Percutaneously absorbable preparation

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a percutaneously absorbable preparation comprising 2-[(1-benzylpiperidin-4-yl)methyl]-5,6~dimethoxyindan-1-one and/or its hydrochloride in a pressure-sensitive adhesive layer, wherein the percutaneously absorbable preparation may be administered into a patient so that Cmax per a surface area unit of the percutaneously absorbable preparation is 0.025 to 0.5 ng/ml·cm2 in the plasma concentration profile. The preparation has a favourable plasma concentration profile of 2-[(1-benzylpiperidin-4-yl)methyl]-5,6~dimethoxyindan-1-one and/or its hydrochloride with no jump of the plasma concentration.

EFFECT: what is presented is the percutaneously absorbable preparation.

29 cl, 1 tbl, 2 dwg, 4 ex

 

The present invention relates to a transdermally absorbable preparation comprising 2-[(1-benzylpiperidine-4-yl)methyl]-5,6-dimethoxyindole-1-it (which will be referred to as "donepezil") and/or its hydrochloride in the form of 2-[(1-benzylpiperidine-4-yl)methyl]-5,6-dimethoxyindole-1-monohydrochloride (which will be referred to as "donepezil hydrochloride"). Specifically, the present invention relates to a transdermally absorbable drug with a favorable profile of drug concentration in plasma when applied in the form of a patch on the skin surface, for a constant supply of the drug into the living body through the skin.

Prior art

The main drug, donepezil or its hydrochloride, donepezil hydrochloride, has inhibitory activity against acetylcholinesterase and is used against dementia and Alzheimer's. Patients with dementia of Alzheimer's are usually older people and that face difficulty in swallowing oral dosage forms. In some cases, may also be hampered by the introduction of the oral dosage form to patients with severe symptoms of dementia and Alzheimer's. In these cases it is useful Superonline introduction.

In addition, in the case of oral administration of donepezil available in PR is even in the form of quick release tablets, the concentration of drug in the plasma of the patient reach maximum level in the range of 2 to 5 cow after administration of the medicinal product and is characterized by steep sawtoothed curve (patent document 1).

However, the identification of sawtoothed curve of the concentration of drug in plasma in the form of its Tmax is associated with the risk of adverse side effects that accompany a sudden increase in plasma concentrations.

In such cases, suitable drugs, creating a gentle increase in the concentration of the drug in plasma.

On the other hand, transdermally absorbable preparations using donepezil or donepezil hydrochloride, already known in the form of parenteral dosage forms, for example, a drug for percutaneous application (such as an ointment or a skin patch), comprising donepezil hydrochloride, is proposed in patent document 2. In patent document 3 also serves percutaneous absorbable drug for treating dementia, comprising donepezil or its hydrochloride, in the form of adhesive compositions, pressure-sensitive, and describes that the use of donepezil hydrochloride can be achieved a satisfactory rate of skin permeability by incorporating salts of acetic acid in the adhesive composition, sensitive to the making.

Patent document 1: US 2007/0129402

Patent document 2: nested Japanese patent application No. H11-315016

Patent document 3: WO 2003/032960

SUMMARY of the INVENTION

The PURPOSE of the INVENTION

However, unknown percutaneous absorbable drug donepezil, which would have a more favorable profile of drug concentration in plasma and could be characterized by a lower risk of adverse side effects than donepezil, commercially available in tablet form with quick release.

In these circumstances, the present invention is to develop a percutaneous absorbable preparation for percutaneous absorption of donepezil and/or donepezil hydrochloride, which has a favorable profile of drug concentration in plasma without the occurrence of a sudden increase in plasma concentration.

The OBJECTIVES of the INVENTIONS

As a result of a large number of studies to solve the above problems, the authors of the present invention have found that percutaneous absorbable preparation containing donepezil and/or donepezil hydrochloride, is a transdermally absorbable preparation, demonstrating a favorable safety profile of drug concentration in plasma and is able to inhibit the risk of not blagopriyatnyh side effects, thereby carrying out the present invention.

Namely, the present invention relates to the following:

[1] transdermally absorbable preparation comprising 2-[(1-benzylpiperidine-4-yl)methyl]-5,6-dimethoxyindole-1-he and/or its hydrochloride

where percutaneous absorbed the drug can be administered to the patient so that the Cmax per unit surface area percutaneous absorbable drug is from 0.025 to 0.5 ng/ml·cm2the profile of the concentration in plasma;

[2] transdermally absorbable preparation described in [1] above, where Cmax is from 0.025 to 0.45 ng/ml·cm2;

[3] transdermally absorbable preparation described in [1] above, where Cmax is from 0.05 to 0.4 ng/ml·cm2;

[4] transdermally absorbable preparation described in any of [1] to [3] above, where AUC per unit surface area percutaneous absorbable drug is from 7.5 to 75 ng·h/ml·cm2;

[5] transdermally absorbable preparation described in [4] above, where AUC is from 10 to 62.5 ng·h/ml·cm2;

[6] transdermally absorbable preparation described in [4] above, where the AUC ranges from 12.5 to 50 ng·h/ml·cm2;

[7] transdermally absorbable preparation described in any of [1] to [3] above, where Tmax is from 12 to 192 h;

[8] transdermally absorbable preparation described in [7] above, where Tmax is from 24 to 180 h;

[9] percutaneous absorbable ven the rat, described in [7] above, where Tmax is from 48 to 168 h;

[10] transdermally absorbable preparation described in any of [1] to [3] above, where AUC per unit surface area percutaneous absorbable drug is from 7.5 to 75 ng·h/ml·cm2and Tmax ranges from 12 to 192 h;

[11] transdermally absorbable preparation described in [10] above, where Tmax is from 24 to 180 h;

[12] transdermally absorbable preparation described in [10] above, where Tmax is from 48 to 168 h;

[13] transdermally absorbable preparation described in any of [1] to [3] above, where AUC per unit surface area transdermally absorbable preparation is from 10 to 62.5 ng·h/ml·cm2and Tmax ranges from 12 to 192 h;

[14] transdermally absorbable preparation described in [13] above, where Tmax is from 24 to 180 h;

[15] transdermally absorbable preparation described in [13] above, where Tmax is from 48 to 168 h;

[16] transdermally absorbable preparation described in any of [1] to [3] above, where AUC per unit surface area percutaneous absorbable drug ranges from 12.5 to 50 ng·h/ml·cm2and Tmax ranges from 12 to 192 h;

[17] transdermally absorbable preparation described in [16] above, where Tmax is from 24 to 180 h;

[18] transdermally absorbable preparation described in [16] above, where Tmax is from 48 to 168 h;

[19] percutaneous absorbable drug, vkluchaysya-[(1-benzylpiperidine-4-yl)methyl]-5,6-dimethoxyindole-1-he and/or its hydrochloride

where percutaneous absorbed the drug can be administered to the patient so that the AUC per unit surface area percutaneous absorbable drug is from 7.5 to 75 ng·h/ml·cm2the profile of the concentration in plasma;

[20] transdermally absorbable preparation described in [19] above, where AUC is from 10 to 62.5 ng·h/ml·cm2;

[21] transdermally absorbable preparation described in [19] above, where the AUC ranges from 12.5 to 50 ng·h/ml·cm2;

[22] transdermally absorbable preparation described in any of [19] to [21] above, where Tmax is from 12 to 192 h;

[23] transdermally absorbable preparation described in [22] above, where Tmax is from 24 to 180 h;

[24] transdermally absorbable preparation described in [22] above, where Tmax is from 48 to 168 h;

[25] transdermally absorbable preparation comprising 2-[(1-benzylpiperidine-4-yl)methyl]-5,6-dimethoxyindole-1-he and/or its hydrochloride, is able to be patient so that Tmax profile in plasma concentrations ranging from 12 to 192 h;

[26] transdermally absorbable preparation described in [25] above, where Tmax is from 24 to 180 h;

[27] transdermally absorbable preparation described in [25] above, where Tmax is from 48 to 168 h;

[28] transdermally absorbable preparation described in [1] above, which is put on from 5 to 150 cm2the skin of the patient; and

[29] transdermally absorbable preparation described in [1] above, the which is applied to the patient from one to seven times per week.

USEFUL INVENTIONS

The present invention relates to a transdermally absorbable drug, including donepezil, and/or donepezil hydrochloride, which is a favorable profile of drug concentration in plasma.

BRIEF DESCRIPTION of FIGURES

Figure 1 presents the changes in the concentrations of donepezil in plasma after oral administration of tablets Aricept 5 mg, in the test with a single dose healthy adults performed in example 3, or after adhesion transdermally absorbable preparation of example 1. The horizontal axis indicates the time elapsed after injection, and the vertical axis indicates the concentration of drug in plasma. In the graph ♦ indicates the time points of blood collection and plasma concentrations at these time points in the case of the introduction of tablets Aricept 5 mg, while • indicates the time points of blood collection and plasma concentrations at these time points after adhesion transdermally absorbable preparation of example 1.

Figure 2 presents the changes in the concentrations of donepezil in plasma after oral administration of tablets Aricept 5 mg, in the test with a single dose healthy adults performed in example 4, or after adhesion transdermally absorbable preparation of example 2. The horizontal axis indicates the time elapsed pic is e introduction and the vertical axis indicates the concentration of drug in plasma. In the graph ◊ indicates the time points of blood collection and plasma concentrations at these time points in the case of the introduction of tablets Aricept 5 mg, whereas ○ indicates the time points of blood collection and plasma concentrations at these time points after adhesion transdermally absorbable preparation of example 2.

DETAILED DESCRIPTION

This is followed by a more detailed explanation of the present invention.

Transdermally absorbable preparation according to the present invention is intended for percutaneous absorption of donepezil and/or donepezil hydrochloride (hereinafter "donepezil and/or donepezil hydrochloride can be shortened to "donepezil and the like"). Transdermally absorbable preparation according to the present invention is capable graduale to increase the concentration of donepezil and the like in the plasma after adhesion transdermally absorbable preparation that shows the concentration profile of drug donepezil and the like in the plasma, as described below. In addition, transdermally absorbable preparation according to the present invention is a percutaneous absorbable drug, which confers resistance effective concentration of donepezil and the like in the plasma compared with personalnumber tablets or the like, thereby eliminating the need for this replacement.

In citesti, transdermally absorbable preparation according to the present invention, as can be expected, reduces cases of adverse side effects by controlling the Cmax per unit surface area percutaneous absorbable drug to the range of the present invention. In addition, the concentration of donepezil and the like in the plasma in the steady state in the case of the introduction of tablets can be supported percutaneous absorbable drug use in practice, the size composition, by controlling Cmax

and AUC per unit surface area percutaneous absorbable drug to the ranges of the present invention.

Transdermally absorbable preparation according to the present invention allows donepezil and the like absorbed through the skin and is transdermally absorbable drug, which allows you to enter donepezil and the like to the patient so that the Cmax per unit surface area percutaneous absorbable drug is from 0.025 to 0.5 ng/ml·cm2the profile of plasma concentration.

There is no specific limitation regarding percutaneous absorbable preparation according to the present invention, provided that it is a drug that allows you to enter donepezil and is like what the patient that Cmax per unit surface area percutaneous absorbable drug is from 0.025 to 0.5 ng/ml·cm2the profile of plasma concentration of donepezil and the like. For example, the drug can be a drug that allows you to reach Cmax after a single dose, or a drug that allows you to achieve a Cmax similar to the above Cmax, with a repeated.

Transdermally absorbable preparation according to the present invention may be a percutaneous absorbable preparation which allows you to enter donepezil and the like to the patient so that the Cmax per unit surface area percutaneous absorbable drug, single administration ranges from 0.025 to 0.5 ng/ml·cm2the profile of plasma concentration of donepezil and the like, or may be a transdermally absorbable preparation which allows you to enter donepezil and the like to the patient so that the Cmax per unit surface area transdermally absorbable preparation is required for detection of the profile in plasma concentrations characteristic of the present invention, when multiple administrations ranged from 0.025 to 0.5 ng/ml·cm2.

In the present invention, the term "Cmax (ng/ml)" means the maximum concentration of the drug in plasma. The term "maximum conc the tion of the drug in plasma" indicates the maximum value of the concentration of drug in plasma after administration of the drug.

In the present invention, the term "Cmax per unit surface area percutaneous absorbable drug" refers to a value obtained by dividing the Cmax in the case of the introduction of percutaneous absorbable preparation of the present invention on a surface area almost percutaneous absorbable drug in contact with the skin of the patient.

In the present invention, the term "Cmax per unit surface area percutaneous absorbable drug, single administration" refers to a value obtained by dividing the Cmax in the case of a single injection percutaneous absorbable preparation of the present invention on a surface area almost percutaneous absorbable drug in contact with the skin of the patient.

In the present invention, the term "Cmax per unit surface area percutaneous absorbable drug with a repeated" means a value obtained by dividing the Cmax transdermally absorbable preparation of the present invention with multiple introduction on the surface honor percutaneous absorbable drug in contact with the skin of the patient.

In transdermally absorbable preparation according to the present invention Cmax per unit surface area transdermally absorbable preparation is preferably from 0.025 to 0.45 ng/ml·cm2and b is more preferably from 0.05 to 0.4 ng/ml·cm 2.

Transdermally absorbable preparation according to the present invention is a percutaneous absorbable preparation which allows you to enter donepezil and the like to the patient so that the AUC per unit surface area percutaneous absorbable drug is from 7.5 to 75 ng·h/ml·cm2the profile of plasma concentration of donepezil and the like.

There is no specific limitation regarding percutaneous absorbable preparation of the present invention provided that it is a drug that allows you to enter donepezil and the like to the patient so that the AUC per unit surface area percutaneous absorbable drug is from 7.5 to 75 ng·h/ml·cm2. For example, the drug can be a drug which enables to achieve the above AUC after a single dose, or medication, which can achieve the AUC, similar to the above AUC, with a repeated.

Transdermally absorbable preparation according to the present invention may be a percutaneous absorbable preparation which allows you to enter donepezil and the like to the patient so that the AUC per unit surface area percutaneous absorbable drug in a single dose is 7.5 to 75 ng·h/ml·cm2the profile of the concentration in the plasma is donepezil and the like, or may be a transdermally absorbable preparation which allows you to enter donepezil and the like to the patient so that the AUC per unit surface area percutaneous absorbable drug with multiple introduction required for detection profile in plasma concentrations characteristic of the present invention ranged from 7.5 to 75 ng·h/ml·cm2.

In the present invention, the term "AUC (ng·h/ml·cm2)" means the area under the curve of drug concentration with time. The term "area under the curve of concentration of drug against time" refers to the area almost covered by the curve shown on the graph representing the concentration of drug in plasma for elapsed time (curve dependence of the concentration of the drug in plasma from time to time), and the horizontal axis (time axis).

In the present invention, the term "AUC per unit surface area percutaneous absorbable drug" refers to a value obtained by dividing the AUC in the case of the introduction of percutaneous absorbable preparation of the present invention on a surface area almost percutaneous absorbable drug in contact with the skin of the patient.

In the present invention, the term "AUC per unit surface area Creston the absorbable drug, single administration" means the amount obtained by dividing the AUC in the case of a single injection percutaneous absorbable preparation of the present invention on a surface area almost percutaneous absorbable drug in contact with the skin of the patient.

In the present invention, the term "AUC per unit surface area percutaneous absorbable drug with a repeated" means a value obtained by dividing the AUC transdermally absorbable preparation of the present invention with multiple introduction on the surface honor percutaneous absorbable drug in contact with the skin of the patient.

In the present invention, the term "AUC" refers to either AUCinf, or AUClast and, although there is no particular limitation, it is preferable AUCinf.

The term "AUCinf" denotes the value of the AUC when the concentration of drug in plasma, obtained by extrapolation of time to infinity based on the elimination rate from the blood.

The term "AUClast" denotes the value of the AUC to the last measurement point on the curve, the concentration of drug in plasma from time to time. In the present invention, the term "AUClast" represents preferably AUC0→528.

In transdermally absorbable preparation according to the present invention AUC per unit surface area dermal absorbere the second drug is preferably from 10 to 62.5 ng·h/ml·cm 2and more preferably from 12.5 to 50 ng·h/ml·cm2.

Transdermally absorbable preparation according to the present invention is a percutaneous absorbable preparation which allows you to enter donepezil and the like to the patient so that Tmax concentration profile of donepezil and the like in the plasma ranges from 12 to 192 cow.

There is no specific limitation regarding percutaneous absorbable preparation of the present invention provided that it is a drug that allows you to enter donepezil and the like to the patient so that Tmax ranges from 12 to 192 cow. For example, the drug can be a drug, which can achieve the above Tmax, single administration, or a drug that allows you to reach Tmax, similar to the above Tmax, with a repeated.

Transdermally absorbable preparation according to the present invention may be a percutaneous absorbable preparation which allows you to enter donepezil and the like to the patient so that Tmax profile in plasma concentrations of donepezil and the like in a single dose ranges from 12 to 192 h, or may be a transdermally absorbable preparation which allows you to enter donepezil and the like to the patient so that Tmax with multiple introduction required the output for detection of concentration profiles in plasma, characteristic of the present invention, ranges from 12 to 192 hours

In the present invention, the term "Tmax" refers to the time to reach maximum plasma concentrations. The term "time to reach maximum plasma concentration" refers to the time required to reach maximum drug concentration in plasma after administration of the drug.

In the present invention Tmax represents the value of Tmax in the case of the introduction of percutaneous absorbable preparation of the present invention.

In the present invention, the term "Tmax in a single" denotes the value of Tmax in the case of a single injection percutaneous absorbable preparation of the present invention.

In the present invention, the term "Tmax with a repeated" denotes the value of Tmax in the case of repeated administration transdermally absorbable preparation of the present invention.

For transdermally absorbable preparation according to the present invention Tmax

is preferably from 24 to 180 hours, and more preferably from 48 to 168 hours

Transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation which can be administered to the patient so that the Cmax per unit surface area percutaneous absorbable ven the rata is from 0.025 to 0.5 ng/ml·cm 2and AUC per unit surface area percutaneous absorbable drug is from 7.5 to 75 ng·h/ml·cm2the profile of plasma concentration of donepezil and the like.

Transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation which can be administered to the patient so that the Cmax per unit surface area percutaneous absorbable drug is from 0.025 to 0.45 ng/ml·cm2and AUC per unit surface area percutaneous absorbable drug is from 7.5 to 75 ng·h/ml·cm2the profile of plasma concentration of donepezil and the like.

Transdermally absorbable preparation according to the present invention even more preferably is a transdermally absorbable preparation which can be administered to the patient so that the Cmax per unit surface area percutaneous absorbable drug is from 0.05 to 0.4 ng/ml·cm2and AUC per unit surface area percutaneous absorbable drug is from 7.5 to 75 ng·h/ml·cm2the profile of plasma concentration of donepezil and the like.

Transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation which can be entered PA is Ianto so, that Cmax per unit surface area percutaneous absorbable drug is from 0.025 to 0.5 ng/ml·cm2and AUC per unit surface area transdermally absorbable preparation is from 10 to 62.5 ng·h/ml·cm2the profile of plasma concentration of donepezil and the like.

Transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation which can be administered to the patient so that the Cmax per unit surface area percutaneous absorbable drug is from 0.025 to 0.45 ng/ml·cm2and AUC per unit surface area transdermally absorbable preparation is from 10 to 62.5 ng·h/ml·cm2the profile of plasma concentration of donepezil and the like.

Transdermally absorbable preparation according to the present invention even more preferably is a transdermally absorbable preparation which can be administered to the patient so that the Cmax per unit surface area percutaneous absorbable drug is from 0.05 to 0.4 ng/ml·cm2and AUC per unit surface area transdermally absorbable preparation is from 10 to 62.5 ng·h/ml·cm2the profile of plasma concentration of donepezil and the like.

Transdermally absorbable preparation according to the present from which briteney preferably represents a percutaneous absorbable drug, which can be administered to the patient so that the Cmax per unit surface area percutaneous absorbable drug is from 0.025 to 0.5 ng/ml·cm2and AUC per unit surface area percutaneous absorbable drug ranges from 12.5 to 50 ng·h/ml·cm2the profile of plasma concentration of donepezil and the like.

Transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation which can be administered to the patient so that the Cmax per unit surface area percutaneous absorbable drug is from 0.025 to 0.45 ng/ml·cm2and AUC per unit surface area percutaneous absorbable drug ranges from 12.5 to 50 ng·h/ml·cm2the profile of plasma concentration of donepezil and the like.

Transdermally absorbable preparation according to the present invention even more preferably is a transdermally absorbable preparation which can be administered to the patient so that the Cmax per unit surface area percutaneous absorbable drug is from 0.05 to 0.4 ng/ml·cm2and AUC per unit surface area percutaneous absorbable drug ranges from 12.5 to 50 ng·h/ml·cm2the profile of plasma concentration of donepezil and the like.

Percutaneous absorb who financed the preparation according to the present invention preferably is a transdermally absorbable drug, which can be administered to the patient so that the Cmax per unit surface area percutaneous absorbable drug is from 0.025 to 0.5 ng/ml·cm2and Tmax ranges from 12 to 192 h profile in plasma concentrations of donepezil and the like.

Transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation which can be administered to the patient so that the Cmax per unit surface area percutaneous absorbable drug is from 0.025 to 0.45 ng/ml·cm2and Tmax ranges from 12 to 192 h profile in plasma concentrations of donepezil and the like.

Transdermally absorbable preparation according to the present invention even more preferably is a transdermally absorbable preparation which can be administered to the patient so that the Cmax per unit surface area percutaneous absorbable drug is from 0.05 to 0.4 ng/ml·cm2and Tmax ranges from 12 to 192 h profile in plasma concentrations of donepezil and the like.

Transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation which can be administered to the patient so that the Cmax per unit surface area percutaneous absorbable drug is from 0.025 d is 0.5 ng/ml·cm 2and Tmax ranges from 24 to 180 h profile in plasma concentrations of donepezil and the like.

Transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation which can be administered to the patient so that the Cmax per unit surface area percutaneous absorbable drug is from 0.025 to 0.45 ng/ml·cm2and Tmax ranges from 24 to 180 h profile in plasma concentrations of donepezil and the like.

Transdermally absorbable preparation according to the present invention even more preferably is a transdermally absorbable preparation which can be administered to the patient so that the Cmax per unit surface area percutaneous absorbable drug is from 0.05 to 0.4 ng/ml·cm2and Tmax ranges from 24 to 180 h profile in plasma concentrations of donepezil and the like.

Transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation which can be administered to the patient so that the Cmax per unit surface area percutaneous absorbable drug is from 0.025 to 0.5 ng/ml·cm2and Tmax ranges from 48 to 168 h profile in plasma concentrations of donepezil and the like.

Percutaneous absorbable drug is according to the present invention preferably is a transdermally absorbable drug, which can be administered to the patient so that the Cmax per unit surface area percutaneous absorbable drug is from 0.025 to 0.45 ng/ml·cm2and Tmax ranges from 48 to 168 h profile in plasma concentrations of donepezil and the like.

Transdermally absorbable preparation according to the present invention even more preferably is a transdermally absorbable preparation which can be administered to the patient so that the Cmax per unit surface area percutaneous absorbable drug is from 0.05 to 0.4 ng/ml·cm2and Tmax ranges from 48 to 168 h profile in plasma concentrations of donepezil and the like.

Transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation which can be administered to the patient so that the AUC per unit surface area percutaneous absorbable drug is from 7.5 to 75 ng·h/ml·cm2and Tmax ranges from 12 to 192 h profile in plasma concentrations of donepezil and the like.

Transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation which can be administered to the patient so that the AUC per unit surface area transdermally absorbable preparation is from 10 to 62, ng·h/ml·cm 2and Tmax ranges from 12 to 192 h profile in plasma concentrations of donepezil and the like.

Transdermally absorbable preparation according to the present invention even more preferably is a transdermally absorbable preparation which can be administered to the patient so that the AUC per unit surface area percutaneous absorbable drug ranges from 12.5 to 50 ng·h/ml·cm2and Tmax ranges from 12 to 192 h profile in plasma concentrations of donepezil and the like.

Transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation which can be administered to the patient so that the AUC per unit surface area percutaneous absorbable drug is from 7.5 to 75 ng·h/ml·cm2and Tmax ranges from 24 to 180 h profile in plasma concentrations of donepezil and the like.

Transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation which can be administered to the patient so that the AUC per unit surface area transdermally absorbable preparation is from 10 to 62.5 ng·h/ml·cm2and Tmax ranges from 24 to 180 h profile in plasma concentrations of donepezil and the like.

Percutaneous absorbable drug is according to the present invention even more preferably is a transdermally absorbable drug, which can be administered to the patient so that the AUC per unit surface area percutaneous absorbable drug ranges from 12.5 to 50 ng·h/ml·cm2and Tmax ranges from 24 to 180 h profile in plasma concentrations of donepezil and the like.

Transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation which can be administered to the patient so that the AUC per unit surface area percutaneous absorbable drug is from 7.5 to 75 ng·h/ml·cm2and Tmax ranges from 48 to 168 h profile in plasma concentrations of donepezil and the like.

Transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation which can be administered to the patient so that the AUC per unit surface area transdermally absorbable preparation is from 10 to 62.5 ng·h/ml·cm2and Tmax ranges from 48 to 168 h profile in plasma concentrations of donepezil and the like.

Transdermally absorbable preparation according to the present invention even more preferably is a transdermally absorbable preparation which can be administered to the patient so that the AUC per unit surface area percutaneous absorbable drug ranges from 12.5 to 5 ng·h/ml·cm 2and Tmax ranges from 48 to 168 h profile in plasma concentrations of donepezil and the like.

Transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation which can be administered to the patient so that the Cmax per unit surface area percutaneous absorbable drug is from 0.025 to 0.5 ng/ml·cm2AUC per unit surface area percutaneous absorbable drug is from 7.5 to 75 ng·h/ml·cm2and Tmax ranges from 12 to 192 h profile in plasma concentrations of donepezil and the like.

In transdermally absorbable preparation according to the present invention Cmax per unit surface area above transdermally absorbable drug is more preferably is from 0.025 to 0.45 ng/ml·cm2and even more preferably from 0.05 to 0.4 ng/ml·cm2the profile of plasma concentration of donepezil and the like defined by Cmax, AUC and Tmax.

In transdermally absorbable preparation according to the present invention AUC per unit surface area above transdermally absorbable preparation is preferably from 10 to 62.5 ng·h/ml·cm2and more preferably from 12.5 to 50 ng·h/ml·cm2the profile of plasma concentration of donepezil and the like defined what about the Cmax, AUC and Tmax.

In transdermally absorbable preparation according to the present invention Tmax above transdermally absorbable preparation is preferably from 24 to 180 hours, and more preferably from 48 to 168 h profile in plasma concentrations of donepezil and the like defined by Cmax, AUC and Tmax.

Transdermally absorbable preparation according to the present invention even more preferably is a transdermally absorbable preparation which can be administered to the patient so that the Cmax per unit surface area percutaneous absorbable drug is from 0.05 to 0.4 ng/ml·cm2AUC per unit surface area percutaneous absorbable drug ranges from 12.5 to 50 ng·h/ml·cm2and Tmax ranges from 48 to 168 h profile in plasma concentrations of donepezil and the like.

In the present invention, the term "Tlag" refers to the time interval prior to absorption of the drug in the body and its appearance in plasma after administration of the drug.

Transdermally absorbable preparation according to the present invention can be used as drugs against dementia and Alzheimer's. In addition, other possible applications include use against cerebrovascular dementia, the prevention of headaches type m is the verge, and the like.

In the present invention, the patient refers to a mammal and preferably a human. Patients include men and women, and infants, children and adults. In citesti patients include those suffering from dementia, Alzheimer's disease, cerebrovascular dementia and/or headache type migraine.

There is no specific limitation regarding percutaneous absorbable preparation according to the present invention provided that it is a drug that allows you to enter donepezil or donepezil hydrochloride so that it is absorbed through the skin.

Examples of places of application of percutaneous absorbable preparation of the present invention include designated bonding, which usually use the patches, such as back, chest, shoulder and hip.

Transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation having a pressure-sensitive adhesive layer, to demonstrate the preferred concentration of the drug in plasma in relation to donepezil and the like of the present invention. Specifically, transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation having a pressure-sensitive adhesive with the OEM, including donepezil, and/or donepezil hydrochloride, which allows you to enter donepezil and the like to the patient to demonstrate the preferred profile in plasma concentrations of donepezil and the like of the present invention.

Transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation in which a pressure-sensitive adhesive layer is cross stitched. Transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation in which a pressure-sensitive adhesive layer is cross stitched using the agent for cross-linking. Transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation in which a pressure-sensitive adhesive layer includes an acrylic pressure-sensitive adhesive. Transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation in which a pressure-sensitive adhesive layer further includes a liquid plasticizer. Transdermally absorbable preparation according to the present invention preferably represents rescigno absorbable drug, in which a pressure-sensitive adhesive layer further includes a metal chloride. Transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation in which the thickness of the pressure-sensitive adhesive layer is from 20 to 300 μm. Transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation comprising as its active ingredient from 2 to 250 mg of donepezil and the like.

In addition, transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation which is put on from 5 to 150 cm2the skin of the patient to demonstrate the preferred profile in plasma concentrations of donepezil and the like of the present invention. Transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation which is applied to the patient from 1 to 7 times per week to demonstrate the preferred profile in plasma concentrations of donepezil and the like in the present invention.

In transdermally absorbable preparation according to the present invention, the content of donepezil and/or donepezil hydrochloride in h is stiteler to the pressure adhesive layer is usually from 1 to 30 wt.% and preferably from 3 to 20 wt.% to demonstrate the preferred profile in plasma concentrations of donepezil and the like in the present invention. If the content is less than 1 wt.% the amount effective for treatment, may not be released, whereas if the content exceeds 30 wt.%, it is not economical without therapeutic benefit.

In transdermally absorbable preparation according to the present invention there are no particular restrictions on the pressure-sensitive adhesive, which forms a pressure-sensitive adhesive layer, it is proposed to have the ability to cross-linking, its examples include acrylic pressure-sensitive adhesives, rubber pressure-sensitive adhesives, such as silicone rubber composition, branch, Rubezhnoe, Ukraine rubber composition, polyisobutylene rubber composition, styrene-butadiene rubber composition, styrene-isoprene-styrene block copolymer rubber or styrene-butadiene-styrene block copolymer rubber composition; a silicone pressure-sensitive adhesives; and vinyl polymeric pressure-sensitive adhesives, such as polyvinyl alcohol, polyvinyl alkilany ether or polyvinyl acetate.

In transdermally absorbable preparation according to the present invention a pressure-sensitive adhesive layer is preferably transversely sewn and, for example, can be made known chemical treatment for cross-linking or physical processing DL is the cross-linkage (for example, physical cross-linking of using irradiation with gamma rays or other electron beam or ultraviolet light, or chemical transverse cross-linked by adding a cross linking agent). Specifically, transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation having a transversely crosslinked pressure-sensitive adhesive layer, which can be administered to the patient to demonstrate the preferred profile in plasma concentrations of donepezil and the like in the present invention. In addition, transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation having a pressure-sensitive adhesive layer is cross-stitched using the agent for cross-linking, which can be administered to the patient to demonstrate the preferred profile in plasma concentrations of donepezil and the like in the present invention.

In the present invention, functional groups that can be involved in the reaction cross-linkage, such as hydroxyl groups, carboxyl groups or vinyl groups, preferably introduced into a pressure-sensitive adhesive, and the introduction of options the regional groups, able to get involved in the reaction of cross-linking, pressure-sensitive adhesive is carried out using a known method. For example, in the process of synthesis of the polymer, which serves as a pressure-sensitive adhesive, the introduction of functional groups can be carried out by adding a monomer having a hydroxyl group such as hydroxymethyl(meth)acrylate, or a monomer having a carboxyl group such as acrylic acid or maleic acid, with subsequent copolymerization. Moreover, the transverse cross-linked pressure-sensitive adhesive can be carried out by adding a monomer and the like, having two or more vinyl groups such as divinylbenzene or etilenglikolevykh and copolymerization in the process of synthesis of the polymer, which serves as a pressure-sensitive adhesive, with the formation of intermolecular or intramolecular cross-links during the polymerization reaction.

Examples include pressure-sensitive adhesives used in the present invention as described above, preferred is an acrylic pressure-sensitive adhesive from the viewpoint of ease of processing for the cross-linkage and a suitable bonding to the skin in the form of percutaneous absorbable drug and to demonstrate preference is sustained fashion profile in plasma concentrations of donepezil and the like of the present invention. Acrylic pressure-sensitive adhesive is particularly preferred, allowing Cmax to demonstrate the preferred profile of the plasma in the present invention. Although the Cmax is affected by various components of the pressure-sensitive adhesive layer, it is believed that it primarily depends on the concentration of donepezil and the like in the pressure-sensitive adhesive layer. As donepezil and the like is easily dissolved in the acrylic pressure-sensitive adhesives, pressure-sensitive adhesive is preferably an acrylic pressure-sensitive adhesive in order to demonstrate Cmax, as described above.

Specifically, transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation having a pressure-sensitive adhesive layer including the acrylic pressure-sensitive adhesive, which can be administered to the patient to demonstrate the preferred profile in plasma concentrations of donepezil and the like in the present invention.

Acrylic pressure-sensitive adhesive according to the present invention is typically an acrylic pressure-sensitive adhesive comprising alkilany ester of (meth)acrylic acid, and preferably depict is to place an acrylic pressure-sensitive adhesive, containing alkilany ester of (meth)acrylic acid as its main component (main component of the unit). The copolymer Olkiluoto ether (meth)acrylic acid (first monomer component) as a main component with a vinyl monomer having functional groups capable of contributing to the cross-linkage reaction (second monomer component), or a copolymer, copolymerizable with another monomer (third monomer component) is particularly preferred from the viewpoint of ease of cross-linking, pressure-sensitive adhesiveness, such as adhesion to human skin, the ability to control the dissolution of the medicinal product and the like.

Preferred examples Olkiluoto ether (meth)acrylic acid (first monomer component) include alkalemia esters of (meth)acrylic acid in which the alkyl group is a linear, branched or cyclic alkyl group having from 1 to 18 carbon atoms (such as methyl, ethyl, through bucilina, pentilla, hexeline, tsiklogeksilnogo, heptylene, anjilina, 2-ethylhexyl, Danilina, decile, angellina, Godzilla or redecilla), and alkalemia esters of (meth)acrylic acid in which the alkyl group is a linear, branched or cyclic alkyl is Noah band having from 4 to 18 carbon atoms (such as bucilina, pentilla, hexeline, tsiklogeksilnogo, heptylene, anjilina, 2-ethylhexyl, Danilina, decile, angellina, Godzilla or redecilla). Moreover, since the use of a Monomeric component, which reduces the glass transition temperature of the polymer, it is preferable to give a pressure-sensitive adhesiveness at normal temperatures, alkilany ester of (meth)acrylic acid in which the alkyl group is a linear, branched or cyclic alkyl group having from 4 to 8 carbon atoms (such as bucilina, pentilla, hexeline, tsiklogeksilnogo, heptylene, anjilina or 2-ethylhexyl, preferably bucilina, 2-ethylhexyl or tsiklogeksilnogo, and particularly preferably 2-ethylhexyl) is more preferable. More specifically, the preferred acrylate, 2-ethyl hexyl acrylate, 2-ethylhexylacrylate, cyclohexylacetate, cyclohexylmethyl or the like, and among them, most preferred are 2-ethyl hexyl acrylate. Can be used one of these alilovic esters of (meth)acrylic acid (first monomer component), or in combination of two or more.

In the vinyl monomer (second monomer component)containing a functional group capable of uctuate in the reaction is AI is the cross-linkage, examples of functional groups capable of uctuate in the reaction cross-linkage, include hydroxyl group, carboxyl group and vinyl group, and preferred are a hydroxyl group and carboxyl group. Specific examples of the monomer (second monomer component) include esters of hydroxyethyl(meth)acrylate, esters of hydroxypropyl(meth)acrylate, (meth)acrylic acid, taconova acid, maleic acid, maleic anhydride, metaconule acid, citraconate acid and glucagonoma acid. Of them from the standpoint of availability, preferred are acrylic acid, methacrylic acid and an ester of hydroxyethylacrylate, and most preferred is acrylic acid. Can be used one of these monomers (second monomer component) or can be used two or more in combination.

The above-mentioned another monomer (third monomer component) is used mainly to bring cohesion ability of pressure-sensitive adhesive layer and to bring the solubility or the ability to release donepezil and the like. Examples of the monomer (third monomer component) include vinyl acetate, finalproject and other complex vinyl ethers; metilidinovy simple ether, ethylvinyl the first simple ether and other simple vinyl esters; N-vinyl-2-pyrrolidone, N-vinylcaprolactam and other vinyl amides; methoxyethyl(meth)acrylate ester, ethoxyethyl(meth)acrylate ester, tetrahydrofurfuryl(meth)acrylate ester and other alkoxy(meth)acrylate esters; hydroxypropyl(meth)acrylate, α-hydroxyethylacrylate and the other containing a hydroxyl group monomers (which do not provide the sites of cross-linking, because they are used as the third monomer component); (meth)acrylamide, dimethyl(meth)acrylamide, N-butyl(meth)acrylamide N-methylol(meth)acrylamide, and other derivatives of (meth)acrylic acid-containing amide groups; aminoethyl(meth)acrylate ester, dimethylaminoethyl(meth)acrylate ester, 1-butylaminoethyl(meth)acrylate ester and other aminoalkyl(meth)acrylate esters; methoxyestradiol(meth)acrylate ester, ethoxydiglycol(meth)acrylate ester, methoxypolyethyleneglycol(meth)acrylate ester, methoxypolyethyleneglycol(meth)acrylate ester and other alkoxyalkanols(meth)acrylate esters; (meth)Acrylonitrile; styrelseledamot, arylsulfonate, sulfopropyl(meth)acrylate, (meth)acryloyldimethyltaurate, acrylamidoglycolate and other monomers containing acid; and vinylpyridine, vinylpyridin, vinylpyrazine, vinylpyrrole, vinylimidazole, vinylacetal, vinylmation and the other containing the vinyl group of the monomer. Of them, preferred is a vinyl ester or vinylamide, and vinyl acetate is the preferred vinyl ether complex, and N-vinyl-2-pyrrolidone is the preferred vinylamides. Can be used one of these monomer (third monomer component) or can be used two or more in combination.

When a pressure-sensitive acrylic adhesive composition is a copolymer of (meth)acrylic acid Olkiluoto of ester (first monomer component) and a vinyl monomer containing a functional group capable of uctuate in the cross-linkage reaction (second monomer component), (meth)acrylic acid alkilany ester and a vinyl monomer containing a functional group capable of uctuate in the reaction cross-linkage, mix and copolymerized preferably in a mass ratio of from 99 to 85 CTA (meth)acrylic acid Olkiluoto of ester at from 1 to 15 CTA vinyl monomer containing a functional group capable of to uctuate in the reaction cross-linkage, and more preferably in a mass ratio of from 99 to 90 CTA from 1 to 10 CTA.

In addition, when a pressure-sensitive acrylic is the first adhesive composition is a copolymer of (meth)acrylic acid Olkiluoto of ester (first monomer component), the vinyl monomer containing a functional group capable of uctuate in the cross-linkage reaction (second monomer component), and another monomer (third monomer component), (meth)acrylic acid alkilany ester, vinyl monomer containing a functional group capable of uctuate in the reaction cross-linkage, and the other monomer are mixed and copolymerized preferably in a mass ratio of from 40 to 94 CTA (meth)acrylic acid Olkiluoto of ester at from 1 to 15 CTA vinyl monomer containing a functional group capable of uctuate in the reaction cross-linkage, and from 5 to 50 CTA another monomer, and more preferably in a mass ratio of from 50 to 89 CTA from 1 to 10 CTA and from 10 to 40 CTA, respectively.

Although the polymerization reaction is not imposed special restrictions, provided that it is conducted by using a known method, for example, by adding to the above-mentioned monomers of the polymerization initiator (such as benzoyl peroxide, azobisisobutyronitrile and the like) with the subsequent interaction for 5 to 48 cow at a temperature of from 50 to 70°C. in a solvent (such as ethyl acetate).

Particularly preferred examples of pressure-sensitive acrylic adhesive compositions include copolymers of 2-ethylhexylacrylate complex the ester/acrylic acid/N-vinyl-2-pyrrolidone, the copolymer of 2-ethylhexylacrylate ester/2-hydroxyethylacrylate ester/vinyl acetate and a copolymer of 2-ethylhexylacrylate ester/acrylic acid, while a more preferred example is a copolymer of 2-ethylhexylacrylate ester/acrylic acid/N-vinyl-2-pyrrolidone.

In addition, although the glass transition temperature varies depending on the composition of the copolymer, from the viewpoint of adhesiveness transdermally absorbable preparation preferably, this temperature pressure sensitive acrylic adhesive composition of the present invention is generally equal to -100 to -10°C. and more preferably from -90 to -20°C.

In the pressure-sensitive adhesive layer percutaneous absorbable preparation of the present invention may be included liquid plasticizer for softening of pressure-sensitive adhesive layer and reduce the pain and soften the skin irritation caused by removal from the skin is glued to the skin transdermally absorbable preparation and to demonstrate the preferred profile in plasma concentrations of donepezil and the like in the present invention. Specifically, transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation containing pressure-sensitive CL is icy layer, containing a liquid plasticizer, which can be administered to the patient in such a way as to demonstrate the preferred profile in plasma concentrations of donepezil and the like in the present invention. Although liquid plasticizer can be used without any particular limitations, it is suggested that he preferred was a liquid at room temperature, showed a plasticizing action and was compatible with pressure-sensitive adhesive polymer constituting the pressure-sensitive adhesive composition, and improved percutaneous absorption and stability store donepezil and the like. In addition, the liquid plasticizer may also be included to further increase the solubility of donepezil and the like in the pressure-sensitive adhesive composition and the like. Examples of such liquid plasticizers include alkalemia esters of fatty acids such as esters of lower monovalent alcohols containing from 1 to 4 carbon atoms, and saturated or unsaturated fatty acids containing from 12 to 16 carbon atoms); saturated or unsaturated fatty acids containing from 8 to 10 carbon atoms such as Caprylic acid (octanoic acid, C8), pelargonia acid (novanova acid, C9), capric acid (cekanova acids is, C10) or lauric acid (C12)); ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol, propylene glycol, polypropyleneglycol and other glycols; olive oil, castor oil, squalene, lanolin and other oils and fats; ethyl acetate, ethyl alcohol, dimethyldisulphide, decylmethacrylate, dimethylsulfoxide, dimethylformamide, dimethylacetamide, dimethylacrylamide, dodecylmercaptan, isosorbid, alerby alcohol and other organic solvents; liquid surface-active compounds; diisopropylamide, esters of phthalic acid, diethylbenzene and other plasticizers; and liquid paraffin and other hydrocarbons. In addition, other examples include ethoxylated stearyl alcohol, esters of glycerin (which are liquid at room temperature), attributelist, N-organic, etiloleat, oleic acid, diisopropylamide, octylpyrimidine, 1,3-propandiol and glycerin. Which one is preferable from the viewpoint of stability of the composition and the like are alkilany ester of fatty acid, saturated fatty acid, a hydrocarbon solvent, and citesti, from the point of view of the percutaneous absorption preferable alkilany ester of a fatty acid lower monovalent alcohol containing from 1 to 4 carbon atoms, and saturated or Nena is yennai fatty acids, containing from 12 to 16 carbon atoms. Can be used one of these plasticizers or may be used two or more in combination.

In addition, in the case of using the acrylic pressure-sensitive adhesive composition for a pressure-sensitive adhesive composition from the viewpoint of compatibility with the acrylic pressure-sensitive adhesive composition and the like of the liquid plasticizer preferably is alkilany ester fatty acids and more preferably is a complex ester of lower monovalent alcohol containing from 1 to 4 carbon atoms, and saturated or unsaturated fatty acids containing from 12 to 16 carbon atoms. Saturated or unsaturated fatty acid containing from 12 to 16 carbon atoms, preferably represents a saturated fatty acid and a lower monovalent alcohol containing from 1 to 4 carbon atoms may be either linear or branched. Preferred examples of fatty acids containing from 12 to 16 carbon atoms include lauric acid (C12), myristic acid (C14) and palmitic acid (C16), while preferred examples of the monovalent alcohols containing from 1 to 4 carbon atoms include isopropyl alcohol, ethyl alcohol, methyl alcohol and propyl alcohol. Specific pemeriksaan preferred alilovic esters of fatty acids include isopropylmyristate, tillaart and isopropyl. Specifically, transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation containing pressure-sensitive adhesive layer including the acrylic pressure-sensitive adhesive composition, cross stitched using a crosslinking agent, and a liquid plasticizer in the form Olkiluoto complex fatty acid ester, such as an ester of a lower monovalent alcohol containing from 1 to 4 carbon atoms, and saturated or unsaturated fatty acids containing from 12 to 16 carbon atoms, such as isopropylmyristate, and which you can enter the patient to demonstrate the preferred profile in plasma concentrations of donepezil and the like in present invention.

Moreover, in the case of Olkiluoto of ester of fatty acid from the viewpoint of improving percutaneous absorption of donepezil and the like may be used fatty acid containing from 8 to 10 carbon atoms, and/or glycerol in combination with alkilany complex ester of fatty acid.

The amount of liquid plasticizer included in the present invention, is preferably from 10 to 160 CTA by weight and more preferably from 40 to 150 CTA by weight based on 100 CTA on weight-sensitive pressure is of the adhesive composition. If included, the number is less than 10 CTA on weight, you may not get adequate favorable softness or the effect of reducing skin irritation due to inadequate plasticization pressure-sensitive adhesive layer, while if the included amount exceeds 160 CTA by weight, the liquid plasticizer may not be maintained in the pressure-sensitive adhesive composition, even under the force of adhesion of pressure-sensitive adhesive composition, resulting in the adhesion strength is waning due to bleed on the surface of the pressure-sensitive adhesive layer and increases the probability of a gap of the composition from the skin surface during use.

In transdermally absorbable preparation according to the present invention, although treatment for cross-linking is performed using known processing for chemical crosslinking (such as the transverse cross-linked by adding a cross-linking agent or treatment for the physical crosslinking (such as cross-linked by irradiation with gamma rays or other electron irradiation or irradiation with ultraviolet light), as described earlier, the processing for the cross-linkage can be produced using a method commonly used in the art. Moreover, from the point of view of a reducing action on drugs is the preferred treatment for the cross-linkage is adding a cross-linking agent. In the present invention pressure-sensitive adhesive layer preferably transversely stitched in such a way as to hold the required amount of liquid plasticizer in a pressure-sensitive adhesive layer without reducing pressure-sensitive adhesiveness, and because of the adhesive properties of the pressure-sensitive adhesive layer improves the cross-linking of a pressure-sensitive adhesive layer, pressure-sensitive adhesive layer is preferably sewn together, taking into account the possibility of improving the ability to adhere to the skin and affect the profile in plasma concentrations of donepezil and the like.

In the case of the implementation process of chemical cross-linking using a cross-linking agent to cross-linking agent is not imposed special restrictions, if the formation of cross-linking under the influence of such a crosslinking agent is not inhibited in the presence of donepezil and the like, and its examples include peroxides such as benzoyl peroxide (BPO), and the like), metal oxides (such as spinel metasilicate magnesium and the like), a multifunctional isocyanate compounds, ORGANOMETALLIC compounds (such as alanine zirconium, alanine zinc, zinc acetate, glycinamide zinc or compounds of titanium), metal alcoholate such as tetraethyl is itant, tetraisopalmitate, isopropyl aluminum or sec-butyrate aluminum and compounds-metal chelators (such as dipropoxy(acetylacetonate) titanium, tetraethyleneglycol titanium, isopropyl aluminum, diisopropylate of ethylacetoacetate aluminum, Tris(ethylacetoacetate) aluminum or Tris(acetylacetonate) aluminum)). Of them, preferred are peroxide, a metal oxide, an ORGANOMETALLIC compound, a metal alcoholate or metal chelating compound, and a metal alcoholate or metal chelating compound is preferable from the viewpoint of efficiency of formation of cross-links in the presence of donepezil and/or donepezil hydrochloride, while the metal chelating compound is most preferable from the viewpoint of ease of obtaining transverse cross-linked structures with an appropriate density of cross-linkage. In addition, among the metal chelating compounds especially preferred is diisopropylate of ethylacetoacetate aluminum. Can be used one of these cross linking agents or may be used two or more in combination.

Although depending on the type of crosslinking agent and a pressure-sensitive adhesive composition, the number of included cross-linking agent varies, it typically ranges from 0.15 to 0.5 CTA mass Rel is increased by 100 ctam by weight of pressure-sensitive adhesive composition. If included, the amount is less than 0.1 honor by weight, the sites of cross-linking is too rare to give adequate bonding ability of the pressure-sensitive adhesive layer, which leads to the risk of preserving residual stickiness and strong irritation of the skin due to insufficient adhesiveness when peeling, whereas if the included amount exceeds 0.6 CTA by weight, in spite of the high bonding ability, there are cases when you are unable to achieve adequate bonding capacity. In addition, there is also the risk of irritation of the skin under the influence of the residual unreacted cross-linking agent.

Treatment for chemical cross-linking can be effected by adding a cross-linking agent followed by heating at a temperature equal to or higher than the temperature of the reaction cross-linkage, and although the temperature during this treatment are chosen according to the type of crosslinking agent, preferably, it ranged from 60 to 90°C. and more preferably from 60 to 80°C. the heating Time is preferably from 12 to 96 cow and more preferably from 24 to 72 cow.

Preferably, in percutaneous absorbable preparation according to the present invention was added to the chloride of the metal together with donepezil and/or donepezil hydrochloride in the cross what about the crosslinked pressure-sensitive adhesive layer. The inclusion of metal chloride in a pressure-sensitive adhesive layer reduces the adhesiveness of the pressure-sensitive adhesive layer and provides adhesion of percutaneous absorbable drug to human skin and reduces the likelihood of failure bonding ability when removing the pressure-sensitive adhesive layer. Specifically, in the case of pressure-sensitive adhesive layer, optionally including the chloride of the metal, transdermally absorbable preparation according to the present invention is able to prevent the separation, removal or repositioning of percutaneous absorbable drug from the skin, caused by reduced bonding ability of the pressure-sensitive adhesive layer. Thus, transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation containing pressure-sensitive adhesive layer, optionally including the chloride of the metal, and which you can enter the patient to demonstrate the preferred profile in plasma concentrations of donepezil and the like in the present invention.

In respect of the chloride of the metal there is no particular limitation, and examples include alkali metal chloride, such as sodium or potassium; chloride alkaline earth metal is a, such as calcium or magnesium; aluminum chloride, tin chloride and ferric chloride. From the point of view of higher stability and ability to inhibit a decrease in the bonding ability of the pressure-sensitive adhesive layer is preferred sodium chloride, calcium chloride, aluminium chloride, tin chloride or ferric chloride, more preferred is sodium chloride or calcium chloride, and particularly preferred is sodium chloride. Can be used any of them in isolation, or may be used two or more in combination.

The diameter of ctic of metal chloride is usually roughly divided into primary diameter of ctic and secondary diameter of ctic. When rendering of metal chloride using a light microscope or electron microscope, the primary readers look how small the readers, and the secondary of readers come in the form of large ctic formed by the aggregation of many primary ctic. In the present description corresponds to a maximum diameter of CITIC refers to the diameter of the primary ctic and diameter of secondary ctic. Although these diameters of ctic of metal chloride is not imposed special restrictions, preferred smaller diameter of ctic from the point of view of ease of manipulation during retrieval, as well as favorable feeling for bonding and species attributed to the smoothness glued on top of the spine of the pressure-sensitive adhesive layer. Thus, the diameter of the secondary of ctic of metal chloride is preferably 300 μm or less, more preferably 250 μm or less, and most preferably 200 μm or less. Moreover, although the lower limit of the diameter of the secondary ctic not imposed specific restrictions, it is preferable that he was 1 μm or more. If the diameter of the secondary of ctic is less than 1 μm, since the diameter of the primary ctic such a chloride of the metal is less, there is a risk of decreasing ease of manipulation during retrieval, such as the dispersion of ctic.

Moreover, although secondary to the readers of metal chloride are pressure-sensitive adhesive layer in various forms, such as flat or amorphous, because it has been unexpectedly discovered that the readers easily included in the pressure-sensitive adhesive layer even in cases when the size of the secondary ctic chloride of the metal is greater than the thickness of the pressure-sensitive adhesive layer, the composition can be obtained in such a way that it is robust to decrease the smoothness of the glued surface of the pressure-sensitive adhesive layer and has no problems in terms of form, provided that the diameter of the secondary ctic corresponds to the preferred diameter of ctic as previously described. As will be described below, in the presence of substrate the substrate has a relatively high is th degree of flexibility, where paper, cloth or non-woven fabric and the like is located on the side of the pressure-sensitive adhesive layer, while CT secondary ctic of metal chloride may be immersed in the substrate, and even in cases where the diameter of the secondary of CITIC chloride of the metal is greater than the thickness of the pressure-sensitive adhesive layer can easily be obtained very smooth pasting surface. When the substrate is relatively inflexible, the diameter of the secondary ctic of metal chloride is preferably equal or inferior to the thickness of the pressure-sensitive adhesive layer with positions effectively achieve adequately high smoothness pasted surfaces, the diameter of the secondary ctic is preferably 1/2 or less, and particularly preferably 1/3 or less of the thickness of the pressure-sensitive adhesive layer.

When the metal chloride is a salt formed by neutralization of donepezil hydrochloride inorganic base, including metal, process of formation of the pressure-sensitive adhesive layer described below can be easily reproduced described above, the preferred diameter of the secondary ctic.

The diameters of ctic (diameter of the primary ctic, the diameter of the secondary ctic) of metal chloride in percutaneous absorbable preparation according to the present from which retenu represent the values measured in accordance with the method of measurement described below.

Pressure-sensitive adhesive side of the pressure-sensitive adhesive layer transdermally absorbable preparation (sample) examined visually (moreover, in the case of the presence in the composition of the releasing plate release plate is removed, and a pressure-sensitive adhesive surface exposed pressure-sensitive adhesive layer is examined visually. The sample was then placed on the table a light microscope with an upward pressure-sensitive adhesive surface of the pressure-sensitive adhesive layer and a light microscope photograph at least 20 ctic together with the scale, starting with those of ctic that look major on the basis of visual inspection. In this case, when measuring the readers are the primary chizami, photographed, at least 20 ctic, consisting only of primary ctic, whereas when measured the readers are secondary chizami, photographed, at least 20 ctic, consisting only of secondary ctic. Among the photographed primary ctic or secondary ctic diameter of readers, certain as the reader with the greatest diameter of CITIC based on measurements using the applied scale is used as the diameter of the primary ctic is whether the diameter of the secondary ctic, respectively. Moreover, the term "diameter of ctic" in the present description refers to the diameter of the circle describing the projected image of readers (diameter equivalent to the diameter describe a circle). Moreover, it is known that the diameter equivalent to the diameter describe a circle," for the sake of convenience is defined as the diameter of readers when measuring the diameter of CITIC microscopic examination and are described, for example, in "Powders - Theory and Application" (Revised 2nd edition, p. 55, published May 12, 1979, Maruzen Co., Ltd.).

Included the amount of metal chloride is preferably from 0.1 to 20 CTA by weight, more preferably from 1 to 15 CTA by weight and most preferably from 3 to 10 CTA by weight to 100 CTA by weight of pressure-sensitive adhesive composition. If included, the amount is less than 0.1 CTA by weight, the effect of inhibiting a decrease in the ability for adhesion of pressure-sensitive adhesive layer may be inadequate, and, on the contrary, if the included amount exceeds 20 CTA by weight, although the inhibitory effect manifests itself, the composition may be deteriorated due to inhomogeneous dispersion of metal chloride in a pressure-sensitive adhesive composition (pressure-sensitive adhesive polymer).

However, because of donepezil hydrochloride more stable than donepezil and as donepezil is Bladet polymorphism of crystals, complicating the manipulation of them, from the point of view of manipulation donepezil hydrochloride more convenient than donepezil. On the other hand, free form donepezil better absorbed through the skin than donepezil hydrochloride. To use both of these advantages in the present invention, the metal chloride may be a salt formed by neutralization of donepezil hydrochloride inorganic base, including the metal during formation of a pressure-sensitive adhesive layer. This salt is the equivalent of the metal chloride formed during the neutralization of donepezil hydrochloride by mixing and stirring of donepezil hydrochloride in a solvent with an inorganic base, including metal, such as sodium hydroxide. The result contains the drug solution comprising a chloride of the metal, can be obtained without the addition of metal chloride, and containing a drug solution comprising a metal chloride, and the chloride of the metal, and the donepezil and the like can be included in the final pressure-sensitive adhesive layer. Moreover, after the formation of metal chloride by mixing and stirring of donepezil hydrochloride in a solvent with an inorganic base, including the metal, the metal chloride may be further added to the resulting solution, containing drug (donepezil). Moreover, examples of inorganic bases containing metal, include inorganic bases alkali metals or alkaline earth metals such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate, and from the point of view of reducing the likelihood of side products formation are preferred hydroxides of alkali metals or alkaline earth metals, preferred are sodium hydroxide, calcium hydroxide and magnesium hydroxide, and particularly preferred is sodium hydroxide.

In the pressure-sensitive adhesive layer percutaneous absorbable preparations according to the present invention, if necessary, additives may be incorporated, such as antioxidants, pigments of different types of fillers of different types, stabilizers, agents, contributing to the dissolution of the drugs or inhibitors of dissolution of the drug. For example, although there are no particular restrictions on such stabilizers or antioxidants, preferred are 2-mercaptobenzimidazole, ascorbic acid, ascorbyl palmitate, sodium metabisulfite, sodium sulfite and sodium bisulfite, and you can use one type or a combination of TLD is or more types. The content of the stabilizer or antioxidant in the pressure-sensitive adhesive layer is preferably from about 0.0005 to 5 wt.%, more preferably from 0.001 to 3 wt.% and most preferably from 0.01 to 1 wt.% from the total mass of the pressure-sensitive adhesive layer.

In transdermally absorbable preparation according to the present invention, the thickness of the pressure-sensitive adhesive layer is preferably from 20 to 300 μm, more preferably from 30 to 300 μm and most preferably from 50 to 300 μm to demonstrate the preferred profile in plasma concentrations of donepezil and the like in the present invention. Specifically transdermally absorbable preparation according to the present invention is preferably transdermally absorbable preparation containing pressure-sensitive adhesive layer of a thickness of from 20 to 300 μm and which you can enter the patient in such a way as to demonstrate the preferred profile in plasma concentrations of donepezil and the like in the present invention. Because AUC depends on the number of donepezil and the like in the pressure-sensitive adhesive composition per unit surface area, it is useful to take into account the thickness of the pressure-sensitive adhesive layer in the correction of the AUC.

If the thickness of the senses is in the pressure adhesive layer is less than 20 μm, there is a risk of difficulties with obtaining adequate adhesiveness, the inclusion of an effective amount of donepezil and the like, and the inclusion of secondary ctic chloride of the metal, whereas if the thickness of the pressure-sensitive adhesive layer exceeds 300 μm, there is a risk of difficulties with the floor.

Transdermally absorbable preparation according to the present invention typically includes a substrate, a pressure-sensitive adhesive layer and remove the film. Namely transdermally absorbable preparation according to the present invention has a structure in which the above-described pressure-sensitive adhesive layer applied at least on one side of the substrate, and the adhesive surface of the pressure-sensitive adhesive layer (the surface opposite to the side of the pressure-sensitive adhesive layer facing the substrate) is preferably protected by a coating film to be removed immediately prior to use. In addition, the composition may also be in the form of a roll without the use of a removable film coated substrate of silicon, fluorine-containing or wax cushioning agent and the like.

Although the substrate is not imposed special restrictions, such preferred substrate, which ensures that there is no decrease in the content of donepezil and the like in sensitivity is entrusted to the pressure adhesive layer as a result of loss from the back side of the substrate by passing through it (namely material, impervious to donepezil and the like), and, as will be described below, in the case of the variant, in which the pressure-sensitive adhesive layer include a liquid plasticizer, the preferred substrate, which provides no reduction of the proportions of donepezil and the like and liquid plasticizer loss from the back side of the substrate by passing through it (namely, a material impervious to liquid plasticizer and donepezil and the like).

Specific examples include polyester (such as polyethylene terephthalate (PET), nylon, polyvinyl acetate, polyethylene, polypropylene, copolymer of ethylene-vinyl acetate, polytetrafluoroethylene, ionomer resins, and other single film, metal foil, and a layered film obtained by layering two or more films. Among them, preferred substrate, in which a layered film obtained by layering non-porous film consisting of one of the aforementioned materials in porous film as described below, to improve adhesiveness (zakurivaya properties) of the substrate for a pressure-sensitive adhesive layer, and pressure-sensitive adhesive layer is formed on the side of the porous film.

On the porous film is not imposed special restrictions, if it improves zakalivayuschie properties for pressure-sensitive CL is icogo layer, and examples include paper, textiles, non-woven fabrics (such as polyester including polyethylene terephthalate (PET) non-woven fabric)and the film obtained by mechanical perforation of the above-mentioned films (such as polyester, nylon, Saran, polyethylene, polypropylene, copolymer of ethylene-vinyl acetate, polyvinyl chloride, copolymer of ethylene-acrylate, polytetrafluoroethylene, metal foil, polyethylene terephthalate and other single film, and a layered film obtained by layering two or more of these films), whereas from the standpoint of flexibility of the substrate are preferred for paper, textiles and non-woven fabrics (such as polyester nonwoven canvas or polyethylene terephthalate non-woven fabric). Whereas zakalivayuschie properties and flexibility of the pressure-sensitive adhesive layer, the thickness of the porous film is usually from 10 to 500 μm, and in the case of thin percutaneous absorbable drug, such as a bandage or adhesive tape, the thickness is usually from 1 to 200 microns. In the case of textile or nonwoven fabric basis weight is preferably from 5 to 30 g/m2in terms of improving zakurivaya properties.

The thickness of the substrate for transdermally absorbable preparation of the present invention is not restricted by special limitations, and it is preferably from 2 to 200 μm, most preferably from 10 to 50 μm. If the thickness of the substrate is less than 2 μm, there is a trend of decreasing ease of manipulation, such as reduced ability for self-maintenance, whereas if the thickness exceeds 200 μm, the substrate can cause discomfort (rigidity), and compatibility with the skin tends to decrease.

To remove the film is not imposed special restrictions, and can be used known to remove the film. Specific examples of the removed film include removed the film, in which the layer to be deleted agent consisting of a deleted agent, is formed on the surface of the substrate, remove foil, plastic film, which itself has good properties delete, and remove film structure in which the removed layer consisting of a plastic film material with good properties removal, is formed on the substrate surface of a removable film. The surface separating the removed film can only be on one side of the base or on both sides.

To remove the agent to remove this film is not imposed special restrictions, and examples include polymers containing long-chain alkyl groups, silicone polymers (silicone releasing agents), fluorine-containing polymer (fluorine-containing releasing agents) and other deleted agents. Examples of the substrate for prowess is my film include polyethylene terephthalate (PET) film, polyimide film, polypropylene film, polyethylene film, polycarbonate film, polyester (other than PET) film or other plastic film; plastic film with a metallic coating, obtained by deposition of metal on one of these films; Japanese paper, plain paper, Kraft paper, glassine, thin paper or other paper; non-woven fabric, textile or other fibrous material; and a metal foil.

In addition, examples of plastic films, which themselves have a good ability to remove, include polyethylene (such as polyethylene with a low density or linear polyethylene with a low density), polypropylene, copolymer of ethylene-propylene and other copolymers of ethylene-α-olefin (block copolymers or random copolymers), and the polyolefin film formed from a polyolefin resins consisting of mixtures thereof, and Teflon (registered trademark) film.

Moreover, the removed layer formed on the surface of the above substrate removed film can be formed by layering or coating material of the above-mentioned plastic film with a good ability to remove the above mentioned substrate is removed film.

The thickness (total thickness) of the removed film is not imposed special restrictions, and usually it is 200 MK is or less, and preferably from 25 to 100 microns.

On the way to obtain percutaneous absorbable preparation of the present invention is not restricted by special limitations, and preferably it is obtained, for example, using the following methods to obtain (i) to (iii).

(i) is Prepared containing the drug pressure-sensitive adhesive liquid in which donepezil or donepezil hydrochloride is dissolved or dispersed in a solvent together with a pressure-sensitive adhesive composition and, optionally, a liquid plasticizer or other additive, and the like, and this liquid is then mixed and stirred with a metal chloride or a dispersion of metal chloride in a solvent such as ethanol, followed by addition of a crosslinking agent. Thus obtained mixture is applied to one side of the substrate or exposing it to remove the side of the removed film, followed by drying with formation of a pressure-sensitive adhesive layer, and after a layup remove film or a substrate for a pressure-sensitive adhesive layer follow the procedure of aging for the cross-linkage pressure-sensitive adhesive layer.

(ii) In the case of using liquid plasticizer donepezil and/or donepezil hydrochloride, a pressure-sensitive adhesive composition, a liquid plasticizer and uses the needful if necessary, the additive is directly mixed and stirred, it is mixed and stirred with a metal chloride or a dispersion obtained by dispersing the metal chloride in a solvent such as ethanol, and the mixture followed by addition of a crosslinking agent, cover one side of the substrate or exposing it to remove the side of the removed film, followed by drying with formation of a pressure-sensitive adhesive layer, and after a layup remove film or a substrate for a pressure-sensitive adhesive layer follow the procedure of aging for the cross-linkage pressure-sensitive adhesive layer.

(iii) Receive containing the drug solution by mixing and stirring the dispersion, obtained by dispersion of metal chloride in a solvent such as ethanol, donepezil, and/or donepezil hydrochloride. In the case of donepezil hydrochloride as a drug chloride of the metal is formed by mixing and stirring donepezil hydrochloride, a metal hydroxide, and optionally solvent, such as ethanol, and neutralization, and then further adding a chloride of the metal, if necessary, with the receipt containing the drug solution. On the other hand, receive a fluid containing pressure-sensitive composition, by dissolving and/and the and dispersion pressure-sensitive composition in a solvent together with a liquid plasticizer or other additive, if it is necessary, or in the case of using liquid plasticizer containing pressure-sensitive composition of the liquid receive immediate mixing and stirring pressure-sensitive composition, a liquid plasticizer and used when necessary additives. Then the above-mentioned containing the drug solution is added to the fluid containing pressure-sensitive composition, followed by stirring, and further adding a cross-linking agent, applying the resulting mixture on one side of the substrate or exposing it to remove the side of the removed film and drying with formation of a pressure-sensitive adhesive layer, and after a layup remove film or a substrate for a pressure-sensitive adhesive layer follow the procedure of aging for the cross-linkage pressure-sensitive adhesive layer.

In the methods described in paras.(i)to(iii) above, examples of the solvent used for dissolution and/or dispersion pressure-sensitive adhesive composition and the like, include ethyl acetate, toluene, hexane, 2-propanol, methanol, ethanol and water. In addition, they can also be used to bring the viscosity after addition of the crosslinking agent.

Moreover, as in method (iii) can be obtained composition, in which the drug is a means of ultimately included in the pressure-sensitive adhesive layer includes mainly donepezil (free form), possessing an excellent ability to percutaneous absorption, it is possible to easily obtain a composition with an excellent ability to percutaneous absorption, which you can enter the patient to demonstrate the preferred profile in plasma concentrations of donepezil and the like in the present invention.

In the present invention each of Tmax, Cmax and AUC varies depending on the concentration of donepezil and the like in the pressure-sensitive adhesive layer, the thickness of the pressure-sensitive adhesive layer-type pressure-sensitive adhesive composition and the type of liquid plasticizer and its concentration in the pressure-sensitive adhesive layer. In transdermally absorbable preparation according to the present invention by a corresponding change in the concentration of donepezil and the like in the pressure-sensitive adhesive layer, the thickness of the pressure-sensitive adhesive layer, type adhesive composition and the type of liquid plasticizer and its concentration in the pressure-sensitive adhesive layer it is possible to obtain values of each of the Tmax, Cmax and AUC, lying in the respective preferred ranges of the present invention.

So, the example formula percutaneous absorbable drug donepezil and the like, having a high commercial practicality, is the following:

Konz is ntrace donepezil and the like in the pressure-sensitive adhesive layer: 1 to 30 wt.% and preferably 3 to 20 wt.%;

the thickness of the pressure-sensitive adhesive layer is from 20 to 300 μm and preferably from 60 to 240 microns;

type pressure-sensitive adhesive composition: acrylic pressure-sensitive adhesive composition;

the type of liquid plasticizer: alkilany ester of fatty acid and preferably an ester of a lower monovalent alcohol containing from 1 to 4 carbon atoms, and saturated or unsaturated fatty acids containing from 12 to 16 carbon atoms; and

the concentration of the liquid plasticizer in the pressure-sensitive adhesive layer: 10 to 160 CTA by weight and preferably from 40 to 150 CTA by weight to 100 CTA by weight of pressure-sensitive adhesive composition.

On the form percutaneous absorbable preparation of the present invention is not restricted by special limitations, and examples of forms include tapes and sheets. In addition, although it depends on a pressure-sensitive adhesive composition, the type and quantity of liquid plasticizer, and the age, body weight of the patient, symptoms and the like, the dose transdermally absorbable preparation of the present invention is preferably such that in the case of adult transdermally absorbable preparation containing from 2 to 250 mg of donepezil or donepezil hydrochloride, was usually glued to ucdw skin from 5 to 150 cm2from about the nogo times every seven days to once a day to demonstrate the preferred profile in plasma concentrations of donepezil and the like in the present invention. Specifically, transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation containing from 2 to 250 mg of donepezil or donepezil hydrochloride, which can be administered to the patient in such a way as to demonstrate the preferred profile in plasma concentrations of donepezil and the like in the present invention. In addition, transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable preparation which is applied to wcstok skin of the patient from 5 to 150 cm2that may be administered to the patient in such a way as to demonstrate the preferred profile in plasma concentrations of donepezil and the like in the present invention. Moreover, transdermally absorbable preparation according to the present invention preferably is a transdermally absorbable drug, administered to the patient once every seven days to once a day, which you can enter the patient in such a way as to demonstrate the preferred profile in plasma concentrations of donepezil and the like in the present invention.

EXAMPLES

Although below is a more detailed explanation of the present invention by way of examples, the present is invention is not limited to these examples. It should be noted that "honor" in all the following descriptions refer to ctam mass.

1. Obtaining a solution of an acrylic pressure-sensitive adhesive composition

75 CTA 2-ethylhexyl acrylate, 22 revere N-vinyl-2-pyrrolidone, 3 honor of acrylic acid and 0.2 honor azobisisobutyronitrile has polymerizable in solution in ethyl acetate at 60°C in an atmosphere of inert gas to obtain a solution of a pressure-sensitive adhesive composition (solid content, a pressure-sensitive adhesive composition: 28 wt.%).

2. Obtaining percutaneous absorbable preparation with the use of donepezil hydrochloride

Example 1

Solution of acrylic pressure-sensitive adhesive composition containing 40,38 CTA solids pressure-sensitive adhesive composition and 49,82 CTA isopropylmyristate, were mixed and stirred to homogeneity in the container, and the 8,27 CTA donepezil hydrochloride and a solution in ethanol containing 0,80 CTA sodium hydroxide, were mixed and stirred in a separate container. Then containing the drug and the mixture was added to a mixture solution of a pressure-sensitive adhesive composition and isopropylmyristate, and the mixture was stirred followed by successive addition of 0.05, CTA ascorbic acid, 0.50 CTA of sodium metabisulfite and 0.18 CTA of diisopropylate ethylacetate is that aluminium and mixing with bringing viscosity using ethyl acetate, coating this liquid silicone treated remove PET film (thickness: 75 μm) to a thickness of 150 μm and drying with formation of a pressure-sensitive adhesive layer. After layering the sides of nonwoven fabric laminated PET film (thickness 2 μm) and nonwoven PET (basic weight: 12 g/m2) this pressure-sensitive adhesive layer was carried out by the procedure of aging for 48 cow at 70°C To produce percutaneous absorbable drug.

Example 2

Percutaneous absorbable drug was obtained similar to example 1 by the way, except for the formation of a pressure-sensitive adhesive layer by coating to a thickness of 200 μm after drying.

3. Testing the introduction of a single dose transdermally absorbable preparation

Testing the introduction of a single dose were performed as described below using percutaneous absorbable preparations of examples 1 and 2.

Examples 3 and 4

Testing the introduction of a single dose was carried out on healthy adults by dividing into two groups A and B to 12 individuals in each.

Each group orally was administered one tablet of 5 mg commercially available Aricept™ water for drinking in period 1. During the period up to 288 cow after the introduction of the collected blood samples to measure the level donepezil in plasma.

After tested the I introduction of tablets 5 mg Aricept™ has provided adequate breeding season.

Transdermally absorbable preparation of donepezil hydrochloride was pasted on the skin of each individual 1 week period 2. This time on the back of individuals, groups A pasted one film transdermally absorbable preparation of example 1 (40 cm2), and on the back of individuals of group B were pasted one film transdermally absorbable preparation of example 2 (40 cm2). After bonding over a period of up to 528 cov collected blood samples to measure the level donepezil in plasma.

The measurement of donepezil in the plasma is produced in accordance with the method described below. To 100 μl of the obtained plasma was added to the internal standard, followed by extraction donepezil and internal standard organic solvent (solvent extraction). Then the organic solvent drove away. To the obtained residue was added a solution for application to HPLC for dissolution, followed by quantitative analysis using HPLC/MS/MS.

Changes in the concentration of donepezil in plasma is shown in figure 1 and 2. In addition, the expected pharmacokinetic parameters using analysis without the compartmentalization (program: WinNonlin Ver. 5.1.1) on the basis of concentrations of donepezil in plasma in group A and in group B presented in table 1.

Table 1
Pharmacokinetic parameters of donepezil hydrochloride after administration of a single dose in the form of tablets of 5 mg, the patch 150 μm and plaster of 200 microns
ModeT1/2 (h)Tlag (h)Tmax (h)Cmax (ng/ml)AUClast (ng·h/ml)AUCinf (ng·h/ml)
Tablet Aricept 5 mg (A)Average71,250,502,967,15253,40286,95
Stocks.13,850,210,752,9079,2585,56
Tablet Aricept 5 mg (B)Average78,540,543,385,04232,85267,90
Stocks.17,38 0,141,611,0254,4861,11
Example 1 (A)Averagethan 94.695,3370,835,801038,871084,51
Stocks.39,78the 3.6521,28with 3.27614,36613,06
Example 2 (B)Average80,735,33114,006,691331,201362,86
Stocks.15,023,4543,574,06648,39647,21

Based on the results of table 1 and figures 1 and 2 it can be expected that percutaneous absorbable preparations according to the present invention reduce the risk of side effects, because nenablyudaemo peak concentrations of donepezil in plasma between 2 and 5 came after injection.

Besides containing donepezil percutaneous absorbable preparations according to the present invention are compositions which exhibit preferred pharmacokinetic parameters related to Cmax, AUC and Tmax, and the like, and is able to provide in the form of compositions of the ability of adhesion to the skin for a long period of time.

This application is based on priority patent application Japan 2008-143591,

registered on may 30, 2008, and provisional patent application U.S. 61/129010, registered on may 30, 2008, the full contents of which are thereby incorporated by reference.

1. Transdermally absorbable preparation comprising 2-[(1-benzylpiperidine-4-yl)methyl]-5,6-dimethoxyindole-1-he and/or its hydrochloride in a pressure-sensitive adhesive layer,
where percutaneous absorbed the drug can be administered to the patient so that the Cmax per unit surface area percutaneous absorbable drug is from 0.025 to 0.5 ng/ml·cm2the profile of plasma concentration.

2. Transdermally absorbable preparation according to claim 1, where Cmax is from 0.025 to 0.45 ng/ml·cm2.

3. Transdermally absorbable preparation according to claim 1, where Cmax is from 0.05 to 0.4 ng/ml·cm2.

4. Transdermally absorbable preparation according to any one of claims 1 to 3, where AUC per unit surface area percutaneous absorbable what about the drug ranges from 7.5 to 75 ng·h/ml·cm 2.

5. Transdermally absorbable preparation according to claim 4, where the AUC ranges from 10 to 62.5 ng·h/ml·cm2.

6. Transdermally absorbable preparation according to claim 4, where the AUC ranges from 12.5 to 50 ng·h/ml·cm2.

7. Transdermally absorbable preparation according to any one of claims 1 to 3, where Tmax is from 12 to 192 hours

8. Transdermally absorbable preparation according to claim 7, where Tmax is from 24 to 180 hours

9. Transdermally absorbable preparation according to claim 7, where Tmax is from 48 to 168 hours

10. Transdermally absorbable preparation according to any one of claims 1 to 3, where AUC per unit surface area percutaneous absorbable drug is from 7.5 to 75 ng·h/ml·cm2and Tmax ranges from 12 to 192 hours

11. Transdermally absorbable preparation of claim 10, where Tmax is from 24 to 180 hours

12. Transdermally absorbable preparation of claim 10, where Tmax is from 48 to 168 hours

13. Transdermally absorbable preparation according to any one of claims 1 to 3, where AUC per unit surface area transdermally absorbable preparation is from 10 to 62.5 ng·h/ml·cm2and Tmax ranges from 12 to 192 hours

14. Transdermally absorbable preparation according to item 13, where Tmax is from 24 to 180 hours

15. Transdermally absorbable preparation according to item 13, where Tmax is from 48 to 168 hours

16. Transdermally absorbable preparation according to any one of claims 1 to 3, where AUC per unit surface area percutaneous absorbable drug ranges from 12.5 to 50 ng·h/ml·cm2

17. Transdermally absorbable preparation according to item 16, where Tmax is from 24 to 180 hours

18. Transdermally absorbable preparation according to item 16, where Tmax is from 48 to 168 hours

19. Transdermally absorbable preparation comprising 2-[(1-benzylpiperidine-4-yl)methyl]-5,6-dimethoxyindole-1-he and/or its hydrochloride in a pressure-sensitive adhesive layer, where percutaneous absorbed the drug can be administered to the patient so that the AUC per unit surface area percutaneous absorbable drug is from 7.5 to 75 ng·h/ml·cm2the profile of plasma concentration.

20. Transdermally absorbable preparation according to claim 19, where the AUC ranges from 10 to 62.5 ng·h/ml·cm2.

21. Transdermally absorbable preparation according to claim 19, where the AUC ranges from 12.5 to 50 ng·h/ml·cm2.

22. Transdermally absorbable preparation according to any one of p-21, where Tmax is from 12 to 192 hours

23. Transdermally absorbable preparation according to item 22, where Tmax is from 24 to 180 hours

24. Transdermally absorbable preparation according to item 22, where Tmax is from 48 to 168 hours

25. Transdermally absorbable preparation comprising 2-[(1-benzylpiperidine-4-yl)methyl]-5,6-dimethoxyindole-1-he and/or its hydrochloride in a pressure-sensitive adhesive layer,
where percutaneous absorbed the drug can be administered to the patient so that Tmax profile in plasma concentrations ranging from 12 to 192 hours

26. Transdermally absorbable preparation according to claim 2, where Tmax is from 24 to 180 hours

27. Transdermally absorbable preparation according A.25, where Tmax is from 48 to 168 hours

28. Transdermally absorbable preparation according to claim 1, which is put on from 5 to 150 cm2the skin of the patient.

29. Transdermally absorbable preparation according to claim 1, which is applied to the patient from one to seven times per week.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new gamma-secretase inhibitors of formula I: , wherein L1,R1, R2,X,n and Ar have the values specified in the description, their pharmaceutically acceptable salts and solvates, as well as to pharmaceutical compositions based on these compounds for treating Alzheimer's disease and the use of drugs for gamma-secretase and beta-amyloid protein inhibition, and for treating neurodegenerative diseases such as Alzheimer's disease.

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38 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention represents adhesive medication, consisting of applied on at least one base surface adhesive layer, which consists of donepezil and acrylic adhesive agent, water content in active layer constituting 1000-8000 fractions/mln.

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2 cl, 23 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new tetracyclic compounds of general formula (I), wherein is a single or double bond; no bonds or a single bond; or V means N; T and X as shown in structure fragments above; U and W independently mean C or N with one of them shall be N; R3, R4, R5 and R6 - H; Rv is absent; Ru and Rw are independently absent or mean (C1-12)alkyl; Y =N-OR1 or NP'1, wherein R1 - H, (C1-12)alkyl optionally substituted by phenyl, phenyloxy, carboxy, (C1-12)alkoxy, (C1-12)alkoxycarbonyl, or (C2-12)alkenyl; R'1 is phenyl, or pharmaceutically acceptable salts thereof, or diastereomers thereof, or regioisomers thereof, or: mixtures thereof, a pharmaceutical composition containing them, and specific compounds for cysteine protease inhibition.

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8 cl, 1 tbl

FIELD: chemistry.

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EFFECT: novel compounds are obtained and described, which have strong affinity towards 4 serotonin receptors, which are useful as an agent which stimulates enterokinesis or an agent which improves functioning of the alimentary canal.

28 cl, 233 ex, 29 tbl

FIELD: chemistry.

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10 cl, 3 tbl, 6 ex, 7 dwg

FIELD: medicine, pharmaceutics.

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EFFECT: there are produced new compounds and a preventive or therapeutic agent on the basis of said compounds which can find application in medicine for treating dementia, Alzheimer's disease, attention deficit/hyperactivity disorder, schizophrenia, epilepsy, convulsions of central genesis, eating behaviour disorders, obesity, diabetes, hyperlipidemia, sleep disturbances, narcolepsy, sleeping apnoea syndrome, circadian rhythm disorder, depression or allergic rhinitis.

12 cl, 3 tbl, 72 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, in particular to neuroophthalmology, and may be used for treating the visual pathway disorders in the patients with multiple sclerosis. For this purpose, the preparation cortexin is introduced retrobulbar or parabulbar. Then 30 minutes after the introduction of cortexin, upper cervical and stellate ganglia of the sympathetic nervous system are percutaneously exposed to a rotating electric pulse field. This field is generated in a space between the left and right ganglia using two multiple electrodes. The electrodes consist of a number of partial galvanic isolated conductive elements functioning as cathodes and two anodes which are placed in a projection of the ganglia. While forming the electric current pulses, the partial elements of the multiple electrodes are switched; the exposure is paused. Thereafter, a zone of ganglia activity block is switched. It is followed by electrical stimulation of the visual pathway via an electrode applied on the eyelids. For this purpose, the rotating electric pulse field is generated in the space between this electrode which is as the anode, and the partial elements of the multiple electrodes.

EFFECT: method provides relieved demyeliniation, neurodegenerative processes within the visual pathway, improved visual function, including visual acuity and functional characteristics.

5 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and veterinary medicine, namely to neurosurgery, and may be used for targeted drug delivery into the central nervous system of a living body. That is ensured by making a surgical approach to a segment of the central nervous system specified for local administration of the drug. Further, a drug source is placed therein. The drug source is a block of carbon composite - nanodiamond graphite-like carbon of the diamond content of 50-95 wt % and the porosity of 40-75 vol % pores of which are filled with the drug. The ratio of the block volume to its outer surface is 10-1000 mcm.

EFFECT: method provides a simplified and accurate targeted drug delivery to the specified region of the central nervous system.

2 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to producing new 5,8,9,10-tetrahydropyrimido[4,5-d]azocine derivatives having triflate, secondary and tertiary amino groups in the 4th position of general formula specified below. In general structural formula: 2-12 2 X=OTf (Tf means triflate), X means NR1R22 related to the groups 3-12

.

The method consists in the fact that 6-isopropyl-2-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one reacts with methyl propyolate in methanol at room temperature to produce methyl 8-isopropyl-4-oxo-2-phenyl-5,8,9,10-tetrahydropyrimido[4,5-d]azocine-6-carboxylate (1). Thereafter, the prepared compound reacts with triftalane hydride in dichloromethane in the presence of pyridine at t°=-10°C; it is recovered and purified with by means of column chromatography to prepare methyl 8-isopropyl-2-phenyl-4-{[(trifluoromethyl)sulphonyl]oxy}-5,8,9,10-tetrahydropyrimido[4,5-d]azocine-6-carboxylate (2); then the solution I mmole of the prepared product (2) in absolute dioxide is added with 2 mmole of K2CO3 and 1.5 mmole of appropriate amine. After being boiled for two hours and removing the solvent, respective 4-amino substituted 5,8,9,10-tetrahydropyrimido[4,5-d]azocine of formula 3-12 is prepared. The method is directed to prepare the products in the form of white or yellow powder, or in the form of drying oil.

EFFECT: after the primary screening, the compounds appeared to be acetyl- and butyrylcholin esterase inhibitors and can find application as scaffolds in searching the preparations for treating neurodegenerative diseases.

10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new indanone derivatives which may be preferentially used for treating and/or preventing a medical state for which cholinesterase inhibition is desired.

EFFECT: there are presented the new indanone derivatives which may be preferentially used for treating and/or preventing a medical state for which cholinesterase inhibition is desired.

11 cl, 36 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine. Described is system of transdermal delivery of medication for passive transdermal delivery of one or more than one ionised active agent onto biological surface of subject. System of transdermal medication delivery includes carrying substrate and layer of active agent. Layer of active agent includes thickening agent, plasticiser and therapeutically efficient quantity of ionised active agent.

EFFECT: claimed is novel system of transdermal medication delivery for passive transdermal delivery of one or more than one ionised active agent onto biological surface of subject.

23 cl, 32 dwg, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention represents adhesive medication, consisting of applied on at least one base surface adhesive layer, which consists of donepezil and acrylic adhesive agent, water content in active layer constituting 1000-8000 fractions/mln.

EFFECT: improved release of donepezil from adhesive layer is achieved and change of adhesive layer colour with the course of time is prevented.

2 cl, 23 ex, 4 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine. What is described is a surgical barrier which includes a wound-facing polymeric coating comprising an enteric polymer, and at least one flexible substrate wherein at least one mentioned flexible substrate having at least one exterior surface with said polymeric coating is applied on at least one mentioned flexible substrate so that substantially cover at least one exterior surface thereof. There are also described a method for inhibiting the formation of adhesions in a patient who has undergone a surgical procedure, and a method for repairing a gastric or duodenal perforation.

EFFECT: reduced probability or prevention of the formation of adhesions associated with the surgical intervention.

27 cl, 4 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: declared group of inventions which refers to an adsorbent, a mask with adsorbent and an absorbent layer for organic substance adsorption, an adsorbent for allergen adsorption, an adsorbent to be used in medicine and an oral adsorbent. Said adsorbents, mask and adsorbent layer contains a porous carbon material comprising spherical pores having average diameter of 1×10-9 to 1×10-5 and regularly spaced (in an orderly fashion) with a surface area of the material making more than 3x102 m2/g.

EFFECT: invention provides preparing the adsorbents with high adsorbent ability.

37 cl, 4 dwg, 20 tbl, 7 ex

Adhesive plaster // 2474418

FIELD: medicine.

SUBSTANCE: invention refers to medicine. What is described is an adhesive plaster containing an elastic carrier and an adhesive layer applied on at least one side of the carrier wherein the elastic carrier contains a woven material knitted by stocking stitch on both sides, containing two or more lines of wavy multifilament PET yarns; the adhesive layer contains 25 to 50 wt % of a liquid organic ingredient and 25 to 50 wt % of a thermoplastic elastomer in relation to total weight of the layer, and contains 10 wt % or more of methyl salicylate as a liquid organic ingredient in relation to total weight of the layer, and a dynamic modulus of elasticity (G') of the adhesive layer makes 30000 to 75000 Pa at 10 rad/s and 37°C.

EFFECT: adhesive plaster possess the improved properties of drug release and skin absorption.

6 cl, 5 dwg, 6 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine. Described is cellulose leaf for paper towel, which includes cellulose fibre and composition of lotion, which can be carried onto the surface, including softening means and antimicrobial agent.

EFFECT: composition of lotion ensures possibility of cellulose fibre to retain speed of water adsorption for further ensuring of lotion transfer on skin and increase of efficiency of lotion transfer.

25 cl, 2 dwg, 4 tbl, 22 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine. Described is medication in form of plaster, which has glue layer, at least, on one surface of bottom layer, in which glue layer contains glue, badly soluble medication, first organic liquid component, second organic liquid component, third organic liquid component and linked polyvinylpyrrolidone. Solubility of badly soluble medication in first organic liquid component is not less than solubility of badly soluble medication in second organic liquid component, and solubility of badly soluble medication in second organic liquid component is not less, than solubility of badly soluble medication in third organic liquid component.

EFFECT: medicine in form of plaster has small area and ensures adhesion during long time.

4 cl, 1 dwg, 10 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine. What is described is a donepezil-containing adhesive composition. At least one type of a stabiliser specified in a group consisting of ascorbic acid, metal salt or ester of such, isoascorbic acid or metal salt of such, ethylene-diamine-tetraacetic acid or metal salt of such, 2-mercaptobenzimidazole, 3(2)-tert-butyl-4-hydroxyanisol, 2,6-di-tert-butyl-4-methylphenol, tetrakis[3-(3',5'-di-tert-butyl-4'-hydroxyphenyl)]propionate pentaerythrite, (±)-α-tocopherol, (±)-α-tocopherol acetate, rutin, hypophosphoric acid, metabisulphite metal salt and metal salt of hydroxymethansulphinic acid; it is added to a layer of a pressure sensitive adhesive containing a pressure hardened adhesive and donepezil.

EFFECT: donepezil-containing adhesive composition inhibits time fading.

3 cl, 3 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine. What is described is a method for staining inhibition of an adhesive composition having a substrate and a layer of a pressure sensitive adhesive containing a pressure hardened adhesive and donepezil in the layer of the pressure sensitive adhesive; the layer of the pressure sensitive adhesive contains ascorbic acid, metal salt or ester of such, and metabisulphite metal salt. The method involves: the stage of preparing a mixture containing the pressure hardened adhesive, donepezil, ascorbic acid, metal salt or ester of such, and metabisulphite metal salt, and the stage of formation of the film of the pressure sensitive adhesive by applying the mixture on the substrate surface. Staining inhibition of the donepezil-containing adhesive composition enables implementing a natural colour appearance.

EFFECT: what is presented is the method for staining inhibition of donepezil-containing adhesive composition and the method for reduction of donepezil-related compounds.

4 cl, 3 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine. What is described is a biodegradable plaster containing at least one bioadhesive layer, and at least one non-bioadhesive layer with the bioadhesive layer containing at least one polyarphon dispersion, and at least one bioadhesive polymer with the polyarphon dispersion containing at least one pharmacologically active substance.

EFFECT: biodegradable plaster can deliver drugs, including poorly water soluble ones.

21 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to tetrahydroquinoline derivatives of formula (I), where values of C3-C4, R2, R3, R4, R5, L1, L2, Y and X are given in claim 1, as muscarinic receptor agonists; compositions containing said compounds; methods of inhibiting muscarinic receptor activity using said compounds; methods of treating diseased conditions associated with the muscarinic receptor using said compounds, and methods of identifying a subject suitable for treatment using said compounds.

EFFECT: improved properties of compounds.

22 cl, 1 tbl, 3 ex, 3 dwg

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