Method for staining inhibition of donepezil-containing adhesive composition and method for reduction of formed donepezil-related compounds

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

 

[Technical field to which the invention relates]

The present invention relates to a method for suppressing coloring of adhesive composition containing donepezil and to a method of reducing the amount of generated related to donepezil connections.

[The prior art]

Conventional pharmaceutical composition containing donepezil, acts as an inhibitor of acetylcholinesterase and is used as a drug against dementia in Alzheimer's disease. Patients suffering from dementia in Alzheimer's disease, are usually elderly and elderly patients often have difficulty swallowing oral medication. In addition, in some cases, it may be difficult introduction of oral medications for patients with advanced symptoms of dementia of the Alzheimer's type. In these cases applies percutaneous parenteral administration of donepezil.

Adhesive composition containing donepezil for percutaneous parenteral administration of donepezil, known and described, for example, in Japanese Laid Patent Application No. H11-315016 (Patent Document 1), the prospectus, the application WO 2003/032960 (Patent Document 2) and the prospectus to the application WO 2006/082728 (Patent Document 3), and the like.

However, the problem faced by the authors of this patent application during the research the Finance, is that the effective content of donepezil in the composition decreases significantly with time after preparation containing donepezil adhesive composition. Namely, it is necessary to take countermeasures to prevent the formation related to donepezil compounds in the adhesive composition (adhesive layer means, adhesive when pressed). However, in the adhesive composition for parenteral administration it is not necessary that donepezil is stable, because the environment in which the drug is very different from the environment in preparation for oral administration, the composition is in the form of a sheet is particularly sensitive to the effects of the environment (oxygen), even if it is blended with antioxidant (stabilizer), commonly used in oral preparations. On the contrary, the quantity of generated related to donepezil connections can grow.

Although Patent Documents 2 and 3 describe that antioxidants such as tocopherol and ester derivatives, ascorbic acid, ascorbicacid, nordihydroguaiaretic acid, dibutylaminoethanol (BHT, OSH), butylhydroxyanisole and the like, if necessary, can be used in the layer of the adhesive means, the adhesive under pressure, they do not report neither is akih examples of compositions which really were blended with antioxidants, or does not properly verify the effectiveness of antioxidants in the compositions, therefore, stabilization of donepezil antioxidants was not found.

Japanese Laid Patent Application No. 2000-136134 (Patent Document 4) reports that the increase in the number of related donepezil compounds can be suppressed by adding antioxidants such as hydrosulfite sodium, sodium sulfite, sodium pyrosulfite (sodium metabisulfite), cysteine, citric acid, disodium edetate (disodium salt of ethylenediaminetetraacetic acid), ascorbic acid, altarboy acid (isoascorbic acid) and the like, containing donepezil composition for oral administration. However, this document proposes a liquid, syrupy or other compositions for oral administration and does not include the use of antioxidants for adhesive compositions.

On the other hand, there is a tendency to select such drugs, which are painted, in such extent that it does not cause discomfort, such as feeling pedalnote, for such reasons as creating a sense of authenticity and purity, and, in particular, since the adhesive compositions often paste directly on the skin of the patient, predpochtitel the appearance with a natural color, such as the color white. However, no concrete way, providing the appearance of natural color by inhibiting the staining of adhesive compositions containing donepezil.

For example, Japanese Patent No. 3124069 (Patent Document 5), Japanese Laid Patent Application No. H11-047233 (Patent Document 6), Japanese translation of PCT application No. 2006-523637 (Patent Document 7) and Japanese translation of PCT application No. 2003-530422 (Patent Document 8) represent a technology of suppressing fading in adhesive compositions for long-term storage. However, these documents do not report as a way to implement the appearance of the composition with the natural color, and the way in providing the appearance of natural color adhesive composition containing donepezil.

Patent Document 1: Japanese Laid Patent Application No. H11-315016

Patent Document 2: prospect to the application WO 2003/032960

Patent Document 3: the Avenue to the application WO 2006/082728

Patent Document 4: Japanese Laid Patent Application No. 2000-136134

Patent Document 5: Japanese Patent No. 3124069

Patent Document 6: Japanese Laid Patent Application No. H11-047233

Patent Document 7: Japanese translation of PCT application No. 2006-523637

Patent Document 8: Japanese translation of PCT application No. 2003-530422

[Description]

[Problems to be solved by the invention of the Sabbath.]

In these circumstances, the objective of the present invention consists in creating the appearance of the composition with the natural color by suppressing coloring containing donepezil adhesive compositions, as well as in reducing the amount of generated related to donepezil connections.

[Means of resolution]

As a result of extensive studies, the authors of the present invention have found that the appearance with the natural color can be realized by suppressing coloring containing donepezil adhesive composition by adding two specific types of additives and the amount of concrete produced related to donepezil compounds that are found in relatively large quantities in containing donepezil adhesive compositions can be effectively reduced, at the same time also unexpectedly found that the total number of generated related to donepezil compounds also reduced, which thereby led to the completion of the present invention.

Namely, the present invention is as follows:

(1) a method of suppressing staining adhesive composition having a substrate and a layer of adhesive with pressure adhesive means, the adhesive layer by pressing the adhesive agent containing curable pressure adhesive agent is donepezil, the method including:

stage injection of ascorbic acid, metal salts or its complex ether and metabisulfites metal salt in the adhesive layer by pressing the adhesive funds;

(2) the method described above in paragraph (1), which includes:

the stage of preparation of the mixture comprising curing under pressure adhesive means, donepezil, ascorbic acid, metal salt or its ester and metabisulfite salt of the metal; and

the stage of forming the film layer adhesive with pressure adhesive means applying the mixture on the surface of the substrate;

(3) the method described above in paragraphs (1) or (2), including:

the mixture of from 0.02 to 1.5 parts by weight of ascorbic acid, metal salts or its complex with ether and 1.0 part by weight metabisulfite metal salt;

(4) a method of suppressing staining adhesive composition having a substrate and a layer of adhesive with pressure adhesive means, the adhesive layer by pressing the adhesive agent containing curable pressure adhesive means and donepezil, and reducing the number of generated related to donepezil compounds, the method including:

stage injection of ascorbic acid, metal salts or its complex ether and metabisulfites metal salt in the adhesive layer in which allivane adhesive means;

(5) the method described above in paragraph (4), which includes:

the stage of preparation of the mixture comprising curing under pressure adhesive means, donepezil, ascorbic acid, metal salt or its ester and metabisulfite salt of the metal, and

the stage of forming the film layer adhesive with pressure adhesive means applying the mixture on the surface of the substrate;

(6) the method described above in paragraphs (4) or (5), including:

the mixture of from 0.02 to 1.5 parts by weight of ascorbic acid, metal salts or its complex with ether and 1.0 part by weight metabisulfite metal salt;

(7) the adhesive composition having a substrate and a layer of adhesive with pressure adhesive means and including adhesive and donepezil in the adhesive layer under pressure adhesive means, in which

ascorbic acid, a metal salt or its ester and metabisulfite salt of the metal included in the adhesive layer by pressing the adhesive funds;

(8) the adhesive composition described above in paragraph (7), in which the layer of adhesive with pressure adhesive means includes ascorbic acid, metal salt or its ester in the ratio of from 0.02 to 1.5 parts by weight to 1.0 part by weight metabisulfite metal salt;

(9) the adhesive composition having mean the ku and the adhesive layer under pressure adhesive means and including curing under pressure adhesive means and donepezil in the adhesive layer under pressure adhesive means, in which

the adhesive layer under pressure adhesive means obtained by forming the film from a mixture comprising curing under pressure adhesive means, donepezil, ascorbic acid, metal salt or its ester and metabisulfite salt of the metal; and

(10) the adhesive composition described above in paragraph (9), in which the mixture comprises ascorbic acid, metal salt or its ester in the ratio of from 0.02 to 1.5 parts by weight to 1.0 part by weight metabisulfite metal salt.

[Primary results of the invention]

According to the present invention, since the appearance with a natural color such as white color, is created by the suppression of coloring containing donepezil adhesive compositions using a combination of two specific types of additives can be implemented containing donepezil adhesive composition having an attractive appearance.

In addition, a number of specific related compounds, formed in the composition, can be reliably reduced with the use of combinations of two specific types of additives can be obtained a highly reliable and stable adhesive composition containing donepezil. Moreover, because it can be reduced not only the amount of concrete produced related to donepezil soy is inane, but also the total number of generated related to donepezil compounds, can be achieved only highly reliable and stable adhesive composition containing donepezil.

Moreover, the variation of the applied two types of concrete additives, the amount of generated related compounds can be ingibirovany even more (namely ingibirovany synergistically) compared to the average arithmetic value for the generated related compounds obtained from each of the additives separately. Thus, can be efficiently obtained highly reliable and stable containing donepezil adhesive composition without the necessity to use a large number of additives.

[Best variant of the invention]

The following provides an explanation of the present invention in accordance with a preferred variant implementation thereof.

The method of suppressing coloration of the adhesive composition according to the present invention is one that provides an introduction donepezil, cured under pressure adhesive means and two specific types of additives in the adhesive layer by pressing the adhesive means in the adhesive composition, comprising a substrate and a layer of adhesive with pressure adhesive means formed at least on one side of the substrate.

Here, the term "donepezil" includes not only the (±)-2-[(1-benzylpiperidine-4-yl)methyl]-5,6-dimethoxyindole-1-it is (free form), but also pharmacologically acceptable salts and its esters.

In the present invention donepezil can be either donepezil (free form), or any pharmaceutically acceptable salts or esters thereof. The adhesive layer by pressing the adhesive means from the point of view of the characteristics of percutaneous absorption preferably contains donepezil (free form).

The adhesive composition according to the present invention can be used as drugs against dementia in Alzheimer's disease. In addition, other possible ways of use include the application against dementia with cerebrovascular diseases, for the prevention Migranian headaches and the like.

In the adhesive compositions according to the present invention, the proportion of donepezil in the adhesive layer by pressing the adhesive means is preferably from 1 to 30 weight percent, and more preferably from 3 to 20 weight percent, based on the total weight of the adhesive layer under pressure adhesive means. If the proportion is less than 1 weight percent, cannot be expected to achieve effective for the treatment level is I am content, whereas if the proportion exceeds 30 weight%, there are restrictions therapeutic effect, at the same time, the risk of economic inefficiency.

Two specific types of additives used in the present invention are ascorbic acid, metal salts or its esters (preferably sodium salt or an ester of palmitic acid) and metabisulfite metal salt (preferably the sodium salt). In the blending of these two types of additives colouring containing donepezil adhesive composition can be suppressed, and can be made of a composition having the appearance of natural color. In addition, because these two types of additives also act as stabilizers, as will be described later, can be reduced resulting in compositions related to donepezil connections.

In the above-mentioned additives examples of metal salts include sodium salt, potassium salt, calcium salt and magnesium salt. Examples of esters include esters palmitic acid, esters of stearic acid and esters of myristic acid.

While there are no specific restrictions regarding ascorbic acid, metal salts or its esters, and metabisulfites metal salt, predpochtitel is from about 0.02 to 1.5 parts by weight, more preferably from 0.04 to 1.0 part by weight, and most preferably from 0.04 to 0.2 part by weight of ascorbic acid, metal salts or its esters, admixed per 1.0 part by weight metabisulfite metal salt. Suppression of staining may be inappropriate, if the mixed amount of ascorbic acid, metal salts or its esters is less than 0.02 part by weight or more than 1.5 parts by weight.

Although the content of ascorbic acid, metal salts or its esters in the adhesive composition may be properly adjusted and there are no particular restrictions on such content in units of the solids content thereof is preferably from 0.01 to 0.75 weight percent, more preferably from 0.02 to 0.5 weight percent, and most preferably from 0.02 to 0.10 weight percent, based on the total weight of the adhesive layer under pressure adhesive means. In addition, although the content metabisulfite metal salt in the adhesive layer by pressing the adhesive means can be properly adjusted and there are no particular limitations in this regard, the contents in units of solids is preferably from 0.1 to 1.0 weight percent, and more preferably from 2 to 0.8 weight percent, calculated on the total weight of the adhesive layer under pressure adhesive means.

According to the present invention, the adhesive layer under pressure adhesive means in the adhesive composition may be blended with a stabilizer. Here, the term "stabilizer" means a compound, which functions as able to inhibit the formation of related donepezil compounds (or reduce the number of such related compounds formed in the adhesive layer by pressing the adhesive agent containing donepezil, and in the mixture of materials used for forming the adhesive layer by pressing the adhesive means. Specific examples of the stabilizer include ascorbic acid, metal salts or its esters (preferably sodium salt or an ester of palmitic acid), isoascorbic acid or its metal salt (preferably the sodium salt), ethylenediaminetetraacetic acid or its metal salt (preferably the calcium-disodium salt or TETRANITRATE salt), cysteine, acetylcysteine, 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, pentaerythritol, 3-mercapto-1,2-propandiol, tocopherol acetate, rutin, quercetin, hydroquinone, metal the ski salt hydroxymethanesulfinic acid (preferably the sodium salt), metabisulfite metal salts (preferably sodium salt), sulfite metal salts (preferably sodium salt) and thiosulfate metal salts (preferably sodium salt), and can be used one connection, or two or more compounds may be used in combination.

Stabilizer examples of the above metal salts include sodium salt, potassium salt, calcium salt and magnesium salt. Examples of esters include esters palmitic acid, esters of stearic acid and esters of myristic acid.

Any specific restrictions on the weights of the stabilizer does not exist to the same extent as it has no adverse effect on the properties of the adhesive layer under pressure adhesive means. Preferred examples of the value of the upper limit for the content of the stabilizer, based on the total weight of the adhesive layer under pressure adhesive means (namely, the total weight of the adhesive layer under pressure adhesive means in the adhesive composition), in units of the total content thereof, are such that the proportion exceeding 5 weight percent, creates the possibility of deterioration of adhesion or other characteristics of the adhesive layer by pressing the adhesive is the means, whereas if the content is less than 0,0005 weight percent, there is a likelihood that it will be impossible to get the proper effects of stabilization. Thus, preferred examples of the upper limit value include 5 weight percent, 3 weight percent, 2 weight percent, 1 weight percent to 0.7 wt%, 0.5 wt% and 0.3 wt%, while preferred examples of the value of the lower limit of the amount of 0.0005 wt%, about 0.001 weight percent to 0.01 weight percent to 0.02 weight percent, of 0.03 weight percent, of 0.05 weight percent to 0.1 weight percent to 0.2 weight percent.

More specifically, the percentage of the total weight of the stabilizer, based on the total weight of the adhesive layer under pressure adhesive means (total weight of the adhesive layer under pressure adhesive means in the adhesive composition)is preferably from 0.0005 to 5 weight percent, more preferably from 0.001 to 3 weight percent, more preferably from 0.01 to 1 weight percent, more preferably from 0.01 to 0.91 weight percent, more preferably from 0.01 to 0.7 weight percent, more preferably from 0.02 to 0.7 weight percent, more preferably from 0.02 to 0.5 weight percent, and most preferably from of 0.03 to 0.3 weight percent.

This breath is reenie suppression staining adhesive composition is preferably such the process of obtaining an adhesive composition includes an introduction cured under pressure adhesive means, donepezil and additives in the adhesive layer under pressure adhesive means. Although supplements can dissolve or disappear during storage adhesive composition after the additive has demonstrated its effect in accordance with the present invention, this case is also included in the scope of the present invention.

In the present invention is related to donepezil connections are related to the compounds that are found in relatively large numbers in the adhesive layers with pressure adhesive agent containing donepezil and derive donepezil (connection, generated in connection with donepezil; compounds not found in the layers of adhesive with pressure adhesive means which do not contain donepezil). Specific examples related to donepezil compounds include related connection, detective at retention time of 12.8 min (hereinafter referred to as "related connection 1"), and related connection, detective at retention time of 3.9 minutes (hereinafter referred to as "the related compound 2"), in the case of analysis of adhesive compositions according to the present invention in terms of analysis, opisyvaemyh following examples. In the contact of two specific types of additives present invention demonstrates even greater usefulness in relation to inhibition of specific education related compounds 1 and related compounds 2, at the same time inhibiting the formation of other related compounds, thereby ultimately allowing reduction of the total number of generated related compounds.

In the present invention the combination of ascorbic acid, metal salts or its esters (hereinafter collectively referred to as "derivatives of ascorbic acid") with metabisulfite metal salt provides an advantage in the ability to reduce the number used derivatives of ascorbic acid, at the same time, also in the ability synergistically to reduce the total number of generated related compounds.

In the adhesive compositions according to the present invention there are no particular restrictions on curing under pressure adhesive means contained in the adhesive layer by pressing the adhesive means, and examples include acrylic curing under pressure adhesive means; silicone rubber, branch, Rubezhnoe, Ukraine rubber, polyisobutylene rubber, butadiene-styrene rubber, styrene-isoprene-styrene block copolymer rubbers is, styrene-butadiene-styrene block copolymer rubber and other rubber cured under pressure adhesive means; - curable silicone pressure adhesive means; and polyvinyl alcohol, polyvinylalcohol simple ether, polyvinyl acetate and other cured under pressure adhesive means on the basis of the vinyl polymers.

Since rubber cured under pressure adhesive means often do not have functional groups with high reactivity, donepezil contained in them, is relatively stable, and is formed relatively few related compounds. Examples of such rubber, cured under pressure adhesive means include polyisobutylene and styrene-diene-styrene block copolymers (such as styrene-butadiene-styrene block copolymer (SBS) and styrene-isoprene-styrene block copolymer (SIS)), and can be used one kind or may be applied as a mixture of two or more kinds thereof.

Although curable acrylic pressure adhesive means have a relatively high degree of freedom in terms of their ability to regulate adhesive characteristics and the degree of solubility of the drug and others like him, on the other hand, the polymer chain may contain functional groups that are reactive in respect of the donepezil, and because the residual monomers and the initiators of the polymerization-curable pressure adhesive means can also react with donepezil, depending on the type and proportions copolymerizable monomers, there is reason to worry about reducing effective amount of donepezil. Thus, the present invention is mainly in the form of adhesive compositions using a curable acrylic pressure adhesive means.

Examples of curable acrylic pressure adhesive means in the present invention include curable acrylic pressure adhesive agent containing alkilany an ester of (meth)acrylic acid, and the preferred curable acrylic pressure adhesive means having alkilany an ester of (meth)acrylic acid as its main component (main unit). The copolymer Olkiluoto complex ester of (meth)acrylic acid (first monomer component) as its main component with a vinyl monomer having a functional group capable of participating in a crosslinking reaction (second monomer component), or a copolymer, copolymerizable with another monomer (third monomer component), is particularly preferred for reasons of ease is shivani, exercise under pressure adhesion to the human skin, the ability to regulate the dissolution of the medicinal product and the like.

Preferred examples Olkiluoto complex ester of (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, propyl, butyl, pentyl, hexyl, cyclohexyl, heptyl, octyl, 2-ethylhexyl, nonyl, decyl, undecyl, dodecyl or tridecyl), and alkalemia esters of (meth)acrylic acid in which the alkyl group is a linear, branched or cyclic alkyl group having from 4 to 18 carbon atoms (such as butyl, pentyl, hexyl, cyclohexyl, heptyl, octyl, 2-ethylhexyl, nonyl, decyl, undecyl, dodecyl or tridecyl). Moreover, since the application of the Monomeric component, which reduces the glass transition temperature of the polymer, is preferred for imparting adhesion, manifested under pressure at normal temperatures, it is preferable to alkilany an 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 butyl, pentyl, hexyl, cyclohexyl, heptyl, octyl or 2-ethylhexyl, preferably butyl, 2-ethylhexyl or cyclohexyl, particularly preferably 2-ethylhexyl). More specifically, the preferred acrylate, 2-ethyl hexyl acrylate, 2-ethylhexylacrylate, cyclohexylacetate, cyclohexylmethyl or the like, and among them the most preferred 2-ethyl hexyl acrylate. Can be used one of these alilovic esters of (meth)acrylic acid (first monomer component) or can be applied two or more in combination.

In the vinyl monomer (second monomer component)having a functional group capable of participating in crosslinking reaction, examples of functional groups capable of participating in crosslinking reaction include hydroxyl group, carboxyl group and vinyl group, and preferred is a hydroxyl group and carboxyl group. Specific examples of the monomer (second monomer component) include hydroxyethylamine esters of (meth)acrylic acid, hydroxypropylamino esters of (meth)acrylic acid, (meth)acrylic acid, taconova acid, maleic acid, maleic anhydride, metaconule acid, citraconate acid and glucagonoma acid and the like. Among them, acrylic acid, methacrylic acid, hydroxyethyl the initial ester of acrylic acid (in particular, 2-hydroxyethylacrylate) are preferred from the viewpoint of availability, and the most preferred acrylic acid. Can be used one of these monomers (second monomer component), or may be used two or more in combination.

The above-mentioned another monomer (third monomer component) is used primarily to adjust the cohesive ability of the adhesive layer under pressure adhesive means and to control the solubility or release characteristics of donepezil and the like. Examples of the monomer (third monomer component) include vinyl acetate, finalproject and other vinyl esters; metilidinovy simple ether, ethylenically simple ether, and other vinyl ethers; N-vinyl-2-pyrrolidone, N-vinylcaprolactam and other vinylamide; methoxyethylamine an ester of (meth)acrylic acid ethoxyethyl ester (meth)acrylic acid, tetrahydrofurfurylamine an ester of (meth)acrylic acid and other alkoxysilane esters of (meth)acrylic acid; hydroxypropyl(meth)acrylate, α-hydroxyethylacrylate and other monomers containing a hydroxyl group (which do not create points of the staple, as they are used as the third monomer component); (meth)acrylamide, dimethyl(meth)acrylamide, N(meth)acrylamide, N-methylol(meth)acrylamide, and other derivatives of (meth)acrylic acid having an amide group; aminoacylase an ester of (meth)acrylic acid, dimethylaminoethyl an ester of (meth)acrylic acid, tert-butylaminoethyl an ester of (meth)acrylic acid and other aminoacylase esters of (meth)acrylic acid; ester of methoxyethylamine and (meth)acrylic acid ester of ethoxydiglycol and (meth)acrylic acid ester of methoxypolyethyleneglycol and (meth)acrylic acid ester of methoxypolyethyleneglycol and (meth)acrylic acid and other esters of alkoxyalkanols and (meth)acrylic acid; (meth)Acrylonitrile; styrelseledamot acid, arylsulfonate acid, sulfopropyl(meth)acrylate, (meth)acryloyldimethyltaurate acid, acrylamidophenylboronic acid and other monomers having a sulfonic acid fragment; and vinylpyridine, vinylpyridine, vinylpyridine, vinylpyrrole, vinylimidazole, vinylacetal, vinylmation and other monomers containing a vinyl group. Among those preferred vinyl ester or vinylamide, and as a vinyl ether complex is the preferred vinyl acetate, whereas as vinylamide preferred N-vinyl-2-pyrrolidone. Can be used one of these monomers (the third is nomernye component) or can be applied two or more in combination.

When curable acrylic pressure adhesive means is a copolymer Olkiluoto complex ester of (meth)acrylic acid (first monomer component) and the vinyl monomer having a functional group capable of participating in a crosslinking reaction (second monomer component), an ester of (meth)acrylic acid and a vinyl monomer having a functional group capable of participating in crosslinking reaction, mixed and subjected to copolymerization preferably in a weight ratio of from 99 to 85 parts of ester (meth)acrylic acid in an amount from 1 to 15 parts vinyl monomer having a functional group capable of to participate in the crosslinking reaction, and more preferably in a weight ratio of from 99 to 90 parts by the number from 1 to 10 parts.

In addition, when the curable acrylic pressure adhesive means is a copolymer Olkiluoto complex ester of (meth)acrylic acid (first monomer component), the vinyl monomer having a functional group capable of participating in a crosslinking reaction (second monomer component), and another monomer (third monomer component), alkilany an ester of (meth)acrylic acid, vinyl monomer having a functional group capable of participating in a crosslinking reaction, and the other monomial is mixed and subjected to copolymerization preferably in a weight ratio of from 40 to 94 parts Olkiluoto of ester (meth)acrylic acid in an amount from 1 to 15 parts vinyl monomer, having a functional group capable of participating in a crosslinking reaction, and from 5 to 50 parts of another monomer, and more preferably in a weight ratio of from 50 to 89 parts by the number from 1 to 10 parts, and from 10 to 40 parts, respectively.

While there are no specific restrictions in terms of the polymerization reaction in such a way, how it is conducted in a known manner, as an example of such, to the aforementioned monomers add the polymerization initiator (such as benzoyl peroxide, azobisisobutyronitrile or the like), followed by reaction for 5 to 48 hours at a temperature of from 50 to 70°C. in a solvent (such as ethyl acetate).

Particularly preferred examples of the curable acrylic pressure adhesive means in the present invention include a copolymer of 2-ethylhexanol of ester of acrylic acid, acrylic acid and N-vinyl-2-pyrrolidone, copolymer of 2-ethylhexanol of ester of acrylic acid, 2-hydroxyethylamide of ester of acrylic acid and vinyl acetate, and copolymer of 2-ethylhexanol of ester of acrylic acid and acrylic acid, and the like, while a more preferred example is a copolymer of 2-ethylhexanol of ester of acrylic acid, acrylic acid and N-vinyl-2-pyrrolidone.

In addition, despite the change of sotwesoora, the glass transition temperature curable acrylic pressure adhesive means in the present invention is usually preferably from -100 to -10°C., and more preferably from -90 to -20°C., from the viewpoint of adhesiveness of the adhesive composition.

In the adhesive compositions according to the present invention in the adhesive layer by pressing the adhesive means may be included liquid component for providing a soft layer of adhesive with pressure adhesive means and reduce the pain sensation and irritation of the skin resulting from sticking to the skin when the adhesive composition is separated from the skin. The organic liquid component is preferred from the viewpoint of compatibility with the adhesive layer under pressure adhesive means. In the adhesive compositions according to the present invention contains an organic liquid component, there is a possibility of reducing the stability of donepezil due to chemical reactions with donepezil and the like, depending on the type of organic liquid component. Thus, the present invention is mainly in the form of an adhesive composition containing an organic liquid component, is able to inhibit the decrease in stability.

Although organic liquid component can be is used without any specific limitation as long as as far as it is liquid at room temperature, exhibits a plasticizing effect and is compatible with pressure-sensitive polymer adhesives, curable components under pressure adhesive agent, it is preferable that improves the characteristics of the percutaneous absorption and stability donepezil during storage. In addition, the organic liquid component can also be added to further increase the solubility of donepezil in curing under pressure adhesive agent and the like. Examples of such organic liquid components include alkalemia esters of aliphatic acids such as esters of lower monohydroxy alcohols having from 1 to 4 carbon atoms, and saturated or unsaturated aliphatic acids having from 12 to 16 carbon atoms); saturated or unsaturated aliphatic acid having 8 to 10 carbon atoms such as Caprylic acid (octanoic acid, C8), pelargonia acid (novanova acid, C9), capric acid (cekanova acid, 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, Dimity decylsulfate, decelerated, dimethylsulfoxide, dimethylformamide, dimethylacetamide, dimethylacrylamide, dodecylmercaptan, isosorbid, alerby alcohol and other organic solvents; liquid surfactants; diisopropylamide, esters of phthalic acid, diethylbenzene and other plasticizers; and liquid paraffin and other hydrocarbons. In addition, other examples include ethoxylated stearyl alcohol, glycerol esters of (those that are liquid at room temperature), attributelist, N-organic, etiloleat, oleic acid, diisopropylamide, octylpyrimidine, 1,3-propandiol and glycerin. Among them from the viewpoint of stability of the composition and the like are preferable alkilany esters of aliphatic acids, saturated aliphatic acid, a hydrocarbon or organic solvent, and preferable alkilany ester of aliphatic acid. Can be used one of these liquid organic components separately, or may be used two or more in combination.

In addition, in the case of the use of the curable acrylic pressure adhesive means for attaching with pressure adhesive means, the organic liquid component preferably represents alkilany complex is the ester of aliphatic acid for compatibility reasons and the like with curable acrylic pressure adhesive means, and more preferred is an ester of a lower monohydroxy alcohol having from 1 to 4 carbon atoms, and saturated or unsaturated aliphatic acid having 12 to 16 carbon atoms. Here is a saturated or unsaturated aliphatic acid having 12 to 16 carbon atoms, preferably represents a saturated aliphatic acid, whereas the lower monohydroxy alcohol having from 1 to 4 carbon atoms, may be linear or branched. Preferred examples of aliphatic acids having from 12 to 16 carbon atoms include lauric acid (C12), myristic acid (C14) and palmitic acid (C16), and the like, while preferred examples of the lower monohydroxy alcohols having from 1 to 4 carbon atoms include isopropyl alcohol, ethyl alcohol, methyl alcohol and propyl alcohol, and the like. Specific examples of particularly preferred alilovic esters of aliphatic acids include isopropylmyristate, tillaart and isopropyl, and the like.

Further, in the case of the use Olkiluoto of ester of aliphatic acid, aliphatic acid having 8 to 10 carbon atoms, and/or glycerin can be used in combination with alkilany complex ester of aliphatic acid, from the viewpoint of improving x is the new percutaneous absorption of donepezil.

The contents mixed with the organic liquid component in the present invention preferably ranges from 10 to 160 parts by weight, and more preferably from 40 to 150 parts by weight, per 100 parts by weight of curing under pressure adhesive means. If the content is less than 10 parts by weight, an appropriate enabling softness or the effect of reducing skin irritation may not be obtained due to insufficient plastifitsirovanie layer adhesive with pressure adhesive means, whereas if the content exceeds 160 parts by weight of the organic liquid component may not be maintained in the curing under pressure adhesive means even cohesive forces in adhesive with pressure adhesive means, thereby causing weakening of the adhesion forces due to bleed on the surface of the adhesive layer under pressure adhesive means and increase the possibility of exfoliation of the composition from the skin surface during use.

In the adhesive compositions according to the present invention, the adhesive layer by pressing the adhesive means may be subjected to crosslinking, for example, in a known manner by chemical crosslinking (using a cross-linking reagent, and the like) or by way of physical crosslinking (exposure region is to increase UV light or gamma rays (γ), or, alternatively, an electron beam, and the like), as described previously, the fusion process may be such as is usually used in the field of technical applications. In the adhesive compositions according to the present invention the stability of donepezil may be reduced (and it may increase the number of related compounds formed during the manufacture or storage of the composition, depending on the used method of chemical or physical crosslinking. Thus, the present invention is implemented particularly mainly in the adhesive composition, in which the layer of adhesive with pressure adhesive means is sewn. Next, the method of chemical crosslinking using a crosslinking reagent preferred reasons, less likely to have an adverse impact on donepezil.

In case of carrying out the process of chemical crosslinking using a crosslinking reagent no specific restrictions on cross-linking reagent such as education crosslinking ligaments using a cross-linking reagent is not inhibited in the presence of donepezil, and examples include peroxides such as benzoyl peroxide (VRO), and the like), metal oxides (such as metasilicate-magnesium aluminate, and the like), a polyfunctional isocyanate is soedineniya, ORGANOMETALLIC compound (such as alanine zirconium, alanine zinc, zinc acetate, glycine, ammonium compounds of zinc or titanium), metal alcoholate such as tetraethylsilane, tetraisopalmitate, isopropyl aluminum or second-butyrate aluminum), and chelate metal compounds (such as dipropoxy-bis(acetylacetonate) titanium, tetraethyleneglycol titanium, isopropyl aluminum, ethylacetoacetate of diisopropylate aluminum, Tris(ethylacetoacetate) aluminum or Tris(acetylacetonate) aluminum). Among those preferred peroxide, a metal oxide, an ORGANOMETALLIC compound, a metal alcoholate or a chelate compound of the metal, and a metal alcoholate or a chelate compound of the metal is more preferable from the point of view of efficiency of formation of crosslinks in the presence of donepezil, while the chelate compound of the metal is most preferably for reasons of ease of formation of cross-linked structures with the proper density of the stitching. In addition, among the compounds of the metals are particularly preferred ethylacetoacetate of diisopropylate aluminum. Can be used one of these cross-linking reagents, or may be used two or more in combination.

Despite the variation in the nature of a cross-linking reagent and cured under pressure adhesive means, the content of remeshing cross-linking reagent is typically from 0.1 to 0.6 parts by weight, and preferably from 0.15 to 0.5 parts by weight, per 100 parts by weight of curing under pressure adhesive means. If the content is less than 0.1 part by weight, the number of points stitching is too small to give adequate cohesive ability of the adhesive layer under pressure adhesive means that is the result of the danger of leaving residues on the skin and severe irritation such due to cohesive fracture during exfoliation, whereas if the content exceeds 0.6 part by weight, despite a high cohesive ability, there are situations in which it is impossible should receive adhesion. In addition, there is also the risk of skin irritation due to residual unreacted cross-linking reagent.

The procedure of chemical crosslinking can be carried out, for example, by adding a cross-linking reagent with subsequent holding phase, consisting of heating and keeping at the reaction temperature stitching or above it, or, in other words, the stage of curing. The temperature of heating in this process is chosen according to the type of cross-linking reagent, preferably from 60 to 90°C., and more preferably from 60 to 80°C. the Duration of heating is preferably varies from 12 to 96 hours, and more preferably at up to 72 hours.

In the adhesive compositions according to the present invention in the layer of adhesive with pressure adhesive means along with donepezil may contain chloride of the metal. The presence of metal chloride in the adhesive layer under pressure adhesive means reduces the cohesive ability of the adhesive layer under pressure adhesive means and the adhesive composition adhered to the human skin, and makes it less likely cohesive failure, which can occur when a layer of adhesive with pressure adhesive means separate.

In respect of the chloride of the metal is no particular limitation, and examples thereof include alkali metal chloride, such as sodium or potassium; chloride of the alkali earth metal such as calcium or magnesium; aluminum chloride, chloride of divalent tin and ferric chloride. From the viewpoint of excellent stability and ability to inhibit the reduction of the cohesive ability of the adhesive layer under pressure adhesive means, preferably sodium chloride, calcium chloride, aluminum chloride, ferrous chloride tin or ferric chloride, the preferred sodium chloride or calcium chloride, and particularly preferred sodium chloride. Any of those can be used for separate the spine, or two or more may be used in combination. The contents mixed with chloride of the metal preferably ranges from 0.1 to 20 parts by weight, more preferably from 1 to 15 parts by weight, and most preferably from 3 to 10 parts by weight, per 100 parts by weight of curing under pressure adhesive means. If the content is less than 0.1 part by weight, the effect of inhibiting the reduction of the cohesive ability of the adhesive layer under pressure adhesive means may be insufficient, while, on the other hand, if the content exceeds 20 parts by weight, although there seems to be inhibitory effect, the appearance of the composition may be deteriorated due to uneven dispersion of metal chloride in cured under pressure adhesive means (pressure-sensitive polymer adhesive).

In the present invention, the metal chloride may be obtained by neutralization of the hydrochloride donepezil inorganic base containing the metal in the process of forming the adhesive layer by pressing the adhesive means. Examples of such inorganic bases containing metals include sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and the other inorganic bases, alkali metal or alkaline earth metal, the hydroxide of an alkali metal or alkaline earth metal is preferable from the viewpoint of a lower probability of formation of by-products, the preferred sodium hydroxide, calcium hydroxide and magnesium hydroxide, and particularly preferred sodium hydroxide.

In the adhesive compositions according to the present invention, the thickness of the layer of adhesive with pressure adhesive means preferably ranges from 20 to 300 μm, more preferably from 30 to 300 μm, and most preferably from 50 to 300 μm. If the thickness of the adhesive layer under pressure adhesive means is less than 20 μm, there is a danger that it would be difficult to get the proper adhesive force or the content of an effective amount of donepezil, whereas if the thickness exceeds 300 μm, there is a risk of difficulties in the coating.

The adhesive composition according to the present invention has a substrate and a layer of adhesive with pressure adhesive means and preferably is equipped remove the release liner. Namely, the adhesive composition according to the present invention has a structure in which the above-described adhesive layer with pressure adhesive means applied to at least one side of the substrate, and the adhesion of the surface layer prikleivayas is gosia with pressure adhesive means (surface, opposite the side on which the adhesive layer under pressure adhesive means facing the substrate) is preferably protected by being covered with a release strip to be removed immediately before use. In addition, the adhesive composition according to the present invention can also be in the form of a roll without the use of removable adhesive strip, with the application on the reverse side of the substrate surface such cover means, as the silicone polymer “Fluorine” (FEP) or wax.

Although the substrate has no particular restrictions, such preferred, in which the share of donepezil in the adhesive layer by pressing the adhesive means is not reduced due to the loss on the reverse side of the substrate due to the penetration through it (namely, a material impervious to donepezil). And, as will be described below, in the case of aspect, in which the layer of adhesive with pressure adhesive means contains an organic liquid component, the preferred substrate, in which the proportions of donepezil and organic liquid component is not reduced due to the loss on the reverse side of the substrate due to the penetration through it (namely, a material that is impermeable to organic liquid component and donepezil).

Specific examples include complex polyester (such to the to the polyethylene terephthalate (PET)), nylon, polyvinyl chloride, polyethylene, polypropylene, ethylene-vinyl acetate copolymer, polytetrafluoroethylene, ionomer polymers and other single-layer film, a metal foil and a multilayer film obtained by laminating two or more of such films. Among them, preferred is such a substrate, in which a multilayer film obtained by laminating non-porous film consisting of one of the above materials with a porous film as described below, in order to improve adhesiveness (adhesion) substrate with a layer of adhesive with pressure adhesive means, and the adhesive layer under pressure adhesive means is formed on the side of the porous film.

In respect of the porous film, there are no specific limitations to the same extent as it improves adhesion characteristics with a layer of adhesive with pressure adhesive means, and examples include paper, textile fabric, non-woven materials (such as a complex polyester (including non-woven materials made of polyethylene terephthalate (PET)), and the film obtained by mechanical punching above films (such as the complex polyester, nylon, polyvinylidenechloride film “SARAN” (product name), polyethylene, polypropylene, ethylene-vinyl acetate copolymer, polyvinyl chloride, ethylene-this is locality copolymer, polytetrafluoroethylene, metal foil, polyethylene terephthalate and other single-layer film, and a multilayer film obtained by laminating one or two or more such films), while from the point of view of flexibility of the substrate is preferable paper, textile fabrics and non-woven materials (such as non-woven material of the complex polyester or non-woven material made of polyethylene terephthalate). In terms of improving friction characteristics and flexibility of the adhesive layer under pressure adhesive means, the thickness of the porous film usually ranges from 10 to 500 μm, and in the case of a thin adhesive composition, such as a bandage or adhesive tape, the thickness is usually from about 1 to 200 microns. In the case of textile fabrics or nonwovens basic weight preferably ranges from 5 to 30 g/m2in terms of improved traction characteristics.

There are no specific limitations to the thickness of the substrate for the adhesive compositions according to the present invention, and preferably it ranges from 2 to 200 μm, and more preferably from 10 to 50 μm. If the thickness of the substrate less than 2 μm, there are problems in terms of ease of handling, such as characteristics of the supporting structure, whereas if the thickness exceeds 200 μm, the substrate may create discomfort (rigidity), and compatibility with the skin is hudaida.

Regarding remove adhesive strip no specific limitation, and can be used known to remove adhesive strip. Specific examples of the removed adhesive strip include remove adhesive strip, in which on the substrate surface remove adhesive strip formed anti-adhesive layer, composed of anti-adhesive agent, a polymer film, which itself has a good anti-adhesion properties, and remove the adhesive strip with the design, in which the surface of the base remove adhesive strip applied anti-adhesive layer consisting of a polymeric film material with good anti-adhesive properties. Anti-adhesive surface remove adhesive strip may be only on one side of the base or on both sides.

There are no specific restrictions on anti-adhesive means to remove this anti-adhesive strip, examples of which include long-chain-containing alkyl groups of the polymers, silicone polymers (silicone anti-adhesive means), polymers “Fluorine” (fluorenone anti-adhesive means) and other anti-adhesive means. Examples of bases for exhaust gaskets include polyethylene terephthalate (PET) film, polyimide p. the evaluation, polypropylene film, polyethylene film, polycarbonate film, a film of a complex of polyester (other than PET) or other polymeric film, metallized polymer films obtained by deposition of metal on one of these films; Japanese paper, plain paper, Kraft paper, glassine, printing paper and other paper; non-woven materials, fabrics or other fibrous materials; and metal foil.

In addition, examples of polymer films, which themselves have a good anti-adhesive properties, include polyethylene such as low density polyethylene or linear low density polyethylene), polypropylene, ethylene-propylene copolymer and other ethylene-α-olefin copolymers (block copolymers or random copolymers), and polyolefin film obtained from polyolefin polymers, consisting of mixtures thereof, and Teflon, a registered trademark) film.

Next, the anti-adhesive layer formed on the surface of the above-mentioned bases remove adhesive strip may be formed by laminating or coating material of the above-mentioned polymer films with good anti-adhesive properties on the above basis remove adhesive strip.

There are no specific limitations to consider is nio thickness (total thickness) remove adhesive strip, and it is usually 200 μm or less, and preferably from 25 to 100 microns.

In the present invention, although the method of producing the adhesive composition has no particular limitation, in one embodiment, such an adhesive composition according to the present invention is manufactured by forming the film from a mixture containing at least a curing under pressure adhesive means, donepezil and the above-mentioned two kinds of additives, with the formation of the adhesive layer by pressing the adhesive agent containing donepezil. Namely, the present invention also relates to a method for producing an adhesive composition containing donepezil, which comprises forming the adhesive layer by pressing the adhesive agent containing donepezil, at least on one side of the substrate, by forming the film from a mixture containing curable pressure adhesive means, donepezil and above the stabilizer. In addition, the present invention relates to a method of stabilizing donepezil in the adhesive composition, which includes the introduction of the above-mentioned two kinds of additives together with donepezil in the presence of curing under pressure adhesive means. Moreover, the present invention also relates to a method for suppressing coloring containing donepezil and gasiunas composition, which includes the introduction of the above-mentioned two kinds of additives together with donepezil in the presence of curing under pressure adhesive means.

In this embodiment, since the above-mentioned two kinds of additives mixed with donepezil in the mixture for forming the adhesive layer by pressing the adhesive means, in addition to the suppression of coloring containing donepezil adhesive composition, donepezil stable after preparation of the mixture for forming the adhesive layer by pressing the adhesive means, and thereby the formation of related compounds can be properly ingibirovalo.

A specific example of the method consists in dissolving or dispersing curable pressure adhesive means, donepezil, the above-mentioned two kinds of additives and stabilizer, and the like in a solvent, and mixing, coating the resulting solution or dispersion of at least one side of the substrate, and drying and deposition in the form of a film for forming the adhesive layer by pressing the adhesive means on the surface of the substrate, and then applying the removed adhesive strip. Alternatively, for example, the above-mentioned solution or dispersion can be applied at least on one side of the protective antiad esional remove strip and then dried and precipitated in the form of a film with the formation of the adhesive layer under pressure adhesive means on the surface of the removed adhesive strip, with the subsequent bonding of the substrate to the layer of adhesive with pressure adhesive means for receiving the adhesive composition.

Examples of the solvent for dissolving and/or dispersing curable pressure adhesive means and the like include ethyl acetate, toluene, hexane, 2-propanol, methanol, ethanol and water. In addition, they can be used for adjusting viscosity after addition of the crosslinking reagent.

Further, if necessary, crosslinking adhesive layer with pressure adhesive means of a crosslinking reagent is preferably added to the above solution or dispersion in the process of conducting chemical crosslinking. In addition, if necessary, crosslinking adhesive layer with pressure adhesive means, the adhesive layer by pressing the adhesive means is preferably able to withstand (the procedure of aging (stage aging)to promote crosslinking in the adhesive layer by pressing the adhesive agent after the formation of a film. The procedure of aging (stage aging) is usually carried out after coating from a solution or dispersion and drying with formation of a film after forming the adhesive layer by pressing the adhesive means) the abandonment of the obtained adhesive layer in which allivane adhesive means to stand for from about 12 to 96 hours, preferably from about 24 to 72 hours), at the same time with heating at a temperature of from 60 to 90°C., preferably from 60 to 80°C). During this time, donepezil may be stabilized by the presence of the stabilizer, thereby inhibiting the formation of related compounds.

In the form of adhesive compositions according to the present invention has no specific limitation, and it may be in the form of a tape, sheet, matrix, reserver, films with controlled-release and the like. The stabilizing effect according to the present invention is advantageous for tapes and sheets, since they are sensitive to the effects of environmental conditions, and in particular oxygen.

Despite variations in the types and content used curing under pressure adhesive means and an organic liquid component, and the patient's age, body weight, symptoms and the like, dispensing adhesive composition according to the present invention preferably is such that, in the case of an adult patient, the adhesive composition comprising from 2 to 150 mg of donepezil or donepezil hydrochloride, usually in the form of application to the skin area from 5 to 120 cm2for a time from about 1 to 7 days.

[Example]

Below is a more detailed explanation of the present invention with OSU examples of such. Unless otherwise specified, "parts" in the description means "weight part".

Examples 1-4 and Comparative Examples 1 and 2

In the atmosphere of inert gas mixture of 75 parts of 2-ethylhexyl acrylate, 22 parts of N-vinyl-2-pyrrolidone, 3 parts of acrylic acid and 0.2 part of azobisisobutyronitrile was subjected to polymerization in solution in ethyl acetate at a temperature of 60°C to obtain an ethyl acetate solution is cured under pressure adhesive means And (solids cured under pressure adhesive means: 28%).

Then the solutions of coatings that contain additives listed in Table 2 and Table 3, were obtained by mixing the components listed below in Table 1, and adjusting the viscosity with ethyl acetate. They were applied as coatings to remove adhesive strip made of polyethylene terephthalate (PET) to a thickness in the dried state, part 60 μm, was dried and was eliminirovali application on the substrate made of polyethylene terephthalate (PET), with the formation of the adhesive compositions, followed by curing for 48 hours at 70°C, to obtain sustained adhesive compositions of Examples 1-4 and Comparative Examples 1 and 2.

Table 1
Curing under pressure glue is the first tool 40 pieces
Isopropylmyristate50 pieces
Hydrochloride donepezil8,3 part
Sodium hydroxide0.8 part
Ethylacetoacetate of diisopropylate aluminum0.2 parts
SupplementsAs shown in Table 2 or Table 3

Control Example 1

Sustained the adhesive composition (placebo-the composition of Control Example 1 was obtained by treatment in the same manner as in Example 1 with the exception that does not have entangled hydrochloride donepezil and two kinds of additives.

Control Example 2

Sustained the adhesive composition (control the composition of Control Example 2 was obtained by treatment in the same manner as in Example 1 with the exception that does not have entangled two types of additives.

(Measurement Staining)

Were measured color coordinates (L*,a*,b*)of the color system on CIE1976 (L*,a*,b*) (color system, the L-star, a-star, b-asterisk", Japanese Industrial Standard JIS Z 8729), and color differences (ΔE*ab1) between the color coordinates (L*1,a*1,b*1) adhesive compositions of Examples 1-4 and Comparative who's Examples 1 and 2, along with the adhesive composition of Control Example 2 (control track), and the coordinate of the color (L*s,a*s,b*s) adhesive composition of Control Example 1 (placebo-song) as reference points were calculated according to the following formula 1. The results are shown in Table 2.

ΔE*ab1=[(L*1-L*s)2+ (a*1-a*s)2+ (b*1-b*s)2]1/2(Formula 1)

Table 2
Adulteration of donepezil hydrochlorideThe content of matabi sulfite salt metalThe content of L(+)-ascorbic acidCoordinate color after conditioning for 48 hours at a temperature of 70°(L*,a*,b*)The color difference from placebo composition of Control Example 1 (ΔE*ab1)
L*a*b*
Control Example 1---96,4-5,58,2
Control Example 2O--95,4-6,111,23,2-
Example 1O0,50 part (0,50%)0,02 part (0,02%)96,3-5,89,81,6
Example 2O0,50 part (0,50%)0.05 part (0,05%)96,5-5,79,51,3
Example 3O0,50 part (0,50%)0,10 part (0,10%)96,5-6,110,32,2
Example 4O0,50 part (0,50%) 0,50 part (0,50%)a 94.2-5,819,111,1O
Comparative Example 1O-1.00 part (1,00%)89,7-4,026,419,5×
Comparative Example 2O1.00 part (1,00%)-to 91.6-5,821,714,3×

(Measurement of share related compounds)

The adhesive compositions of Examples 1-4, Comparative Examples 1 and 2 and reference Example 2 were extracted with methanol, and the extracts were analyzed using high performance liquid chromatography (HPLC, HPLC) under the following conditions.

(Conditions of high performance liquid chromatography (HPLC))

Column HPLC-GC: Inertsil (registered trademark) ODS-2 (with an inner diameter of 4.6 mm × 15 cm length, the carrier 5 μm) GL Science

The column temperature: 35°C

Podvizhnaia: an aqueous solution of 1-decanesulfonate sodium/acetonitrile/70%perchloric acid = 650/350/1 (volume ratio)

The concentration of 1-decanesulfonate sodium: 10 mm, based on all the sliding phase

Flow rate: 1.4 ml/min

Detection: UV detector (UV) (wavelength of 271 nm)

Retention time: Donepezil = 11.0 minutes, kindred connection 1 = 12.8 minutes, the related compound 2 = 3.9 minutes.

The ratio of peak areas in the HPLC chromatograms for related donepezil compounds 1 and 2 and all related compounds in General to the peak area of donepezil on the HPLC chromatograms in layers glued with pressure adhesive means aged adhesive compositions of Examples 1-4 and Comparative Examples 1 and 2 and reference Example 2 are shown in Table 3 in the form of shares related to donepezil connection 1, the proportion related to donepezil compounds 2 and share all related donepezil compounds, respectively.

Table 3
Metabisulfite salt metalL(+)-Ascorbic acidThe share of related compounds 1The share of related compounds 2The percentage of all related compounds in General
Control Example 2 --1,2%0,2%1,9%
Example 10,50 part (0,50%)0,02 part (0,02%)the concentration is0,0%0,4%
Example 20,50 part (0,50%)0.05 part (0,05%)the concentration is0,0%0,2%
Example 30,50 part (0,50%)0,10 part (0,10%)the concentration is0,0%0,2%
Example 40,50 part (0,50%)0,50 part (0,50%)the concentration is0,0%0,2%
Comparative Example 1-1.00 part (1,00%)0,5%0,0%0,6%
Comparative Example 21.00 part (1,00%) -the concentration is1,0%3,6%
Reference Example 3The arithmetic mean value of Comparative Example 1 and Comparative Example 20,25%0,5%2,1%
Note: the "concentration" in the table means "not defined"

As is clear from Table 2, the adhesive compositions of Examples 1-4 containing derivatives of ascorbic acid and metabisulfite salt of the metal, showed lower values of the color differences (ΔE*ab1) with placebo composition of Control Example 1 than those for Comparative Examples 1 and 2. Based on this it is obvious that the painting contains donepezil adhesive compositions was suppressed, and the appearance, natural color was realized by mixing the two compounds as additives.

Moreover, as is clear from comparison of comparative examples, reference examples and examples, the adhesive compositions of Examples 1-4 unexpectedly showed smaller values of the color differences (ΔE*ab1) with placebo composition of Control Example 1 than the control composition of Control Example 2, despite the content in t the signed derivative of ascorbic acid and metabisulfites metal salt. Based on this, the adhesive compositions of Examples 1-4 were confirmed as providing natural colouring containing donepezil adhesive compositions.

In particular, as a result of contact from 0.04 to 0.2 parts by weight derivatives of ascorbic acid (ascorbic acid, metal salts or its esters) to 1.0 part by weight metabisulfite metal salt of the adhesive compositions of Examples 1-3 showed very small values of the color differences (ΔE*ab1) with placebo composition of Control Example 1, thereby confirming the further suppression of coloring containing donepezil adhesive compositions and implementation of appearance with extremely estestvennym color.

In addition, as is clear from Table 3, the adhesive compositions of Examples 1-4, in which the mixed derivatives of ascorbic acid and metabisulfite salt of the metal, was confirmed by the reduction of the number of generated related compounds 1, formed related compounds 2 and all produced similar compounds in General, in comparison with Comparative Example 1, Comparative Example 2 and reference Example 2. Moreover, the adhesive kompozizii Examples 1-4 was also confirmed by a synergistic reduction in the number of generated related compounds 1, formed kindred is about connections 2 and all produced similar compounds in General, on the basis of comparison with reference Example 3 (the average of the values of Comparative Example 1 and Comparative Example 2).

According to the present invention, since the staining containing donepezil adhesive composition can be suppressed to ensure the appearance with a natural color, and because the amount of concrete produced related to donepezil compounds in the composition can be reliably reduced, the present invention can be widely and effectively used as drugs against dementia in Alzheimer's disease, drugs against dementia with cerebrovascular diseases, for the prevention Migranian headaches and other options for pharmaceutical use in parenteral administration, particularly in percutaneous introduction.

1. The method of suppressing staining adhesive composition containing a substrate and a layer of adhesive with pressure adhesive means, where the adhesive layer by pressing the adhesive has cured under pressure adhesive means and donepezil, and the method includes:
stage injection of ascorbic acid, metal salts or its complex ether and metabisulfites metal salt in the adhesive layer under pressure adhesive means, including the non mixing of from 0.02 to 1.5 parts by weight of ascorbic acid, metal salt or its complex with ether and 1.0 part by weight metabisulfite metal salt.

2. The method according to claim 1, which includes:
the stage of preparation of the mixture comprising curing under pressure adhesive means, donepezil, ascorbic acid, metal salt or its ester and metabisulfite salt of the metal; and
the stage of forming the film layer adhesive with pressure adhesive means applying the mixture on the surface of the substrate.

3. The method of suppressing staining adhesive composition having a substrate and a layer of adhesive with pressure adhesive means, reducing the number of generated related to donepezil compounds, where the adhesive layer by pressing the adhesive has cured under pressure adhesive means and donepezil, and the method includes:
stage injection of ascorbic acid, metal salts or its complex ether and metabisulfites metal salt in the adhesive layer under pressure adhesive means, comprising mixing from 0.02 to 1.5 parts by weight of ascorbic acid, metal salts or its complex with ether and 1.0 part by weight metabisulfite metal salt.

4. The method according to claim 3, which includes:
the stage of preparation of the mixture comprising curing under pressure adhesive means, donepezil, ascorbic is islote, metal salt or its ester and metabisulfite salt of the metal; and
the stage of forming the film layer adhesive with pressure adhesive means applying the mixture on the surface of the substrate.



 

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31 cl, 6 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula 1, or their pharmaceutically acceptable salts showing the properties of incretin secretagogues, preferentially the properties of a bile acid receptor TGR5 agonist. The compounds are applicable for treating metabolic diseases associated with glucose metabolism, such as diabetes, obesity, metabolic syndrome, etc. In formula 1 R1, R2 and R3 independently represent a cyclic system substitute specified in: hydrogen, C1-C3alkyl, halogen, a trifluoromethyl group, C1-C3alkoxy, a cyano group, a trifluoromethoxy group; an amino group substituted by C1-C3alkyl; or two radicals R3, found at carbon neighbours in a benzene ring, together with the benzene ring bound therewith form 3,4-methylene dioxyphenyl; R4 represents hydrogen, C1-C5alkyl, a carboxyl group, C1-C3alkoxycarbonyl or an amide group CONHR5; R5 is an optionally substituted by C1-C3alkyl, C5-C6cycloalkyl optionally substituted by phenyl, benzyl, pyridyl; X and Y represent two hydrogen atoms or an oxygen atom, provided Y=O, then X=2H, provided Y=2H, then X=O or X=Y=2H; the sign (N) shows the possibility of bioisosteric substitution of the benzene ring by the pyridine, pyrimidine, pyridazine, triazine or pyrazine ones.

EFFECT: preparing the pharmaceutical composition and the combined drugs with the use of the compounds of formula 1 or the based pharmaceutical composition and a protein kinase DPP-IV inhibitor specified in Vildagliptin or Sitagliptin, and/or an endogenous bile acid or mied bile acid secretagogues.

53 cl, 7 dwg, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I, as well as to their physiologically acceptable salts wherein: X means NH; R1 means (C1-C6)-alkyl; R2 means OH; R2' means H; R5' means (C1-C6)-alkylene-O-S(O)2-R6; R3, R3', R4, R4' and R5 independently mean H, OH, (C1-C6)-alkylene-O-S(O)p-R6, O-(CH2)m-phenyl; at least one of the radicals R3, R3', R4, R4' and R5 has the value -O-(CH2)m-phenyl; R6 means OH; m=1; p=2.

EFFECT: compounds can find application in medicine, eg as lipid-lowering agents.

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new imidazole derivatives of formula I wherein R1 represents a hydrogen atom or C1-7alkyl; R2 represents C1-7alkyl; R3 represents C1-7alkyl, C1-7alkoxy, phenyloxy, benzyloxy, a halogen atom or C1-7alkyl substituted by a halogen atom; R4 represents a hydrogen atom or C1-7alkyl; X represents -CH2-, -CHR2 - or -O; Y represents -CH2-, -CH2CH2- or a bond; provided X represents -O-, Y represents -CH2-; Z represents -CH2- or -CHR2-; provided R2 is found twice, simultaneously for X and Z which are CHR2 , then R2 can be identical alkyls or different; n has the value 0, 1 or 2; provided n has the value 2, R3 can be identical or different; and its pharmaceutically acceptable acid addition salts, except for the following compounds: 1-(1H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinoline and 1-(3H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indole. Also, the invention refers to a method for preparing the compounds of formula I, to a drug based on the compound of formula I and applying the compound of formula I in preparing the drug.

EFFECT: there are prepared new imidazole derivatives effective in treating such pathological conditions, as bipolar disorder, stress-induced disorder, psychotic disorders, schizophrenia, neurological conditions, Parkinson's disease, neurodegenerative disorders, Alzheimer's disease.

13 cl, 61 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new benzimidazole derivatives of general formula (I) or to its pharmacologically acceptable salts wherein R1 represents a C6-aryl group which can be substituted by 1-3 groups optionally specified in a group of substitutes (a), or a heterocyclic group which represents pyridyl, dihydrobenzofuranyl, 1,3-benzodioxolyl, tetrahydropyranyl, tetrahydrofuranyl which can be substituted by 1-3 groups optionally specified in a group of substitutes (a), R2 represents a C1-C6 alkyl group, R3 represents a C6-aryl group which can be substituted by 1-2 groups optionally specified in a group of substitutes (a), Q represents a group represented by formula =CH-, or a nitrogen atom and a group of substitutes (a) represents a group consisting of a halogen atom, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a carboxyl group, a C2-C7 alkylcarbonyl group, a C2-C7 alkoxycarbonyl group, a C1-C6 alkoxy group, a C1-C6 halogenated alkoxy group, an amino group, a 4-morpholinyl group and a di-C1-C6 alkyl)amino group. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I), to a PPARγ activator/modulator based on the compound of formula (I), to using the compound of formula (I), to a method of reducing blood glucose, to a method of activating PPARγ, a method of treating and/or preventing said pathological conditions.

EFFECT: there are produced new benzimidazole derivatives showing PPARγ modulatory activity.

41 cl, 2 dwg, 6 tbl, 76 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a copolymer of sodium carboxy-methylcellulose and gossypol of formula (I) and use thereof in complex therapy of patients with autistic disorders and cognitive impairments, where a:b:c=1:(3-6):(5-7), n=40-50; molecular weight of 120000-130000.

EFFECT: high efficiency of treating mental illnesses.

11 cl, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a pharmaceutical composition containing primary material in form of at least one compound selected from 5-[(1'R)-1'-[(1aS,3aS,4S,7R,7aR,7bS)-decahydro-7-hydroxy-1,1,3a,7-tetramethyl-1H-cyclopropa[A]naphthalen-4-yl]-3'-methylbutyl]-2,4,6-trihydroxy-1,3-benzene dicarboxaldehyde and 5-[(1'S)-1'-[(1aS,3aS,4S,7R,7aR,7bS)-decahydro-7-hydroxy-1,1,3a,7-tetramethyl-1H-cyclopropa[A]naphthalen-4-yl]-3'-methylbutyl]-2,4,6-trihydroxy-1,3-benzene dicarboxaldehyde, in a combination with an acceptable carrier, for treating and/or preventing disorders or pathologies which are a result of a disorder of reuptake of the following neuromediators: dopamine, serotonin and/or noradrenaline, as well as to use of at least one compound selected from 5-[(1'R)-1'-[(1aS,3aS,4S,7R,7aR,7bS)-decahydro-7-hydroxy-1,1,3a,7-tetramethyl-1H-cyclopropa[A]naphthalen-4-yl]-3'-methylbutyl]-2,4,6-trihydroxy-1,3-benzene dicarboxaldehyde and 5-[(1'S)-1'-[(1aS,3aS,4S,7R,7aR,7bS)-decahydro-7-hydroxy-1,1,3a,7-tetramethyl-1H-cyclopropa[A]naphthalen-4-yl]-3'-methylbutyl]-2,4,6-trihydroxy-1,3-benzene dicarboxaldehyde to obtain a medicinal agent.

EFFECT: improved method.

9 cl, 2 ex, 1 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: medicine.

SUBSTANCE: invention refers to medicine. What is described is a therapeutic plaster for local application of natural drugs applicable for oral administration and/or for injection, containing the following components: - a pillow made of a bearing material, at least for one natural drug either fluid, or introduced in a solution, a coating completely covering the pillow and projecting at least from two sides with a skin-adhesive layer, and at least one natural drug either fluid, or introduced in a solution either in the bearing material, or in a reservoir opening to the bearing material, and is used for stimulating or treating, particularly, in trigger and acupuncture points, as well as for meridian therapy.

EFFECT: substances inactive or low-effective percutaneously if applied in certain skin regions, particularly for a long period of time, can exhibit previously unused action ensured by slow release from the bearing material.

10 cl, 4 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and chemical-pharmaceutical industry, particularly creating an oral film drug which when taken adheres to an oral mucosa, and even if adheres is easily detached therefrom. The oral film drug has at least one agent-containing layer, and at least one surface of the oral drug has a convex portion. Said convex portion is presented in the form of at least one forms specified in cones, columns, hemispheres, truncated cones. The agent-containing layer consists of a therapeutic agent and a base.

EFFECT: preparing the oral film agent.

10 cl, 4 ex, 1 tbl, 9 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a collagenic film and a method of making said film. The film contains at least one collagenic layer. The surface of the collagenic layer is formed by a plurality of domains with predominant orientation of collagenic fibres in each domain and continuous variation of orientation of fibres from one domain to another. There are pores on the domain boundary.

EFFECT: possibility of stable formation of structures similar to natural collagen.

22 cl, 21 dwg, 13 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine. What is described is a therapeutic system for introduction of a pharmaceutically active substance, nonvolatile at least at room temperature, with a daily dose max. 30 mg, comprising a skin non-contact and active substance impenetrable external layer, an adjacent skin distant polymeric layer of polyisobutylene of the coating weight at least 80 g/m2, an adjoining skin contact adhesive polymeric layer of acrylate copolymers of the coating weight max. 50 g/m2, and also an active substance impenetrable protective layer (easily) removed from the skin contact layer.

EFFECT: transdermal therapeutic system has a high level of using the active ingredient and a higher dose accuracy.

18 cl, 2 ex

FIELD: medicine.

SUBSTANCE: present invention refers to medicine, more specifically to a gel composition for a medical material or a hygienic material which contains a liquid rubber ingredient having a functional group able to create cross linkages, in a molecule, and 90 weight parts or more and 1250 weight parts or less of an organic liquid ingredient in relation to 100 weight parts of the rubber ingredient with the gel composition being cross-linked.

EFFECT: composition for the medical material or the hygienic material contains a great amount of the organic liquid ingredient, has sufficient elasticity and can hold its shape.

7 cl, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine. What is described is an adhesive composition containing donepezil and a stabiliser. The stabiliser containing one or more compounds 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, cysteine, acetylcysteine, 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, 3-mercapto-1,2-propanediol, tocopherol acetate, rutin, quercetin, hydroquinone, metal salt of hydroxymethansulphinic acid, metabisulphite metal salts, sulphite metal salt and thiosulphate metal salts; it is added to a layer of a pressure sensitive adhesive applied on at least one side of the substrate.

EFFECT: prepared high reliable and stable adhesive composition which inhibits formation of donepezil-related compounds in the layer of the pressure sensitive adhesive.

14 cl, 4 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine. There are described Transdermal Therapeutic Systems having a silicone adhesive layer, and a method for producing and using them.

EFFECT: transdermal therapeutic systems provide achieving a certain plasma concentration.

23 cl, 3 tbl, 4 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine. What is disclosed is a dosage form containing a base and a self-adhesive layer which contains a medicinal agent and covers at least one of the base sides; wherein the base consists of a polyester film of the thickness of 0.5 to 6.0 mcm, and a polyester non-woven material directly coupled with the film. The base is coated with the self-adhesive layer either directly or through an intermediate layer from the non-woven material.

EFFECT: adhesive preparation have sufficient elasticity for the purpose of tracking of the skin shape, as well as shows low ability to irritate the skin and high stability.

7 cl, 5 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine. What is described is a film containing as a film-forming agent an alginic acid salt with monovalent cation or mixed alginic acid salts containing at least one alginic acid salt with monovalent cation with 10% aqueous solution of the film-forming agent at temperature 20°C characterised by the viscosity of 100-1000 mPa-sec in accordance with the values measured at shear velocity 20 rpm with using a Brookfield viscometre equipped with a spindle No.2, as well as a method for making such film.

EFFECT: film is applicable for active ingredient delivery in a mammal's body and fast soluble while contacting with a wet surface.

18 cl, 2 tbl, 10 ex

FIELD: agriculture.

SUBSTANCE: invention relates to means of control of zooparasites. The product contains N-arilpirazole of general formula , where R1 and R3 independently mean halogen, R2 means haloalkyl of 1-3 carbon atoms, R4 means a cyanogroup or -C(=S)NH2. The means additionally comprises an aliphatic cyclic carbonate, an aliphatic acyclic polyether which is a derivative of diols having up to 8 carbon atoms, and pharmaceutically acceptable auxiliary or supplementary materials. It is used for manufacture of a medicinal product.

EFFECT: invention enables to improve the effectiveness and safety of the means.

6 cl, 3 tbl, 5 ex

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