WO2009120002A2

WO2009120002A2 - Percutaneous preparation containing donepezil as active ingredient for treatment of dementia

Info

Publication number: WO2009120002A2
Application number: PCT/KR2009/001472
Authority: WO
Inventors: 최영권; 이정식; 김성수; 구혜란
Original assignee: 아이큐어주식회사
Priority date: 2008-03-24
Filing date: 2009-03-23
Publication date: 2009-10-01
Also published as: WO2009120002A3; KR101454362B1; KR20090101667A

Abstract

The present invention relates to a percutaneous preparation containing donepezil as an active ingredient for treatment of dementia. More specifically, the percutaneous preparation comprising donepezil as the active ingredient consists of a matrix layer containing drugs, a support layer for protecting the drugs, and a release layer. The matrix layer containing drugs comprises: donepezil or pharmaceutically acceptable salts thereof as the active ingredient; polyethylene vinyl acetate adhesives including rosin ester resin as a polymer substrate; and a penetration enhancer mixture of at least two kinds selected from the group consisting of pyrrolidone derivatives, C8-18 aliphatic derivatives, triacetin and triethyl citrate. The disclosed percutaneous preparation can increase dementia patient administration compliance and minimize side effects when compared with an oral preparation. Additionally, the percutaneous preparation is easily applied to skin and can release the drugs sustainably for a long time. Also, due to high skin-penetration properties, the preparation can replace conventional oral preparations for treatment of dementia.

Description

[Revision according to Rule 26.21.07.2009] Transdermal absorption preparation for the treatment of dementia containing donpezil as an active ingredient

The present invention relates to a transdermal absorption preparation for treating dementia containing Donepezil as an active ingredient.

Dementia is a syndrome characterized by complex cognitive impairments characterized by memory loss, loss of intelligence, personality changes, and behavioral problems. This symptom is a degenerative neurological disorder associated with the brain, the central nervous system, resulting in irreversible dysfunction of the neural network by the death of slow neurons that cause central nervous system degenerative disease, and eventually permanent loss of the human body. Will result. A common feature of degenerative neuropathy is the overall or specific cell death. Differentiated neurons are incapable of regenerative, resulting in the loss of irreversible brain function.

It is not fully understood how dementia occurs, and because there are various etiological and pathophysiological factors, there is no treatment for dementia alone. However, indirectly, the brains of dementia patients are known to have reduced 20% to 30% of choline acetyltransferase (ChAT), which synthesizes acetylcholine (ACh), compared to normal humans, and the neurotransmitter concentration of acetylcholine is 16-30%. It is known to decrease in degree. Therefore, research has been conducted using an inhibitor that inhibits cholinesterase (ChE), an enzyme that hydrolyzes the neurotransmitter acetylcholine as an indirect treatment method. Cholinesterases come in two forms: acetylcholinesterase (AChE) and butylcholinesterase (BuChE). The acetylcholinesterase is an enzyme that hydrolyzes acetylcholine, one of the neurotransmitters that mediate the activity of parasympathetic nerves in the body, to choline and acetate, and is formed on the endoplasmic reticulum membrane and moves to the cell membrane to perform its function. . The enzyme is most widely distributed in the choline nerve and its surroundings, especially in the muscle nerve junction, and is an important enzyme found in plasma, liver and other tissues.

Therefore, currently used Alzheimer's treatment for dementia is mainly an acetylcholinesterase inhibitor, an acetylcholine degrading enzyme, and is donepezil (Donepezil, trade name: Aricept), tacrine (Tacrine, Cokenex), rivastigmine ( Rivastigmin, trade name: Exelon), galantamine (Reminil), and the like.

Among the acetylcholinesterase inhibitors, donepezil was licensed for dementia patients from the US Food and Drug Administration (FDA) in 1996, and is used to treat dementia of mild and moderate dementia of Alzheimer's disease.

Donepezil is a drug having the effect of reversibly inhibiting acetylcholine degrading enzymes called acetylcholinesterase and butylcholinesterase, and acetylcholine, a neurotransmitter, is lowered than the normal person through the above inhibitory function. Increasing acetylcholine in the brain of Alzheimer's patients activates cholinergic neurons in the brain. The donepezil preparations currently in use are in tablet form and are prescribed for Alzheimer's dementia patients via the oral route of administration.

In general, acetylcholinesterase inhibitors as oral agents have severe side effects, and there are reports of problems such as liver dysfunction and digestive disorders. The cause of the side effects is generally because oral preparations are unable to avoid the first pass effect to the liver, and as a result it is easy to affect the liver function, because the high concentrations in the digestive tract is likely to cause side effects in the digestive tract. to be.

In the case of oral administration of the inhibitor, the ratio of the blood concentration after the administration of the drug is large, since the ratio of the maximum blood concentration reached after administration and the blood concentration after 24 hours has not been reached for a long time without reaching the concentration at which side effects occur. There is a problem that is not easy to maintain the therapeutic effect over.

In addition, Japanese Laid-Open Patent Publication No. 1999-315016 proposes an ointment and a suppository for rectal administration in order to solve this problem because it is sometimes difficult to take orally in a state in which dementia symptoms are quite advanced. However, these formulations have a problem that it is not practical to continuously administer the active ingredient over a long time.

In addition, US Patent Publication No. 20040258741 and Korean Patent Publication No. 2005-0037405 propose a transdermal absorbent using a synthetic rubber-based polymer of the SIS and PIB series. However, since the permeation rate is insufficient and the transdermal absorption agent having an area of 50 cm 2 or more is applied at a time for 1 to 2 days, long-term administration causes a lot of burden on the skin. In addition, the transdermal absorbent preparation is difficult to contain a high concentration of the drug in a highly hydrophobic matrix, and when the concentration is 8% or more, solid crystals are produced, thereby reducing adhesion, nonuniformity of skin penetration rate, and storage problems. In addition, since the thickness of the matrix to support the required amount of the drug to meet the required dosage in the matrix becomes thicker in proportion, there is no big difference initially but there is a problem of decreasing the penetration rate of the drug over time.

Therefore, the present inventors are studying a transdermal absorption agent for enhancing the patient's medication compliance, while containing a high concentration (10% or more) of the drug in the hydrophobic matrix without generating crystals of the drug, and the drug through the skin for a long time A continuous transdermal absorption preparation that can maintain a therapeutic effect over a long period of time without reaching the concentration of the drug to the concentration of side effects is completed and completed the present invention.

It is an object of the present invention to contain donepezil as an active ingredient in order to increase the patient's compliance with the drug, and even when a high concentration of drug in a hydrophobic matrix of 10% or more is contained, there is no crystallization for a long period of time without reducing the adhesion of the transdermal absorbent. It is to provide a transdermal absorption preparation for treating dementia that can deliver drugs into the body through the skin.

In order to achieve the above object, the present invention is donepezil or a pharmaceutically acceptable salt thereof as an active ingredient, pyrrolidone as an EVA adhesive and skin permeation enhancer comprising a rosin ester resin to prevent crystallization of the active ingredient as a base. A drug-containing matrix layer comprising a combination of two or more kinds selected from the group consisting of derivatives, C _8-18 aliphatic derivatives, triacetin and triethyl citrate; Drug protection support layer; And it provides a transdermal absorption preparation for treating dementia containing Donepezil consisting of a release layer as an active ingredient.

The transdermal absorption agent for treating dementia containing Donepezil as an active ingredient according to the present invention has excellent skin adhesion and prevents a decrease in adhesion by preventing crystal formation even when a high concentration of drug is contained in a hydrophobic matrix of 10% or more. The drug can be continuously released for a long time, and the skin permeability of the drug is excellent and can be usefully used in place of the conventional oral treatment for dementia.

1 is a cross-sectional view of a transdermal absorption preparation for treating dementia containing Donepezil as an active ingredient according to the present invention (A: drug protection support layer, B: drug-containing matrix layer, C: release layer),

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

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

The present invention

In the transdermal absorption preparation for treating dementia comprising a drug protective support layer, a drug-containing matrix layer and a peeling layer,

2.0 to 25% by weight of the drug-containing matrix layer donepezil or a pharmaceutically acceptable salt thereof as an active ingredient; 50 to 80% by weight of an EVA adhesive containing a rosin ester resin as a polymer base; And 10-25 wt% of any two or more mixtures selected from the group consisting of pyrrolidone derivatives, aliphatic derivatives of C _8-18 , triacetin and triethyl citrate as skin permeation enhancers. Provided is a transdermal absorption preparation for treating dementia containing as an active ingredient.

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

First, the drug-containing mattress layer of the transdermal absorption preparation according to the present invention contains donepezil or a pharmaceutically acceptable salt thereof as an active ingredient.

The donepezil used in the present invention is preferably used as the acetylcholinesterase inhibitor of the donepezil or a pharmaceutically acceptable salt thereof in the free base (free base) form. As the pharmaceutically acceptable salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include 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, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide and iodide Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suverate , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, meth Oxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesul Nate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1- Sulfonates, naphthalene-2-sulfonates or mandelate can be used.

In addition, the active ingredient is dissolved or uniformly dispersed in the pressure-sensitive adhesive, it is preferably 2.0 to 25% by weight relative to the total weight of the drug-containing matrix. If the amount of donepezil or a pharmaceutically acceptable salt thereof is less than 2.0% by weight, the drug effect is inadequate, and at high concentrations exceeding 25% by weight, crystals of the drug are formed in the formulation, resulting in a decrease in adhesion. Can be.

Next, the drug-containing matrix layer of the transdermal absorbent preparation according to the present invention preferably uses an EVA adhesive as the polymer substrate and the pressure-sensitive adhesive.

In general, pressure-sensitive adhesives require adhesion to the skin, compatibility with drugs and other excipients, and as such adhesives, TRS (Sekisui Chemical Co., Osaka, Japan), Duro-Tec Acrylic pressure-sensitive adhesives such as (Duro-Tak; National Starch Chemical Co., bridgewater, NJ, USA) are commercially available. However, when the acrylic adhesive is used as a matrix of transdermal absorption agent for treating dementia, drug diffusion in the adhesive layer is slowed due to the interaction between the drug and the acrylic polymer in the adhesive layer, and the drug transition from the adhesive layer to the skin is also reduced. Therefore, it is difficult to deliver the required amount of drug.

Therefore, it is preferable that the adhesive which comprises the drug containing mattress layer of this invention uses EVA adhesive. Polyethylene vinyl acetate copolymer, which is the main raw material of the EVA adhesive, has various uses depending on the content of vinyl acetate, as well as weather resistance, seizure stability, tear strength, stress resistance and ozone resistance, and is transparent and non-toxic. Thermoplastic elastomer. At this time, in order to exhibit a desirable adhesive force, the EVA content used in the EVA pressure-sensitive adhesive is preferably a VA content (vinyl acetate content) of 4 to 50%, more preferably 33 to 41%.

In addition, the EVA adhesive includes a rosin ester resin to prevent crystallization of donepezil, an active ingredient. As an active ingredient of the transdermal absorption preparation of the present invention in most hydrophobic matrices except acrylic, Donepezil has a suitable polarity to increase the solubility of the drug in the matrix base because crystals are formed within a few days or weeks because of the solubility in the base. It is necessary to have a component. In this respect, 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 an appropriate polarity so that the donepezil can be stably dissolved or dispersed in the hydrophobic matrix without crystallization. do. In this case, the rosin ester resin used is preferably pentaerythritol rosin ester, glycerol rosin ester, pentaerythritol hydrogenated rosin ester, glycerol hydrogenated rosin ester, and more preferably 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 total weight of the drug-containing matrix. If it is out of the content range, there are disadvantageous problems in terms of skin applicability, compatibility with drugs and other excipients.

Next, the drug-containing matrix layer of the transdermal absorption preparation according to the present invention comprises any two or more selected from pyrrolidone derivatives, C _8-18 aliphatic derivatives, triacetin and triethyl citrate as skin penetration enhancers. It is preferable. In view 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 weight of the drug-containing matrix.

As the skin permeation enhancer, the pyrrolidone derivative may be N-cyclohexyl-2-pyrrolidone, 1-butyl-3-dodecyl-2-pyrrolidone (1-butyl- 3-dodecyl-2-pyrrolidone), 1,5-dimethyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone , 1-hexyl-4-methyloxycarbonyl-2-pyrrolidone, 1-hexyl-2-pyrrolidone, 1-hexyl-4-methyloxycarbonyl-2-pyrrolidone (2-hydroxyethyl) pyrrolidone (1- (2-hydroxyethyl) pyrrolidone), 3-hydroxy-N-methyl-2-pyrrolidone, 1 1-lauryl-4-methyloxycarbonyl-2-pyrrolidone, N-methyl-2-pyrrolidone, N N-carprylyl-2-pyrrolidone, N-dodecyl-2-pyrrolidone, etc. are preferable, and N-dodecyl-2 is preferred. It is more preferable that it is -pyrrolidone (N-dodecyl-2-pyrrolidone).

In addition, the aliphatic derivative of C _8-18 as the skin permeation enhancer is glycerol lauryl alcohol, oleyl alcohol, isopropyl myristrate, sorbitan monooleate -oleate, propylene monolaurate, propylene mono-oleate, oleyl macrogoglyceride, oleic acid, lauroyl macrogol glyceride macrogoglyceride, linoleoyl macrogoglyceride, propylene glycol caprylate / caprate, sorbitan monostearate mono-oleate, glycerol monolau Glycerol monolaurate, propylene glycol monolaurate, propylene glycol monocap Propylene glycol monocaprylate, sorbitan monolaurate, lauryl lactate, caprylic / capric triglyceride, corn oil PEG-8 ester, corn oil Preference is given to PEG-6 esters, glycerol monooleate, glycerol monolaurate, propylene glycol monolaurate, propylene glycol monocaprylate, sorbitan monolaurate, lauryl lactate, caprylic / capric trigly More preferred are cerides, corn oil PEG-8 esters, corn oil PEG-6 esters, and the like.

Furthermore, triacetin or triethyl citrate can be used as the skin permeation enhancer. The triacetin has been used as a dissolution aid, softener, skin permeation accelerator, etc. Triethyl citrate is a softener of Eudragit-based polyacrylate polymer, and has been used as a softener for oral coating materials. Like cetin, it has a skin permeation enhancing effect on donepezil.

It is preferable that the above-mentioned skin permeation enhancer included in the drug-containing matrix layer of the transdermal absorbent preparation according to the present invention contains 10-25% by weight based on the total weight of the drug-containing matrix by mixing any two or more thereof.

Next, the drug protection support layer and the release layer constituting the transdermal absorption preparation for treating dementia according to the present invention will be described.

The drug-protective support layer of the transdermal absorbent preparation for treating dementia according to the present invention is thin and flexible in order to prevent the loss of donepezil from the preparation during attachment or storage on the skin and does not cause an allergic reaction because it is not reactive with the skin. use.

The support layer according to the present invention is a plastic film such as polyethylene, polypropylene, ethylene vinyl acetate copolymer, vinylon, polyester, polyurethane, nylon, polyacrylonitrile, polyethylene terephthalate, polyolefin, and the like commonly used in transdermal absorbents. (film) or nonwoven fabrics such as rayon and polyester having moisture absorption capability, woven fabrics such as polyester, acrylic, silk, cotton, or lamination thereof in order to prevent the transdermal absorption agent from falling off due to moisture emitted from the human body Hybrid materials may be used, and any of drug-protecting substances used in conventional transdermal absorption preparations may be used.

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

The transdermal absorption agent for treating dementia containing Donepezil as an active ingredient according to the present invention has excellent skin adhesion and prevents a decrease in adhesion by preventing crystal formation even when a high concentration of drug is contained in a hydrophobic matrix of 10% or more. The drug can be released continuously for a long period of time (1-7 days) (see FIG. 2), and the skin penetration rate gradually decreases as the application period becomes longer, but the skin penetration rate is higher than the minimum required penetration rate of 1.2 μg / cm 2 / hr. By maintaining the excellent skin permeability of the drug (see Fig. 3) can be useful to replace the conventional oral treatment for dementia.

Hereinafter, the present invention will be described in detail through Examples and Experimental Examples. However, the following Examples and Experimental Examples are provided only to specifically describe the present invention, but the scope of the present invention is not limited to these Examples and Experimental Examples.

Example 1 Preparation of Transdermal Absorbent for Treatment of Dementia Containing Donepezil as an Active Ingredient

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 pressure-sensitive adhesive so that the total amount of solid content was 50%, completely dissolved, and then the adhesive solution containing the drug. Was applied on a silicone-treated polyester release film fixed on an applicator, and dried at a speed of 1300 rpm for 10 minutes at 90 ° C. to prepare an adhesive layer sheet having a thickness of 85 μm, and then laminated with a polyester support film. It was cut to a certain size to prepare a transdermal absorption preparation for treating dementia containing the donepezil as an active ingredient.

<Examples 2 to 20> Preparation of transdermal absorbent preparation for treating dementia containing Donepezil as an active ingredient

The composition of the matrix layer was changed in the same manner as in Example 1 while changing the composition as shown in Table 1 to prepare a transdermal absorption preparation for treating dementia containing the donepezil as an active ingredient. At this time, the content of each component is weight percent.

Table 1

		ingredient(%)
		Donepezil	EVA adhesive	GML	GMO	SML	NP	CCS	CP8	LL	TA	TC	CP6	PGML
Example	One	13.0	77.0	5.0	5.0
	2	13.0	77.0	5.0		5.0
	3	13.0	77.0	5.0			5.0
	4	13.0	77.0	5.0				5.0
	5	13.0	77.0	5.0					5.0
	6	13.0	77.0	5.0						5.0
	7	13.0	72.0				10.0				5.0
	8	13.0	72.0				10.0				5.0
	9	13.0	72.0				10.0				5.0
	10	13.0	72.0				10.0					5.0
	11	13.0	72.0				10.0				5.0
	12	13.0	72.0				10.0				5.0
	13	13.0	72.0				10.0				5.0
	14	13.0	72.0				10.0				5.0
	15	11.5	73.5				10.0				5.0
	16	10.0	75.0				10.0				5.0
	17	13.0	62.0			10.0	10.0				5.0
	18	13.0	62.0				10.0				5.0		10.0
	19	13.0	62.0				10.0	10.0			5.0
	20	13.0	62.0				10.0				5.0			10.0
EVA: polyethylene vinyl acetate adhesive, GML: glycerol monolaurate, GMO: glycerol monooleate, SML: sorbitan monolaurate, NP: N-dodecyl-2-pyrrolidone, CCS: caprylic / capric Triglyceride, CP8: corn PEG-8 ester, LL: lauryl lactate, TA: triacetin, TC: triethyl citrate, CP6: corn PEG PEG-6 ester, PGML: propylene glycol monolaurate

The composition of the components constituting the matrix layer was changed as shown in Table 2 and Table 3, and was carried out in the same manner as in Example 1 to prepare a transdermal absorption preparation for treating dementia containing the donepezil as an active ingredient. At this time, the content of each component is weight percent.

TABLE 2

division		Comparative example
division		One	2	3	4	5	6	7	8	9	10	11	12	13	14	15
ingredient(%)	Donepezil	13	13	13	13	13	13	13	13	13	13	13	13	13	13	12
	SIS adhesive	77			67
	SEP adhesive		77
	SBS adhesive			77
	Acrylic adhesive							77
	EVA adhesive					77	67		77	77	77	77	77	77	77	77
	NP	10	10	10	20	10	20	10
	SML								10
	SMO									10
	PMO										10
	PML											10
	GMO												10
	GML													10
	IPM														10
	PGML															10
SIS: styrene-isoprene-styrene, SEP: styrene-ethylene-propylene, SBS: styrene-butadiene-styrene, acrylic adhesive: polyacrylate adhesive, EVA: polyethylene vinyl acetate, NP: N-dodecyl-2-pyrrolidone , SML: sorbitan monolaurate, SMO: sorbitan monooleate, PMO: polyoxyethylene monooleate, PML: polyoxyethylene monolaurate, GMO: glycerol monooleate, GML: glycerol monolaurate, IPM Isopropyl myristate, PGML: Propylene glycol monolaurate

TABLE 3

division		Comparative example
division		16	17	18	19	20	21	22	23	24	25	26	27	28	29	30
ingredient(%)	Donepezil	10	13	13	13	13	13	13	13	13	13	13	13	13	13	13
	EVA adhesive	77	77	77	77	77	77	77	77	77	77	77	77	77	77	77
	OMG	10
	LL		10
	OA			10
	TA				10
	CP8					10
	GMLi						10
	CP6							10
	LM6G								10
	LiM6G									10
	PGCC										10
	TC											10
	SMS												10
	DGME													10
	PGML														10
	PGMC															10
EVA: polyethylene vinyl acetate, OMG: oleyl macrogol glyceride, LL: lauryl lactate, OA: oleic acid, TA: triacetin, CP8: corn oil PEG-8 ester, GMLi: glycerol monolinoleate, CP6: corn Oil PEG-6 ester, LM6G: lauroyl macrogol-6 glyceride, LiM6G: linoleyl macrogol-6 glyceride, PGCC: propylene glycol caprylate / caprate, TC: triethyl citrate, SMS: sorb Non-elastic monostearate, DGME: diethylene glycol monoethyl ether (transcutol P), PGML: propylene glycol monolaurate, PGMC: propylene glycol monocaprylate

Skin permeation experiment of the donepezil drug for the transdermal absorption preparations prepared in Examples 1 to 20 and Comparative Examples 1 to 30 were prepared as described above.

Experimental Example 1

Drug permeation experiment diffusion device (Franzcel) was prepared by adding 0.5% by weight of sodium azide to prevent rot of the skin to the phosphate buffer pH 7.4 of the aqueous phase. The experimental diffusion device was filled with an aqueous phase to maintain a temperature of 32 ± 0.5 ° C., and the skin was donated with each matrix prepared in Examples 1 to 20 and Comparative Examples 1 to 30 using a human cadaver skin. Cut to cell size and applied. As time passed, 250 μL of the buffer solution in which the drug was diffused was taken for each hour, and the drug permeated by liquid chromatography was quantified. After the drug permeated through the patches prepared in Examples 1 to 20 and Comparative Examples 1 to 30, the average drug permeation rate of the skin after 7 days was shown in Tables 4 and 5 below.

Table 4

	Skin penetration rate (μg / cm ² / hr)		Skin penetration 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	Example 20	7.72 ± 0.97

Table 5

	Skin penetration rate (μg / cm ² / hr)		Skin penetration 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

When comparing Table 4 and Table 5, it can be seen that donepezil is more effective than the combined use of a specific skin permeation enhancer alone, and also combined use of two or more aliphatic derivatives, N-dodecyl-2-pyrroli It can also be seen that the combined use of the don and aliphatic derivatives, the combined use of the aliphatic derivatives, N-dodecyl-2-pyrrolidone, triacetin and triethyl citrate are effective.

The cumulative penetration rate and skin penetration rate change for Examples 13 to 19, which are relatively good in skin permeation test results, are shown in FIGS. 2 and 3, respectively. It can be seen from FIG. 2 that the drug is continuously released during the experimental period, and through FIG. 3, the initial release rate is high, so that the drug is administered at the initial stage of attachment of the transdermal absorbent, thereby maximizing the therapeutic effect. Donepezil is more specific for acetylcholinesterase (AChE) in the brain than plasma butylcholinesterase (BChE) and has a half-life of 58-90 hours, a bioavailability of 100%, and a protein binding rate of 96%. Excellent inhibitory effect on therapase.

In the case of 5 mg oral administration, the maximum blood concentration was 9.8 ± 1.1 ng / mL in a single oral administration, and when administered repeatedly, the steady-state was reached within 15 days and the average plasma concentration was 26.5 ± in the steady state. It is 3.9 ng / mL and the average plasma cleaning rate is constant at 0.13 L / hr / kg. The calculated skin penetration rate is approximately 3.455 ± 3.9 μg / hr. As can be seen in Figure 3, the prepared transdermal absorption preparations can be seen that the required level of skin penetration rate or maintained at a slightly higher rate during the experimental period.

Claims

In the transdermal absorption preparation for treating dementia comprising a drug protective support layer, a drug-containing matrix layer and a peeling layer,

The drug-containing matrix layer is 2.0-25% by weight of donepezil or a pharmaceutically acceptable salt thereof as an active ingredient, 50-80% by weight of an EVA adhesive containing a rosin ester resin as a polymer base, and pyrrolidone as a skin permeation enhancer. For treating dementia containing donepezil as an active ingredient, comprising 10-25 wt% of a mixture of two or more kinds selected from the group consisting of derivatives, C 8-18 aliphatic derivatives, triacetin and triethyl citrate Percutaneous Absorption.
The method of claim 1, wherein the pyrrolidone derivatives as skin permeation enhancers are N-cyclohexyl-2-pyrrolidone, 1-butyl-3-dodecyl-2-pyrrolidone, 1,5-dimethyl-2- Pyrrolidone, 1-ethyl-2-pyrrolidone, 1-hexyl-4-methyloxycarbonyl-2-pyrrolidone, 1-hexyl-2-pyrrolidone, 1- (2-hydroxyethyl) Pyrrolidone, 3-hydroxy-N-methyl-2-pyrrolidone, 1-lauryl-4-methyloxycarbonyl-2-pyrrolidone, N-methyl-2-pyrrolidone, N-car A transdermal absorption preparation for treating dementia, comprising donepezil as an active ingredient, which is selected from the group consisting of prillyl-2-pyrrolidone and N-dodecyl-2-pyrrolidone.
The method of claim 2, wherein the pyrrolidone derivative is N-dodecyl-2-pyrrolidone, characterized in that the transdermal absorption preparation for the treatment of dementia, containing donepezil as an active ingredient, characterized in that.
The aliphatic derivative of C 8-18 as a skin permeation enhancer is glycerol lauryl alcohol, oleyl alcohol, isopropyl myrilate, sorbitan monooleate, propylene monolaurate, propylene monooleate, oleic acid. Il macrogol glyceride, oleic acid, lauroyl macrogol glyceride, linoleyl macrogol glyceride, propylene glycol caprylate / caprate, sorbitan monostearate monooleate, glycerol monolaurate, propylene glycol monolaurate Selected from the group consisting of laurate, propylene glycol monocaprylate, sorbitan monolaurate, lauryl lactate, caprylic / capric triglycerides, corn oil PEG-8 esters and corn oil PEG-6 esters Percutaneous for the treatment of dementia containing Donepezil as an active ingredient Absorbents.
The method of claim 4, wherein the C 8 - aliphatic derivatives of 18 glycerol monooleate, glycerol monolaurate, propylene articles rilkol monolaurate, propylene glycol caprylate, sorbitan laurate, lauryl lactate, A transdermal absorption agent for treating dementia comprising Donepezil as an active ingredient, which is selected from the group consisting of caprylic / capric triglycerides, corn oil PEG-8 esters and corn oil PEG-6 esters.
The transdermal absorption preparation for treating dementia according to claim 1, wherein the rosin ester resin is used to prevent crystallization of the active ingredient.
The rosin ester resin according to claim 1, wherein the rosin ester resin is selected from the group consisting of glycerol rosin ester, pentaerythritol rosin ester, glycerol hydrogenated rosin ester, and pentaerythritol hydrogenated rosin ester. Percutaneous absorption preparations for treating dementia.
The method of claim 7, wherein the rosin ester resin is pentaerythritol rosin ester, characterized in that the percutaneous absorption preparation for the treatment of dementia containing donepezil as an active ingredient.
The transdermal absorption agent for treating dementia according to claim 1, wherein the EVA used in the EVA pressure-sensitive adhesive contains donepezil as an active ingredient, wherein the VA content (vinyl acetate content) is 4 to 50%.
The transdermal absorption agent for treating dementia according to claim 1, wherein the EVA used in the EVA pressure-sensitive adhesive has donepezil as an active ingredient, wherein the VA content (vinylacetate content) is 33 to 41%.