KR101454362B1 - Percutaneous absorption preparations for the treatment of dementia containg donepezil as an active ingredient - Google Patents

Abstract

The present invention relates to percutaneous absorption preparations for the treatment of dementia comprising donepezil as an active ingredient, and more particularly to a transdermal absorption preparation for the treatment of dementia comprising (a) donepezil or a pharmaceutically acceptable salt thereof as an active ingredient, polyethylene containing a rosin ester resin as a polymer base vinyl acetate pressure-sensitive adhesive (hereinafter, EVA pressure-sensitive adhesive), and as a skin permeation enhancer-pyrrolidone derivative, including one or two or more kinds of mixtures selected from the group consisting of aliphatic derivatives, triacetin and triethyl citrate of C _{8 -18} A drug-containing matrix layer; (b) a support layer; And (c) a release layer as an active ingredient. The percutaneous absorption preparation for treating dementia according to the present invention not only improves adherence and compliance of a patient with dementia, but also minimizes the adverse effects of the drug, as well as easy application to the skin, and sustained release of the drug for a long time And has superior skin permeability of drugs, and thus can be usefully used instead of conventional oral agents for treating dementia.

Dementia, donepezil, patch, skin permeation enhancer, transdermal delivery, transdermal administration, Alzheimer's

Description

[0001] The present invention relates to a percutaneous absorption preparations for treating dementia comprising donepezil as an active ingredient,

The present invention relates to percutaneous absorption preparations for the treatment of dementia containing donepezil as an active ingredient.

Dementia is a syndrome characterized by complex cognitive dysfunction characterized by amnesia, degenerative changes in intelligence, changes in personality, and behavioral abnormalities. This symptom is a degenerative brain disease associated with the central nervous system brain, which causes irreversible dysfunction in the neural network due to the death of the slow nerve cells that cause degenerative diseases of the central nervous system, . A common feature of degenerative brain disease is the degeneration of whole or specific cells, where the differentiated neurons are unable to regenerate, resulting in the loss of irreversible brain function.

It has not been fully clarified how the dementia occurs and there are no treatments for dementia that are administered alone because of various pathologic and pathophysiological factors. However, indirectly, the choline acetyltransferase (ChAT), which synthesizes acetylcholine (ACh), is reduced to 20-30% in the brains of demented patients, and the neurotransmitter acetylcholine concentration is 16-30% . Therefore, studies have been conducted using an inhibitor that inhibits choline esterase (ChE), an enzyme that hydrolyzes acetylcholine, a neurotransmitter, as an indirect treatment method. Cholinesterase has two forms: acetylcholinesterase (AChE) and butylcholinesterase (BuChE). The above-mentioned acetylcholinesterase is an enzyme that hydrolyzes acetylcholine, which is one of neurotransmitters that mediate the activity of parasympathetic nerves in the body, into choline and acetate, and is formed in an endoplasmic reticulum membrane and moves to a cell membrane to perform its function . These enzymes are most widely distributed in the cholinergic nerve and its surroundings, especially in the muscle nerve junction, and are important enzymes found in plasma, liver and other tissues.

Therefore, most of the currently used Alzheimer's dementia treating agents are acetylcholinesterase inhibitors, which are acetylcholinesterase, and include Donepezil (trade name: Aricept), Tacrine (trade name: Cocnex), Rivastigmine Rivastigmin (trade name: excelon), and galantamine (trade name: reminyl).

Donepezil, an acetylcholinesterase inhibitor, was licensed from the US Food and Drug Administration (FDA) in 1996 for the treatment of dementia with mild to moderate dementia of Alzheimer's disease.

Donepezil is a drug that reversibly inhibits acetylcholinesterase and acetylcholinesterase called butylcholinesterase. As a result, the acetylcholine, which is a neurotransmitter, It activates the cholinergic nerves in the brain by increasing acetylcholine in the brain of Alzheimer's patients. The currently used donepezil formulations are in tablet form and are prescribed to patients with Alzheimer ' s Dementia via an oral route of administration.

In general, the acetylcholinesterase inhibitor as an oral agent has serious side effects, and in particular, reports on problems such as hepatic dysfunction and digestive disorders. The cause of the above-mentioned side effects is that it is generally impossible to avoid the primary transit effect to the liver, and as a result, it is easy to affect the liver function, and since the high concentration exists in the digestive tract, side effects are likely to appear in the digestive tract to be.

When the inhibitor is orally administered, since the ratio of the maximum blood concentration reached after administration to the blood concentration after 24 hours is large in the change of the blood concentration of the drug after administration, the blood concentration is not increased to a level at which the side effect appears, There is a problem that it is not easy to maintain the therapeutic effect throughout.

Japanese Patent Application Laid-Open No. 1999-315016 suggests that suppositories for ointments and rectal administrations have been proposed in order to overcome difficulties in oral administration when the symptoms of dementia have progressed considerably. However, these formulations are problematic in that they are not practical for continuously administering the active ingredient over a long period of time.

In addition, US Patent Publication No. 20040258741 and Korean Patent Publication No. 2005-0037405 propose a percutaneous absorption preparation using a synthetic rubber-based polymer of SIS and PIB series. However, since the permeation rate is insufficient and the percutaneous absorption preparation having an area of 50 cm ² or more is applied for 1 to 2 days at a time, long-term administration leads to a burden on the skin. In addition, since the percutaneous absorption preparation is difficult to contain a drug in a highly hydrophobic matrix at a high concentration and solid crystals are formed at a concentration of 8% or more, there is a problem in reduction of adhesive force, unevenness of skin permeation rate, and storage. In addition, since the thickness of the matrix is increased in proportion to the required amount of the drug to be supported on the matrix to satisfy the required dosage, there is no great difference at the beginning, but there is a problem of decreasing the permeation rate of the drug over time.

Therefore, the inventors of the present invention have been studying a percutaneous absorption preparation for improving the patient's compliance with medicines, and have found that a high concentration (10% or more) of a drug is contained in a hydrophobic matrix without generating crystals of a drug, The present invention has been accomplished on the basis of the above results, and the present invention has been accomplished on the basis of these findings.

It is an object of the present invention to provide a pharmaceutical composition containing donepezil as an active ingredient for increasing the compliance of a patient with a medicament and to prevent the formation of crystals even when containing 10% or more of a high concentration drug in the hydrophobic matrix, And to provide a percutaneous absorption preparation for treating dementia that can deliver a drug through the skin into the body.

In order to achieve the above object, the present invention relates to a pharmaceutical composition comprising as an active ingredient donepezil or a pharmaceutically acceptable salt thereof, an EVA adhesive containing a rosin ester resin as a base for preventing crystallization of the active ingredient, derivatives, C _{8 -18} of the aliphatic derivative, triacetin and triethyl complex using at least one selected from the group consisting of citrate drug-containing matrix layer; Supporting layer; And a release layer as an active ingredient. The present invention also provides a percutaneous absorption preparation for treating dementia.

The percutaneous absorption preparation for treating dementia containing donepezil as an active ingredient according to the present invention is excellent in skin adhesion and prevents generation of crystals even when a high concentration drug of 10% or more is contained in the hydrophobic matrix, The drug can be continuously released for a long period of time, and the skin permeability of the drug is excellent, so that it can be usefully used as a substitute for a conventional oral agent for treating dementia.

The present invention

(a) as an active ingredient donepezil or a pharmaceutically acceptable salt, EVA pressure sensitive adhesive, and a skin permeation enhancer-pyrrolidone derivative of the C _{8 -18} aliphatic derivative containing rosin ester resin is used as polymer base, triacetin and A drug-containing matrix layer comprising a mixture of at least one selected from the group consisting of triethyl citrate;

(b) a support layer; And

(c) peeling layer

Which comprises as an active ingredient donepezil.

Hereinafter, the drug-containing matrix layer constituting the percutaneous absorption preparation for treating dementia according to the present invention will be described.

First, the drug-containing mattress layer of the percutaneous absorption preparation according to the present invention comprises donepezil or a pharmaceutically acceptable salt thereof as a beneficial ingredient.

The donepezil used in the present invention is preferably donepezil or a pharmaceutically acceptable salt thereof in the form of a free base as an acetylcholinesterase inhibitor. Such pharmaceutically acceptable salts include acid addition salts formed by pharmaceutically acceptable free acids. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, Dioleate, aromatic acid, aliphatic and aromatic sulfonic acids. Such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, Butyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, succinate, maleic anhydride, maleic anhydride, , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfide Propyl sulphonate, naphthalene-1-yne, xylenesulfonate, phenylsulfate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, Sulfonate, naphthalene-2-sulfonate or mandelate may be used.

The active ingredient is dissolved or uniformly dispersed in the pressure-sensitive adhesive, and is preferably 2.0 to 25% by weight based on the weight of the entire drug-containing matrix. If the content of donepezil or a pharmaceutically acceptable salt thereof is less than 2.0% by weight, the drug effect is insufficient. When the concentration is higher than 25% by weight, crystals of the drug are produced in the preparation, .

Next, the drug-containing matrix layer of the percutaneous absorption preparation according to the present invention preferably uses an EVA pressure-sensitive adhesive as a polymer base material and a pressure-sensitive adhesive.

In general, the pressure-sensitive adhesive is required to have adhesiveness to the skin, suitability with drugs and other excipients, and TRS (Sekisui Chemical Co., Osaka, Japan) as a pressure- (Duro-Tak; National Starch Chemical Co., bridgewater, NJ, USA). However, when such an acrylic pressure-sensitive adhesive is used as a matrix of a percutaneous absorption preparation for treatment of dementia, drug diffusion in the pressure-sensitive adhesive layer is slowed due to interaction between the drug and acrylic polymer in the pressure-sensitive adhesive layer and drug migration from the pressure- It is difficult to deliver the required amount of the drug.

Therefore, it is preferable to use an EVA adhesive agent as the adhesive agent constituting the drug-containing mattress layer of the present invention. The polyethylene vinyl acetate copolymer, which is the main material of the EVA pressure-sensitive adhesive, has various applications according to the content of vinyl acetate, and is excellent in weatherability, aging stability, tear strength, endurance resistance and ozone resistance, It is a thermoplastic elastic resin. In this case, the EVA used in the EVA adhesive preferably has a VA content (vinyl acetate content) of 4 to 50%, more preferably 33 to 41%.

Further, the EVA pressure-sensitive adhesive contains a rosin ester resin to prevent crystallization of donepezil, which is an effective ingredient. In most hydrophobic matrices other than acrylics, donepezil, as an active ingredient of the transdermal absorption preparation of the present invention, has a polarity suitable for enhancing the solubility of the drug to the matrix base due to the formation of crystals within a few days or weeks due to solubility in the base . From this point of view, the rosin ester resin used in the EVA pressure-sensitive adhesive according to the present invention has a structure similar to that of Donepezil and has a proper polarity, so that the donepezil can be stably dissolved or dispersed in the hydrophobic matrix without crystallization do. The rosin ester resin used herein is preferably a pentaerythritol rosin ester, a glycerol rosin ester, a pentaerythritol hydrogenated rosin ester, or a glycerol hydrogen rosin ester, and more preferably a pentaerythritol rosin ester.

The content of the EVA adhesive as the polymer base constituting the drug-containing mattress layer is preferably 50 to 80% by weight based on the weight of the entire drug-containing matrix. If the content is out of the above range, there are disadvantages in terms of skin applicability, compatibility with drugs and other excipients.

Next, the drug-containing matrix layer of the transdermal preparation according to the invention are pyrrolidone derivatives, C ₈ as a skin permeation _{enhancer-containing 18} aliphatic derivatives, triacetin and the tree either individually or in combination of two or more thereof in ethyl citrate . From the viewpoint of enhancing the skin permeability of the drug, the content of the skin permeation enhancer is preferably 10-25% by weight based on the total drug-containing matrix weight.

As the skin permeation enhancer, the pyrrolidone derivative may be N-cyclohexyl-2-pyrrolidone, 1-butyl- 3-dodecyl-2-pyrrolidone, 1,5-dimethyl-2-pyrrolidone and 1-ethyl- 1-hexyl-2-pyrrolidone, 1-hexyl-2-pyrrolidone, 1- (2-hydroxyethyl) pyrrolidone, 3-hydroxy-N-methyl-2-pyrrolidone, 2-pyrrolidone, 1-lauryl-4-methyloxycarbonyl-2-pyrrolidone, N-methyl- 2-pyrrolidone, N-dodecyl-2-pyrrolidone and the like are preferable, and N-dodecyl-2-pyrrolidone More preferably N-dodecyl-2-pyrrolidone.

In addition, derivatives of aliphatic C _{8 -18} as the skin permeation enhancer is glycerol lauryl alcohol (glycerol lauryl alcohol), oleyl alcohol (oleyl alcohol), isopropyl advance straight (isopropyl myristrate), sorbitan monooleate (sorbitan mono propylene monolaurate, propylene mono-oleate, oleyl macrogoglyceride, oleic acid, lauroyl (meth) acrylate, and the like. macrogoglyceride, linoleoyl macrogoglyceride, propylene glycol caprylate / caprate, sorbitan monostearate mono-oleate, glycerol monolaurate, Glycerol monolaurate, propylene glycol monolaurate, propylene glycol monocaprate, Propylene glycol monocaprylate, sorbitan monolaurate, lauryl lactate, caprylic / capric triglyceride, corn oil PEG-8 ester, corn PEG-6 ester and the like are preferable, and glycerol monooleate, glycerol monolaurate, propylene glycol monolaurate, propylene glycol monocaprylate, sorbitan monolaurate, lauryl lactate, caprylic / PEG-8 ester of corn oil, PEG-6 ester of corn oil and the like are more preferable.

Further, triacetin or triethyl citrate may be used as the skin permeation enhancer. The triacetin has been used as a solubilizer, a softener, a skin permeation promoter, etc. Triethyl citrate has been widely used as a softener for an Eudragit-based polyacrylate polymer as an oral emulsion coating material, As with the case of the serum, there is a skin permeation enhancing effect on donepezil.

The above-described skin permeation enhancer contained in the drug-containing matrix layer of the percutaneous absorption preparation according to the present invention may be any of the above-mentioned skin permeation enhancers, which may be used alone or as a mixture of two or more of them in an amount of 10-25% .

Hereinafter, the support layer and the release layer constituting the percutaneous absorption preparation for treating dementia according to the present invention will be described.

The support layer of the percutaneous absorption preparation for treating dementia according to the present invention is thin and flexible and has no reactivity with the skin and does not cause an allergic reaction in order to prevent the loss of donepezil from the preparation during attachment or storage on the skin .

The support layer according to the present invention may be a plastic film such as a polyethylene, a polypropylene, an ethylene vinyl acetate copolymer, a vinylon, a polyester, a polyurethane, a nylon, a polyacrylonitrile, a polyethylene terephthalate and a polyolefin a woven fabric such as rayon, polyester or the like having water absorbing ability, a woven fabric such as a polyester, an acrylic, a silk, a cotton or the like, or a laminated layer thereof such as a film or a woven fabric of water, Any of the drug-protecting materials used in conventional percutaneous absorption preparations may be used.

The release layer of the percutaneous absorption preparation for treating dementia according to the present invention may be a release film commonly used in percutaneous absorption preparations or a laminate thereof. For example, a film, paper, or a laminate thereof such as polyethylene, polyester, polyvinyl chloride, or polyvinylidene chloride coated with a silicone resin or a fluorine resin can be used.

The percutaneous absorption preparation for treating dementia containing donepezil as an active ingredient according to the present invention is excellent in skin adhesion and prevents generation of crystals even when a high concentration drug of 10% or more is contained in the hydrophobic matrix, (See FIG. 2 ), the skin permeation rate is gradually reduced as the application period is prolonged, but the skin permeation rate higher than the minimum required permeation rate of 1.2 μg / cm ² / hr (See FIG. 3 ), it can be usefully used in place of conventional oral agents for treating dementia.

Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples. However, the following examples and experimental examples are provided to specifically explain the present invention, and the scope of the present invention is not limited to these examples and experimental examples.

<Conducted Yes  1> Donepezil  Percutaneous absorption preparation for treating dementia containing active ingredient of  Produce

Toluene was added to 13% by weight of donepezil, 5% by weight of glycerol monolaurate, 5% by weight of glycerol monooleate and 77% by weight of EVA adhesive to completely dissolve the mixture so that the total solid content became 50% Was coated on a silicone-treated polyester release film fixed on the applicator and dried at 90 DEG C for 10 minutes at an air speed of 1300 rpm to prepare an adhesive layer sheet having a thickness of 85 mu m, followed by laminating with a polyester support film This was cut to a certain size to prepare a percutaneous absorption preparation for treating dementia containing the donepezil as an active ingredient.

< Example  2 to 19> Donepezil  Percutaneous absorption preparation for treating dementia containing active ingredient of  Produce

The composition of the matrix layer was changed as shown in the following Table 1, and the same procedure as in Example 1 was repeated to prepare a percutaneous absorption preparation for treating dementia containing the above-mentioned donepezil as an active ingredient. At this time, the content of each component is% by weight.

&Lt; Comparative Examples 1 to 31 >

The composition of the matrix layer was changed as shown in Table 2, and the same procedure as in Example 1 was repeated to prepare a percutaneous absorption preparation for treating dementia containing the donepezil as an active ingredient. At this time, the content of each component is% by weight.

Skin permeation experiments of donepezil drug on the percutaneous absorption preparations prepared in Examples 1 to 19 and Comparative Examples 1 to 30 were carried out as follows.

< Experimental Example  1>

The diffusion device for drug permeation experiment (Franzcel) was prepared by adding 0.5% by weight of sodium azide to a phosphate buffer solution having a pH of 7.4 in order to prevent skin from being rotted. The experimental diffuser was filled with the receiving phase, the temperature was maintained at 32 ± 0.5 ° C, and the skin was treated with human cadaver skin, and each matrix prepared in Examples 1 to 19 and Comparative Examples 1 to 30 was donated The cell size was cut and applied. As time elapsed, 250 μL of the buffer solution in which the drug was diffused over time was taken, and the drug permeated by liquid chromatography was quantified. Table 3 and Table 4 show the average drug permeation rate of the drug after passing the drug through the patches prepared in Examples 1 to 19 and Comparative Examples 1 to 30 over a period of 7 days.

Skin permeation rate (μg / cm ² / hr) Skin permeation rate (μg / cm ² / hr) Example 1 4.85 ± 1.22 Example 11 4.94 ± 1.30 Example 2 4.39 ± 0.86 Example 12 5.40 ± 1.40 Example 3 4.36 ± 1.10 Example 13 7.74 + - 0.85 Example 4 4.90 ± 0.64 Example 14 5.56 + - 0.62 Example 5 5.68 ± 0.68 Example 15 7.25 ± 0.91 Example 6 5.34 0.35 Example 16 6.07 ± 0.93 Example 7 5.81 ± 0.21 Example 17 7.62 ± 0.05 Example 8 6.05 + 0.44 Example 18 6.88 ± 2.15 Example 9 6.50 + - 0.74 Example 19 7.40 ± 2.40 Example 10 5.34 ± 0.58

Skin permeation rate
(μg / cm ² / hr) Skin permeation rate
(μg / cm ² / hr) Comparative Example 1 3.58 ± 0.87 Comparative Example 16 3.33 + - 0.86 Comparative Example 2 3.89 ± 0.13 Comparative Example 17 2.53 + - 0.62 Comparative Example 3 3.82 ± 0.58 Comparative Example 18 2.87 ± 0.01 Comparative Example 4 3.88 ± 0.52 Comparative Example 19 2.10 ± 0.05 Comparative Example 5 2.39 0.34 Comparative Example 20 2.90 + - 0.32 Comparative Example 6 3.21 + - 0.62 Comparative Example 21 1.94 + - 0.36 Comparative Example 7 1.46 0.10 Comparative Example 22 2.89 ± 0.96 Comparative Example 8 2.68 ± 0.40 Comparative Example 23 2.30 ± 0.20 Comparative Example 9 1.73 ± 0.20 Comparative Example 24 0.79 + 0.02 Comparative Example 10 1.64 ± 0.50 Comparative Example 25 1.67 ± 0.06 Comparative Example 11 0.98 + 0.03 Comparative Example 26 3.20 0.31 Comparative Example 12 1.84 0.80 Comparative Example 27 2.43 + 0.04 Comparative Example 13 3.83 ± 0.22 Comparative Example 28 2.68 ± 0.31 Comparative Example 14 2.67 ± 0.96 Comparative Example 29 2.32 ± 0.08 Comparative Example 15 1.60 ± 1.13 Comparative Example 30 1.35 + 0.04

Comparing Tables 3 and 4, it can be seen that the combined use of donepezil is more effective than the single use of a specific skin permeation enhancer, and that the combination use of two or more aliphatic derivatives, N-dodecyl- It can also be seen that the combined use of monosaccharides and aliphatic derivatives, aliphatic derivatives, N-dodecyl-2-pyrrolidone, triacetin and triethyl citrate is effective.

The cumulative permeation amount and the skin permeation rate change for Examples 13 to 19 in which the skin penetration test results are comparatively good are shown in Figs . 2 and 3 , respectively. FIG. 2 shows that the drug is continuously released during the experiment period. As shown in FIG. 3 , since the initial release rate is high, the drug is administered more than the drug is removed at the early stage of adherence of the percutaneous absorption preparation. Donepezil is also more specific for acetylcholinesterase (AChE) in the brain than plasma butyric cholinesterase (BChE) and has a half-life of 58 to 90 hours, a bioavailability of 100% and a protein binding rate of 96% It has excellent inhibitory effect on terazepam.

In the case of 5 mg oral administration, the maximum plasma concentration was 9.8 ± 1.1 ng / mL when administered orally once, and the steady-state was reached within 15 days after repeated administration. The mean plasma concentration in the steady state was 26.5 ± 3.9 ng / mL and mean plasma clearance is constant at 0.13 L / hr / kg. The required skin permeation rate is about 3.455 ± 3.9 ㎍ / hr. As can be seen from FIG. 3 , it can be seen that the manufactured percutaneous absorption preparation is maintained at a level of skin permeation rate required at the time of experiment or at a slightly higher rate.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a cross-sectional view of a percutaneous absorption preparation for treating dementia comprising donepezil according to the present invention as an active ingredient (A: support layer, B: drug-containing matrix layer, C:

FIG. 2 is a graph showing cumulative skin permeation amount of percutaneous absorption preparation for treating dementia containing donepezil as an active ingredient according to the present invention,

3 is a graph showing an average skin permeation rate of a percutaneous absorption preparation for treating dementia containing donepezil as an active ingredient according to the present invention.

Claims (10)

(a) 2.0 to 25% by weight of donepezil or its pharmaceutically acceptable salt as an active ingredient, 50 to 80% by weight of an EVA pressure-sensitive adhesive containing a rosin ester resin as a polymer base, and a pyrrolidone derivative, C A drug-containing matrix layer comprising 10 to 25% by weight of a mixture of one or more compounds selected from the group consisting of aliphatic derivatives of _8-18 , triacetin and triethyl citrate; (b) a support layer; And (c) peeling layer A dermal absorption preparation for the treatment of dementia comprising donepezil as an active ingredient, The pyrrolidone derivatives include N-cyclohexyl-2-pyrrolidone, 1-butyl-3-dodecyl-2-pyrrolidone, Pyrrolidone, 1-hexyl-4-methyloxycarbonyl-2-pyrrolidone, 1-hexyl-2-pyrrolidone, 1- (2- Pyrrolidone, N-caprylyl-2-pyrrolidone, N-methyl-2-pyrrolidone, - dodecyl-2-pyrrolidone, The C _8-18 aliphatic derivative is selected from the group _consisting of glycerol monooleate, glycerol lauryl alcohol, oleyl alcohol, isopropyl myristate, sorbitan monooleate, propylene monolaurate, propylene monooleate, oleylmarkoglyceride Propylene glycol monolaurate, propylene glycol monolaurate, propylene glycol monolaurate, propylene glycol monolaurate, propylene glycol monolaurate, propylene glycol monolaurate, propylene glycol monolaurate, propylene glycol monolaurate, propylene glycol monolaurate, Characterized in that it is selected from the group consisting of sorbitan monolaurate, glycol monocaprylate, sorbitan monolaurate, lauryl lactate, caprylic / capric triglyceride, corn oil PEG-8 ester and corn oil PEG- A percutaneous absorption preparation for the treatment of dementia comprising a pheasant as an active ingredient. delete 2. The percutaneous absorption preparation for treating dementia as claimed in claim 1, wherein the pyrrolidone derivative is N-dodecyl-2-pyrrolidone. delete The composition of claim 1, wherein the C _8-18 aliphatic derivative is selected from the group consisting of glycerol monooleate, glycerol monolaurate, propylene glycol monolaurate, propylene glycol monocaprylate, sorbitan monolaurate, lauryl lactate, Wherein the active ingredient is selected from the group consisting of caprylic / capric triglyceride, corn oil PEG-8 ester, and corn oil PEG-6 ester. The percutaneous absorption preparation for treating dementia according to claim 1, wherein the rosin ester resin is used to prevent crystallization of the active ingredient. The method according to claim 1, wherein the rosin ester resin is selected from the group consisting of glycerol rosin ester, pentaerythritol rosin ester, glycerol hydrogen rosin ester and pentaerythritol hydrogen ester. Percutaneous absorption preparation for treating dementia. 8. The percutaneous absorption preparation for treating dementia according to claim 7, wherein the rosin ester resin is pentaerythritol rosin ester. 2. The percutaneous absorption preparation for treating dementia according to claim 1, wherein the EVA used in the EVA adhesive contains a donepezil (VA) content (vinyl acetate content) of 4 to 50% as an active ingredient. The percutaneous absorption preparation for the treatment of dementia according to claim 1, wherein the EVA used in the EVA pressure-sensitive adhesive has a VA content (vinyl acetate content) of 33 to 41%.

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