepezil in the patch which concerns on 1 aspect of this invention. It is a figure which shows the skin permeation amount of donepezil in the patch which concerns on 1 aspect of this invention. It is a figure which shows the skin irritation of donepezil by the patch which concerns on 1 aspect of this invention. It is a figure which shows the skin irritation of donepezil by the patch which concerns on 1 aspect of this invention. It is a figure which shows the skin irritation of donepezil by the patch which concerns on 1 aspect of this invention. It is a figure which shows the skin irritation of the rivastigmine containing patch which is a reference example.

  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. The patch of the present invention has a technical feature in that it is continuously applied to a patient for 65 hours or more and 96 hours or less. Hereinafter, each configuration of the patch of the present invention will be described.

[Adhesive layer]
The pressure-sensitive adhesive layer in the present invention includes at least donepezil and / or a pharmaceutically acceptable hydrochloride thereof, an absorption enhancer, and a pressure-sensitive adhesive.

(Donepezil)
As donepezil in the present invention, donepezil (free form) exhibiting an acetylcholinesterase inhibitory action and / or a pharmaceutically acceptable hydrochloride thereof 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. Donepezil tends to cause erythema on the skin surface and has skin irritation. ADVANTAGE OF THE INVENTION According to this invention, skin irritation can be reduced, fully exhibiting the medicinal effect by donepezil.

  The lower limit of the content of donepezil in the pressure-sensitive adhesive layer is not particularly limited, but is preferably 0.1% by mass or more, more preferably 1.0% by mass or more, and further preferably 5.0% by mass in the pressure-sensitive adhesive layer. % Or more, most preferably 8.0% by mass or more. When the lower limit of the content of donepezil in the pressure-sensitive adhesive layer is within the above range, the medicinal effect of donepezil is easily achieved.

  The upper limit of the content of donepezil in the pressure-sensitive adhesive layer is not particularly limited, but is preferably 25% by mass or less, more preferably 20% by mass or less, and further preferably 15% by mass or less in the pressure-sensitive adhesive layer. Also good. When the upper limit of the content of donepezil in the pressure-sensitive adhesive layer is within the above range, crystallization and yellowing of donepezil are easily suppressed.

(Absorption accelerator)
The “absorption enhancer” in the present invention refers to a substance having an action of promoting the skin permeability of donepezil in a patch. By incorporating an absorption enhancer into the patch, a sufficient amount of donepezil can penetrate the skin even if the amount of donepezil blended into the patch is reduced, and the skin can be stimulated by donepezil. Can be reduced. Examples of the absorption accelerator in the present invention include surfactants (polyoxyethylene alkyl ethers such as polyoxyethylene cetyl ether, polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, and polyoxyethylene stearyl ether), fatty acid esters, and the like. (Isopropyl myristate, hexadecyl isostearate, cetyl 2-ethylhexanoate, etc.), fatty acids (isostearic acid, etc.), alcohols (octyldodecanol, etc.), ester compounds (propylene carbonate, etc.) and the like. These absorption promoters are preferable in that they have not only the effect of improving the skin permeability of donepezil but also the effect of suppressing the crystallization of donepezil. One or a combination of two or more absorption promoters can be used.

  The lower limit of the content of the absorption accelerator in the pressure-sensitive adhesive layer is not particularly limited, but the total amount of the absorption accelerator in the pressure-sensitive adhesive layer is preferably 0.10% by mass or more, more preferably 0.50% by mass or more. It may be included. When the lower limit value of the content of the absorption accelerator in the pressure-sensitive adhesive layer is within the above range, the effect of promoting the skin permeability by the absorption accelerator can be easily achieved.

  The upper limit of the content of the absorption accelerator in the pressure-sensitive adhesive layer is not particularly limited, but the total amount of the absorption accelerator in the pressure-sensitive adhesive layer is preferably 10.0% by mass or less, more preferably 5.00% by mass or less. More preferably, it may be contained at 2.00% by mass or less. When the upper limit of the content of donepezil in the pressure-sensitive adhesive layer is within the above range, crystallization and yellowing of donepezil are easily suppressed.

  As the absorption enhancer in the present invention, polyoxyethylene lauryl ether is particularly preferable from the viewpoint of easily increasing the skin permeation amount of donepezil while reducing the skin irritation of the patch.

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

  An acrylic pressure-sensitive adhesive is preferred as the pressure-sensitive adhesive in the present invention because it has 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.

The acrylic pressure-sensitive adhesive which does not substantially contain a carboxyl group is not particularly limited, and may be an acrylic pressure-sensitive adhesive containing a copolymer containing at least diacetone acrylamide as a constituent component. Moreover, even if it is an acrylic adhesive containing the copolymer of diacetone acrylamide and the polyacrylate containing 1 or more types selected from the group which consists of 2-ethylhexyl acrylate, ethyl acrylate, and butyl acrylate, etc. Good. The following acrylic copolymer (A) is low in that it has low self-adhesiveness (a phenomenon in which the adhesive layer surfaces adhere to each other) and can keep the blood concentration of donepezil in the patch at a predetermined level for a long time. A resin mixture (hereinafter also referred to as “adhesive Acr”) comprising 100 parts by mass 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 is preferable.
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 Acr is used for a crosslinking reaction 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 can be formed on the entire pressure-sensitive adhesive layer, and donepezil or the like can be retained in the network structure.

  Since the patch of the present invention is continuously applied for 65 hours or more and 96 hours or less, it is preferable to use an adhesive that maintains adhesiveness for a long time and has low self-adhesiveness. Since such a request can be satisfied, the pressure-sensitive adhesive Acr can be particularly preferably used as the pressure-sensitive adhesive in the present invention.

  The pressure-sensitive adhesive Acr can be prepared according to, for example, International Publication No. 2011/027786 pamphlet or Japanese Patent Application Laid-Open No. 2005-325101.

  Specific methods for preparing the pressure-sensitive adhesive Acr 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 Acr, a resin mixture composed of 100 parts by mass of an acrylic copolymer (A) and 0.05 to 2 parts by mass of a polyamine compound can be used as a 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.

  The lower limit of the content of the pressure-sensitive adhesive in the pressure-sensitive adhesive layer is not particularly limited, but the total amount of the pressure-sensitive adhesive in the pressure-sensitive adhesive layer is preferably 20% by mass or more, more preferably 50% by mass or more, more preferably 65% by mass. % Or more may be included. If the lower limit of the content of the pressure-sensitive adhesive in the pressure-sensitive adhesive layer is within the above range, donepezil can be sufficiently dissolved in the pressure-sensitive adhesive layer.

  The upper limit of the content of the pressure-sensitive adhesive in the pressure-sensitive adhesive layer is not particularly limited, but the total amount of the pressure-sensitive adhesive may be preferably 90% by mass or less, more preferably 86% by mass or less in the pressure-sensitive adhesive layer. . When the upper limit of the content of the pressure-sensitive adhesive in the pressure-sensitive adhesive layer is within the above range, a sufficient amount of donepezil or an absorption accelerator can be blended in the pressure-sensitive adhesive layer.

(Other ingredients)
The pressure-sensitive adhesive layer in the present invention may contain other components as necessary. Examples of such components include antioxidants (such as dibutylhydroxytoluene), excipients (such as polyvinylpyrrolidone and aminoalkyl methacrylate copolymer E), tackifiers (such as hydrogenated rosin glycerin ester), plasticizers, preservatives, Examples include pH adjusters, chelating agents, fragrances, coloring agents, fatty acids (such as oleic acid), fats and oils, and cholesterols.

  The lower limit of 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 preferably 0.1% by mass or more, more preferably 1.0% by mass or more. More preferably, it may be contained in an amount of 5.0% by mass or more. The upper limit of 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 preferably 30% by mass or less, more preferably 20% by mass or less, and still more preferably. 15 mass% or less may be contained.

[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. For example, the components constituting the pressure-sensitive adhesive layer are uniformly stirred, and the obtained composition is used as a support or a release sheet (polyethylene terephthalate) using a coating machine. After coating and drying on the surface of a film or the like, the patch of the present invention can be obtained.

  The shape and thickness of the patch can be adjusted according to the degree of skin permeability of donepezil to be obtained, the affected part to be applied, and the like. For example, the thickness of the pressure-sensitive adhesive layer may be 40.0 μm or more and 200 μm or less, and preferably 70.0 μm or more and 110 μm or less.

[Patch of the present invention]
The patch of the present invention can be continuously applied to a patient for 65 hours or more and 96 hours or less to reduce skin irritation (erythema formation, scab formation, edema formation, etc.). The skin irritation of the patch is evaluated based on the evaluation criteria of Draize et al. (1959) by the method shown in the Examples. According to the present invention, by continuously administering a donepezil-containing patch to a patient for 65 hours or more and 96 hours or less, the patch is replaced every day (ie within 24 hours) and administered over the same number of days. Compared to the case, the stimulation score specified based on the evaluation criteria of Draize et al. (1959) can be reduced to, for example, half or less.

  The application period of the patch of the present invention is not particularly limited as long as it is about 3 to 4 days, that is, 65 hours or more and 96 hours or less. However, it is preferable in consideration of the duration of the medicinal effect of donepezil and the risk of peeling of the patch. May be adjusted to 84 hours or less, more preferably 80 hours or less. Moreover, the pasting period may be adjusted according to the patient's life situation. For example, it is pasted before going to bed (for example, 23:00) and until the evening after 3 days (for example, 16:00) (total time of about 65 hours), or after bathing after 3 days (for example, 21:00) (total time of about 70 hours) ) May be the pasting period.

  The patch of the present invention can be suitably applied to Alzheimer's type dementia patients who often forget to apply the patch and are required to have a low frequency of application.

  The patch of the present invention can also be excellent in the skin permeability of donepezil. According to the present invention, the skin permeability of donepezil can increase over time. The skin permeability of donepezil is evaluated by specifying the amount of donepezil through the skin by the method shown in the examples. The patch of the present invention is continuously applied to a patient for 65 hours or more and 96 hours or less. According to the present invention, for example, the patch is replaced every day (that is, every 24 hours). In spite of the amount of donepezil permeating through the skin when administered over the same time, an unexpected effect is achieved in that skin irritation is significantly reduced. Therefore, according to the present invention, sufficient skin permeability and reduced skin irritation can be realized even if the patch is replaced at a lower frequency.

  The reason why skin irritation is reduced in the patch of the present invention is not clear, but is presumed as follows. That is, for example, if the patch is replaced every day (that is, every 24 hours), a large amount of donepezil accumulates on the skin surface before passing through the skin at the initial stage of applying the patch, Accumulation can cause skin irritation. On the other hand, in the patch of the present invention, such accumulation is unlikely to occur, and skin irritation is reduced.

  When preparing a patch that is applied continuously for more than 96 hours (for example, for one week or more), the skin is likely to be irritated by sweating or the like. In addition, a patch applied for over 96 hours is more likely to be peeled off from the affected area. On the other hand, in the present invention, by setting a shorter appropriate application time, it is possible to reduce skin irritation and peeling from the application site.

  The application site | part of the patch of this invention is not specifically limited, It can affix on arbitrary sites, such as a back part, an upper arm part, and a chest. After applying the patch of the present invention to the application site, the effect of the present invention of reducing skin irritation can be achieved by continuously applying the patch for 65 hours or more and 96 hours or less. In the present invention, “applying continuously for 65 hours or more and 96 hours or less” means that the state where the patch of the present invention is applied to the application site is maintained for 65 hours or more and 96 hours or less. It is not excluded that the patch is immediately re-applied after the patch of the invention is peeled off from the application site for a short time.

  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 pressure-sensitive adhesive used in this example is the following pressure-sensitive adhesive Acr.

[Adhesive Acr]
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 Acr was obtained.

(Copolymer of pressure-sensitive adhesive Acr (A))
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 Acr having a solid concentration of 30% by mass.

(Copolymer of adhesive Acr (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 Acr was obtained.

[Example 1: Examination of composition of pressure-sensitive adhesive layer]
A composition having the composition shown in Table 1 was prepared and applied to a support (using a polyethylene terephthalate (PET) film) and dried to obtain a patch having an adhesive layer. In any of the obtained patches, the thickness of the pressure-sensitive adhesive layer was adjusted to 107 μm. In addition, the abbreviation in a table | surface shows the following meaning.
IPM: isopropyl myristate PVP: polyvinylpyrrolidone BC-2: polyoxyethylene cetyl ether BL-2: polyoxyethylene lauryl ether BL-4.2: polyoxyethylene (4.2) lauryl ether BO-2V: polyoxyethylene Oleyl ether BS-2: Polyoxyethylene stearyl ether BS-20: Polyoxyethylene stearyl ether

(Examination of donepezil skin permeation)
The extracted human skin was punched out to 24 mmΦ, and the obtained skin pieces were placed in a 6-well cell culture plate (each well was filled with 1.2 mL of a buffer solution containing 20% polyethylene glycol 400 in PBS as a receiver solution). And the dermis layer side was the well side. A pressure-sensitive adhesive layer of a patch punched to a size of 15 mmΦ was affixed to the stratum corneum side of the skin. The temperature condition was maintained at 32 ° C. (humidity 95%), and 0.6 mL of the receiver solution was replaced at each time point after 0, 24, 48, and 72 hours from the placement of the skin, and the receiver solution at each time point was collected. The donepezil concentration in the collected receiver solution was measured by HPLC, and the amount of donepezil permeated per skin area was calculated based on the obtained numerical value.

  The evaluation results of the amount of donepezil permeated through the skin are shown in FIG. 1 (mean value ± SD, n = 4). As shown in FIG. 1, the amount of skin permeation with respect to time (which corresponds to the slope of the graph of FIG. 1) increased from 24 to 72 hours than from 0 to 24 hours, and the amount of skin penetration of donepezil Increased over time. The effect of increasing the skin permeation amount of donepezil was excellent in polyoxyethylene lauryl ether (particularly BL-4.2).

[Example 2: Examination of concentration of absorption accelerator and thickness of adhesive layer]
A composition having the composition shown in Table 2 was prepared and applied to a support (using a polyethylene terephthalate (PET) film) and dried to obtain a patch having a pressure-sensitive adhesive layer.

  For each of the obtained patches, donepezil permeation through the skin in the same manner as in Example 1 except that the time when the receiver solution was collected was 0, 24, 48, 72, 96, 120 hours from the installation of the skin. The amount was evaluated. The results are shown in FIG. 2 (mean value ± SD, n = 4). As shown in FIG. 2, according to the patch of the present invention, the amount of skin permeation with respect to time (this corresponds to the slope of the graph of FIG. 2) is increased at 24 to 120 hours from 0 to 24 hours. The amount of donepezil permeated through the skin increased over time.

[Example 3: Examination of irritation of patch]
A composition having the composition shown in Table 3 was prepared and applied to a support (using a polyethylene terephthalate (PET) film) and dried to obtain a patch having a pressure-sensitive adhesive layer.

  About each obtained patch, irritation was examined by the following method.

(Irritation test of Example 17)
It examined using the healthy skin of a Japanese white rabbit (male, 18 weeks old). The back skin of a Japanese white rabbit was shaved and the shaved part was divided into several sections. A patch (diameter 2 cm) of Example 17 was applied to each section, covered with an impervious oil paper and a non-woven adhesive bandage (trade name “Mesh Pore”, manufactured by Nichiban Co., Ltd.), and then an adhesive cloth stretched. It was fixed with a bandage (trade name “Elastopore”, manufactured by Nichiban Co., Ltd.). After fixing, the patch was pasted continuously for 3 days (72 hours), and the patch was applied once a day (that is, the district where the pasting was performed 3 times) and 3 days (72 hours). The total number of sections used in the ward (that is, the ward in which the patch was not replaced for 3 days) was the same. This was done for 2 cycles (3 days x 2 cycles, ie 6 days total) using 4 different rabbits.

  After fixing the patch, peel off the patch at each time point after 3 days (72 hours) and 6 days (144 hours) (after 3 days, after peeling and observing the skin, another unattached The patch was reapplied.) After lightly wiping the application site of the patch with absorbent cotton moistened with warm water, skin observation was performed according to the evaluation criteria of Draize et al. (1959) shown in Table 4. Regarding the evaluation results, the scores of “erythema and crust formation” and “edema formation” were summed, and the total value was divided by the number of animals (n = 4) to obtain the stimulation score for each observation day. Moreover, the sum total of the stimulation score for 3 days or 6 days was calculated | required based on the obtained stimulation score of each observation day, and the average stimulation score for 3 days or 6 days was computed. The result is shown in FIG.

  As shown in “3 days later” in FIG. 3, in the section (“3-day patch” in FIG. 3) in which the patch was applied continuously for 3 days, re-pasting was performed once a day for 3 days. Compared to the section (“1-day patch” in FIG. 3), the average stimulation score was significantly lower. On the other hand, the amount of donepezil permeated through the skin was the same in all sections (data not shown). Therefore, according to the patch of the present invention, it was found that the skin irritation can be reduced while donepezil sufficiently permeates the skin even when applied continuously for at least 3 days. This tendency was observed even if the same cycle was repeated one more time (see “after 6 days” in FIG. 3).

(Irritation test of Examples 18 and 19)
The irritation test was conducted in the same manner as in Example 17 except that the patches of Examples 18 and 19 were used and only the time point 3 days after fixation was examined. The result is shown in FIG.

  As shown in FIG. 4, according to the patch of the present invention, it was found that the skin irritation can be reduced even if it is applied continuously for at least 3 days.

(Irritation test of Example 20)
In the same manner as in Example 17, the patch of Example 20 was fixed to the back skin of a Japanese white rabbit. After fixing, the patch was pasted continuously for 4 days (96 hours), and the patch was pasted for 4 days (96 hours). The total number of sections used in the ward (that is, the ward where the patch was not replaced for four days) was the same. This was done for 2 cycles (4 days x 2 cycles, ie 8 days total) using 4 different rabbits.

  After fixing the patch, peel off the patch at each time point after 4 days (96 hours) and 8 days (192 hours) (after 4 days, after peeling and observing the skin, another unattached The patch was applied again.), Skin observation was performed in the same manner as in Example 17, and the average stimulation score for 4 days or 8 days was calculated. The result is shown in FIG.

  As shown in “4 days later” in FIG. 5, in the section where the patch was pasted continuously for 4 days (“4-day patch” in FIG. 5), the pasting was performed once a day for 4 days. Compared with the section (“1-day patch” in FIG. 4), the average stimulation score was significantly lower. On the other hand, the amount of donepezil permeated through the skin was the same in all sections (data not shown). Therefore, according to the patch of the present invention, it was found that the skin irritation can be reduced while donepezil sufficiently penetrates the skin even if it is applied continuously for 4 days. This tendency was observed even when the same cycle was repeated one more time (see “after 8 days” in FIG. 5).

[Reference example: Examination of irritation of rivastigmine-containing patch]
As a reference example, the irritation of a patch using rivastigmine instead of donepezil was examined. Specifically, a composition having the composition shown in Table 5 was prepared, and coated and dried on a support (using a polyethylene terephthalate (PET) film) to obtain a patch having an adhesive layer.

  Using the patches of Reference Examples 1 and 2, the irritation test was conducted in the same manner as in Example 17. The result is shown in FIG. In FIG. 6, “1-day patch” indicates the results of the section where the patch of Reference Example 1 was used and the patch was replaced once a day for 3 days. In FIG. 6, “3-day patch” indicates the results of the section where the patch of Reference Example 2 was used and the patch was applied for 3 consecutive days.

  As shown in “3 days later” in FIG. 6, is there a difference in skin irritation when the rivastigmine-containing patch is applied for 3 consecutive days compared to the case where the application is performed once a day? The former skin irritation was slightly higher. This tendency is observed when the same cycle is repeated one more time (“6 days later” in FIG. 6), or when an absorption accelerator is further added to the adhesive layer described in Table 5 (data not shown). .) Was not changed.

  When the donepezil-containing patch was applied continuously for 3 days or 4 days, the skin irritation was reduced as compared with the case where the application was performed once a day (see FIGS. 3 and 5). ). On the other hand, such a tendency was not observed when the rivastigmine-containing patch was used. The reason is not clear, but is presumed as follows. Rivastigmine's half-life (1.5 hours) is significantly shorter than that of donepezil (70 hours). That is, administered rivastigmine is rapidly absorbed into the body from the skin or rapidly metabolized in the skin as compared with donepezil, and rivastigmine disappears rapidly from the skin. Furthermore, since the period of 1 day or 3 days on which the rivastigmine-containing patch was continuously applied was significantly longer than the half-life of rivastigmine, there was no significant difference in terms of effects and skin irritation. It is thought that.

Claims (6)

A patch comprising a support and an adhesive layer located on the support,
The pressure-sensitive adhesive layer is
Donepezil and / or a pharmaceutically acceptable hydrochloride thereof;
An absorption enhancer,
With adhesive,
Including at least
A patch that is continuously applied to a patient for 65 hours or more and 96 hours or less.   The patch according to claim 1, wherein the content of the absorption accelerator is 0.10% by mass or more and 10.0% by mass or less with respect to the pressure-sensitive adhesive layer.   The patch according to claim 1 or 2, wherein the pressure-sensitive adhesive layer contains an acrylic pressure-sensitive adhesive.   The patch according to claim 3, wherein the content of the acrylic adhesive is 20% by mass or more and 90% by mass or less with respect to the adhesive layer.   The adhesive patch according to any one of claims 1 to 4, wherein the pressure-sensitive adhesive layer has a thickness of 40.0 µm to 200 µm.   The patch according to any one of claims 1 to 5, wherein the patient is an Alzheimer type dementia patient.

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