Percutaneously absorbable preparation

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a percutaneously absorbable layer having a base and an adhesive layer which is placed on the base and which comprises an adhesive agent and a therapeutic ingredient. The adhesive agent contains a mixture of resins containing 100 portions by weight of an acrylic copolymer (A) and 0.1 to 30 portions by weight of an acrylic copolymer (B) or 0.05 to 2 portions by weight of a low-molecular polyamine compound having at least two amino groups in one molecule and non-polymerising with a polymer or an oligomer formed. The adhesive layer additionally contains an organic acid. The acrylic copolymer (A) represents an acrylic copolymer, which contains acrylic ester of (meth)acrylic acid as a main monomer ingredient and contains 3 to 45 wt % of diacetone acrylamide as a target monomer ingredient, but free from a free carboxylic group. The acrylic copolymer (B) represents an acrylic copolymer, which contains acrylic ester of (meth)acrylic acid as a main monomer ingredient and contains a primary amino group and/or carboxyhydrazidase group on side chains, but free from a free carboxylic group.

EFFECT: reducing the aging period of the adhesive layer considerably.

7 cl, 8 tbl, 39 ex

 

The technical FIELD

The present invention relates to percutaneous absorbed the drug and more specifically relates to percutaneous absorbing the drug, which has on one surface a basis of the adhesive layer contains at least an adhesive agent, and which is used by application to the skin.

PRIOR art

Have been proposed various types of dermal absorbed drugs that enter the drug through the skin surface in a living organism, which have the form of a tape or strip, in which an adhesive layer containing a drug component formed on one surface of a nonwoven fabric or plastic film. Thus, the type of percutaneous absorbed drug, which is applied to the skin, requires properties to maintain a given level of concentration in the blood for a long time through the maintenance of a sufficient number of the medicinal component in the adhesive layer.

From this point of view were studied various types of cross-linking adhesive agent as the adhesive agent for percutaneous absorbed drug. For example, in Patent document 1 is proposed type cross-linking adhesive agent for skin, in which copolymer a, which contains a complex alkilany ester of (meth)acrylic acid as the main com is Ananta and copolymerization with diacetonitrile, and the copolymer B, which contains a complex alkilany ester of (meth)acrylic acid as a main component and contains a primary amino group and/or carboxylicacid group on side chains, mixed and sew.

Patent document 1: Published patent application of Japan No. 2005-325101.

Tasks solved with the help of inventions

Type cross-linking adhesive agent, as described in Patent document 1, is preferably used as the adhesive agent for percutaneous absorbed drug, because of the medicinal component and the like can be kept in a mesh structure formed around the adhesive agent, by stitching.

At the same time, the adhesive agent described in Patent document 1, acquires the specified mesh structure, and cohesion (strength) required for the adhesive agent for percutaneous absorbed drug, because when mixing the copolymer a and copolymer In which they are sewn to each other with increasing degree of crosslinking. As the crosslinking reaction proceeds in time, the degree of crosslinking of the adhesive agent is not sufficient, and its quality is not constant during a certain period of time after mixing of the copolymer a and copolymer Century is Thus required stage keeping percutaneous absorbed drug, ochomogo, for example, at room temperature, i.e. ageing (maturation) as long as the degree of crosslinking of the adhesive agent will not be sufficient, and as long as percutaneous absorbed drug is stable. However, aging requires several days and is one of the factors that reduce the rate of production (output) in the production of dermal absorbed drug using adhesive agent as described above. This tendency is reinforced when as a medicinal component used main drug. Thus, in particular, there was a reduction in the rate of production in the manufacture of percutaneous absorbed drug, which contains a basic drug.

The present invention was made in light of the above situation, and its objective is to offer percutaneous absorbed drug, in which an adhesive agent obtained by crosslinking one or more copolymers contained in the adhesive layer and in which the period of aging in obtaining an adhesive layer may be reduced.

The ways to solve the aforementioned problems

As a result of intensive research aimed at solving the above problems, the present invention unexpectedly discovered that p is the period of aging can be reduced, even when using the essential medicine as a medicinal component, by combining the use of organic acids, when the acrylic copolymer (A), which contains a complex alkilany ester of (meth)acrylic acid as a main monomer component and which copolymerization with diacetonitrile, and acrylic copolymer (B), which contains a complex alkilany ester of (meth)acrylic acid as a main monomer component and which contains a primary amino group and/or carboxylicacid group on side chains, mixed and stitched with each other. The authors present invention also found that the period of aging in the basic drug as a medicinal component can be reduced by sharing organic acid, when the above-mentioned acrylic copolymer (A) sew with polyamines connection, such as dehydrated adipic acid. The present invention was completed based on this study.

Namely, in the present invention is proposed (1) dermal absorbed preparation having a base and an adhesive layer which is placed on the base and which contains an adhesive agent and a medicinal component, where percutaneous absorbed drug is different in that the adhesive agents which contains a mixture of resins, containing 100 parts by weight of acrylic copolymer (A) described below, and from 0.1 to 30 parts by weight of acrylic copolymer (B) described below, or from 0.05 to 2 parts by weight polyamino connection, and that the adhesive layer further comprises an organic acid

The acrylic copolymer (A) is an acrylic copolymer that contains complex alkilany ester of (meth)acrylic acid as a main monomer component and contains from 3% to 45% by weight of diacetonitrile as an essential monomer component, but does not contain a free carboxyl group

The acrylic copolymer (B) is an acrylic copolymer that contains complex alkilany ester of (meth)acrylic acid as a main monomer component and contains a primary amino group and/or carboxylicacid group on side chains, but does not contain a free carboxyl group.

In the present invention is proposed (2) dermal absorbed preparation containing as an organic acid of at least any of lactic acid, salicylic acid, succinic acid, thioglycolic, maleic acid, malonic acid, adipic acid, benzoic acid, capric acid, sorbic acid, malic acid, citric acid, tartaric acid, palmitic is islote, fumaric acid, propionic acid, beganovi acid, myristic acid, and their hydrates.

The present invention also proposed (3) dermal absorbed the preparation described in (1) or (2) where the medicinal component is a nicotine, or lidocaine, or their salts.

In the present invention is proposed (4) dermal absorbed the drug described in (3), where the medicinal component is a nicotine or its salt.

In the present invention is proposed (5) dermal absorbed the preparation described in any of (1) to(4), where the adhesive layer further comprises an antioxidant.

In the present invention is proposed (6) dermal absorbed the drug described in (5), where the antioxidant is dibutylaminoethanol.

In the present invention is proposed (7) transdermally absorbed the preparation described in any of (1) to(6), further containing an adhesive layer, which provides the property of adhesion to the skin, or sequentially containing membrane controlled release, which controls the release of the medicinal component of the adhesive layer, and an adhesive layer, which provides the property of adhesion to the skin on the surface of the adhesive layer.

The effects of the invention

In the present invention is proposed percutaneous absorbed the drug, in what oterom adhesive agent, obtained by crosslinking one or more copolymers contained in the adhesive layer and in which the period of aging in the manufacture of the adhesive layer may be reduced.

The PREFERRED METHOD of IMPLEMENTATION of the INVENTION

The first embodiment of the percutaneous absorbed drug according to the present invention

Next will be described the first embodiment of the percutaneous absorbed drug of the present invention.

Percutaneous absorbed the drug according to the present embodiment is impregnated with the medicinal product surface-based and manufactured to the active ingredient absorbed through the skin into the body, when percutaneous absorbed drug is applied to lead impregnated drug surface in contact with the skin. Such medications may include drugs that are intended to deliver the active ingredient into the bloodstream through the skin, as well as drugs intended for local delivery of the active ingredient through the skin First classified as a "percutaneous system" in the Japanese Pharmacopoeia, while the latter are classified as "patches" in the Japanese Pharmacopoeia, and percutaneous absorbed the drug of the present invention can be any of these types.

Percutaneous absorbed the drug according to the present embodiment has the one surface of the substrate, at least an adhesive layer. In the adhesive layer add medicinal component, and the surface of the adhesive layer, which is brought into contact with the skin, corresponds to the saturated drug surface. Next will be described adhesive layer, the medicinal component and the base.

The adhesive layer

The adhesive layer is a layer that provides the property of bonding to link percutaneous absorbed with the skin. The adhesive layer contains a drug component, and the medicinal component is absorbed into the skin from the adhesive layer through the saturated drug surface. The adhesive layer contains an adhesive agent, a medicinal component, an organic acid and, optionally, other components. Among these components of the medicinal component is described below, and the adhesive agent, organic acid and other components will be discussed here.

The adhesive agent

The adhesive agent in the present embodiment comprises a mixture of resins containing 100 parts by weight of acrylic copolymer (a) and from 0.1 to 30 parts by weight of acrylic copolymer (B) described below. In a mixture of resins mesh structure can be formed by crosslinking an acrylic copolymer (a) and acrylic copolymer (B). Thus, the mesh structure is formed around the adhesive layer, and Cresco what about the absorbed drug according to the present embodiment may contain a sufficient quantity of the medicinal component and the like by holding the medicinal component and the like in the network structure. Therefore, percutaneous absorbed the drug according to the present embodiment can maintain the concentration of active ingredient in the blood at a given level for a long period of time.

The above-mentioned acrylic copolymer (a) and acrylic copolymer (B) are acrylic resin, which essentially does not contain a free carboxyl group. Thus, percutaneous absorbed the drug according to the present embodiment, even when a medicinal component contained in the adhesive layer has properties to interact and communicate with a carboxyl group, a decrease in percutaneous absorption, which is accompanied by interaction and drug binding component ingredients of the adhesive agent (acrylic copolymers), can be prevented. The phrase "essentially no free carboxyl group" means that all of the carboxyl groups converted into substituents such as ester bond in terms of design. Of them can be considered in cases where only some of the ester groups and the like are converted into a free carboxyl group by hydrolysis, and the case where the free carboxyl groups are contained as impurities derived from the starting materials.

The acrylic copolymer (A) contained in vishey the marks of a mixture of resins, is an acrylic copolymer that contains complex alkilany ester of (meth)acrylic acid as a main monomer component and from 3% to 45% by weight of diacetonitrile as an essential monomer component. The acrylic copolymer (B) contained in the above mixture of resins is also an acrylic copolymer, which contains a complex alkilany ester of (meth)acrylic acid as a main monomer component, and a primary amino group and/or carboxylicacid group on side chains. In such a mixture of resins, melcochita structure, based on the crosslinking reaction of the carbonyl group originating from diacetonitrile contained in the acrylic copolymer (A), and primary amino groups, and carboxyimide group contained in the acrylic copolymer (B) may be formed around the adhesive layer, and the medicinal component and the like can be maintained in such a mesh structure. Thus, the mixture of resins can be preferably used for the adhesive layer percutaneous absorbed drug.

An example of obtaining the acrylic copolymer (A) includes a method that allows for complex alkylamino ether, (meth)acrylic acid, the main monomer component, add diacetonitrile also Monomeric component in an amount of from 3 to 45% by weight of all monomers and the resulting mixture is subjected to radical polymerization. These monomer components can be polimerizuet according to the traditional method using a polymerization initiator such as peroxide oxidized compound or ataegina. In the polymerization of these monomers is preferable to add a suitable solvent to adjust the viscosity of the reaction solution.

As difficult alilovic esters of (meth)acrylic acid is preferably used complex alkilany ester of (meth)acrylic acid in which the alkyl group has from 1 to 12 carbon atoms. Specific examples include methyl(meth)acrylate, ethyl(meth)acrylate, propyl(meth)acrylate, butyl(meth)acrylate, 2-ethylhexyl(meth)acrylate, octyl(meth)acrylate, dodecyl(meth)acrylate and the like. These complex alkalemia esters of (meth)acrylic acid can be used individually or two or more esters can be used in combination.

In the acrylic copolymer (A) it srednedlinny molecular weight is preferably from 100,000 to 1,500,000, and it srednevekovaja molecular weight is preferably from 300,000 to 2500000.

The molecular weight of the acrylic copolymer (A) within the above range is preferred because the adhesive layer percutaneous absorbed drug demonstrates a suitable adhesion to the skin. In the above-mentioned range, the medium is Islena molecular weight acrylic copolymer (a) is more preferably from 300,000 to 1,000,000 and most preferably from 500000 to 800000. In the above range srednevekovaja molecular weight acrylic copolymer (a) is more preferably from 500,000 to 2000000, and most preferably from 1000000 to 1500000.

An example of obtaining the acrylic copolymer (B) includes a method that allows for complex alkylamino ether, (meth)acrylic acid, the main monomer component, add the monomer component for the introduction of primary amino groups and/or Monomeric component for introduction carboxyimide group in an amount of from 1% to 30% by weight of all monomers, and the resulting mixture is subjected to radical polymerization, and then the side chain derived from a monomer component for introduction carboxyimide group, in turn carboxybenzene group. Radical polymerization of the Monomeric components may be implemented in the traditional way using a polymerization initiator such as peroxide oxidized compound or ataegina. When the radical polymerization of the Monomeric components is preferable to add a suitable solvent to adjust the viscosity of the reaction solution. As difficult Olkiluoto ether (meth)acrylic acid used in the preparation of acrylic copolymer (B) may be used in the same monomer, as shown as an example in the above is Krylova copolymer (A).

In addition, the number of primary amino groups and/or carboxylicacid groups in the acrylic copolymer (b) is preferably two or more and more preferably three or more in molecular chains of the acrylic copolymer (B) to demonstrate appropriate stevenote with acrylic copolymer (A).

Moreover, it is preferable that the monomer component for the introduction of primary amino groups and/or Monomeric component for introduction carboxyimide group and the monomer complex Olkiluoto ether (meth)acrylic acid were mixed so as to obtain a molar ratio of from 1:5 to 1:100, and subjected to copolymerization.

Monomeric component for the introduction of primary amino groups in the acrylic copolymer (B) includes a compound having a vinyl group capable of polymerization with complex alkilany ether (meth)acrylic acid, and a primary amino group. Examples of such compounds include vanillin and the like.

Monomeric component for introduction carboxyimide group in the acrylic copolymer (B) includes a compound having a vinyl group capable of polymerization with complex alkilany ether (meth)acrylic acid, and ketogroup capable of interacting with a hydrazide compound. Examples of such compounds include diacetonitrile, acrolein, acetoacetanilide the acrylate and the like.

For the conversion of the side chain derived from a monomer component for introduction carboxyimide group in carboxylicacid group, the polymer obtained by the above-mentioned radical polymerization, is dissolved in a polar solvent, and the resulting solution may be subjected to interaction with dihydrazide dicarboxylic acid in the presence of an acid catalyst. Examples of dihydrazide dicarboxylic acids include dehydrated adipic acid, dihydrazide glutaric acid, dihydrazide pipelinewall acid and the like.

In the acrylic copolymer (C) srednedlinny molecular weight is preferably from 1,500 to 50,000, and its srednevekovaja molecular weight is preferably from 2,000 to 100,000. The molecular weight of the acrylic copolymer (b) which is not less than the above lower limit, is preferred because the gelation of the mixed liquid is inhibited, and covering the property becomes good when receiving adhesive layer. The molecular weight of the acrylic copolymer (b) which does not exceed the above upper limit, is preferred since it can be obtained cross-linked state with the acrylic copolymer (A). In the above range srednedlinny molecular weight acrylic copolymer (B) which leaves more preferably from 2000 to 10,000 and most preferably from 3000 to 8000. In the above range srednevekovaja molecular weight acrylic copolymer (b) is more preferably from 5,000 to 20,000 and most preferably from 8,000 to 15,000.

The adhesive layer percutaneous absorbed drug according to the present embodiment may contain an adhesive agent other than the above-mentioned mixture of resins, with the aim, for example, improving the bonding ability to the skin, and the like.

Organic acid

Next will be described an organic acid. The organic acid used in the present embodiment, is contained in the adhesive layer and acts to accelerate crosslinking acrylic copolymer (a) and acrylic copolymer (B). As described above, when two or more types of resins are mixed and stitched with the formation of the adhesive layer, the same as percutaneous absorbed drug according to the present embodiment, such an adhesive layer requires a period of aging until such time as the adhesive layer will not acquire the necessary cohesion (strength) as the reaction stitching. The authors of the present invention examined a long period of aging, especially when using essential medicine as a medicinal component, as problems and found a way that can reduce the period of aging. As a result, the authors of this izopet is of unexpectedly discovered, even when using essential medicine as a medicinal component, by further adding an organic acid to the mixture of the acrylic copolymer (a) and acrylic copolymer (B), the reaction of the crosslinking acrylic copolymer (a) and acrylic copolymer (B) is accelerated, and the period of aging can be significantly reduced. The present invention was completed based on survey data.

The organic acid is added to the mixture of the acrylic copolymer (a) and acrylic copolymer (B). An illustrative method of adding the organic acid include a method in which an acrylic copolymer (a) and acrylic copolymer (B) is dissolved in a solvent to obtain a mixed solution, and the organic acid of the medicinal component and the like, described below, optionally dissolved in a mixed solution and then applying the resulting solution onto the canvas and then the solvent contained in the mixed solution is evaporated to obtain an adhesive layer. In this case, the amount of the mixed solution to be applied to the base, can be properly defined with obtaining the desired thickness of the adhesive layer after evaporation of the solvent. After evaporation of the solvent to form an adhesive layer initiate the reaction of acrylic staple FOSS is the iMER (a) and acrylic copolymer (B), contained in the adhesive layer, and the aging can be performed up until the adhesive layer will not acquire sufficient cohesion as reaction stitching. As used in this application, the cohesion means strength adhesive logo. Low cohesion may lead to undesirable situations where dermal absorbed drug is spontaneously released when applied to the skin, and the adhesive layer remains on the skin when percutaneous absorbed drug is released.

Examples of organic acids used for percutaneous absorbed drug according to the present embodiment, include dairy kislota, salicylic acid, succinic acid, thioglycolic acid, maleic acid, malonic acid, adipic acid, benzoic acid, capric acid, sorbic acid, malic acid, citric acid, tartaric acid, palmitic acid, fumaric acid, propionic acid, beenbuy acid, myristic acid, and their hydrates, and the like. Among them, it is most preferable to use lactic acid. Although inorganic acids such as hydrochloric acid, phosphoric acid and the like, other than organic acids may also be present as an acid, in the present invention using an organic acid, the village is olcu inorganic acid has a very limited effect of accelerating the reaction of crosslinking acrylic copolymer (a) and acrylic copolymer (B).

The amount of organic acid is preferably from 0.05% to 5% by weight, more preferably from 0.1% to 2% by weight and most preferably from 0.3% to 1% by weight on the total weight of the adhesive layer. When the amount used of the organic acid is 0.05 mass% or more on the total weight of the adhesive layer, the reaction of the crosslinking acrylic copolymer (a) and acrylic copolymer (B) can be successfully accelerated. In addition, when the amount used of the organic acid is 5% by mass or less by weight on the total weight of the adhesive layer, the skin irritation caused by the application of a percutaneous absorbed drug may be reduced.

Other components

Next will be described the other components contained in the adhesive layer, if necessary. These components represent the various additives that are added to the adhesive layer as necessary to provide different functions percutaneous absorbed drug. Examples of such additives include plasticizers, antioxidants, solvents for dissolution of the medicinal component, various adhesive agents, antiseptic agents, agents for adjusting the pH, chelating agents, accelerators, percutaneous absorption, excipients, flavors, colorants and the like.

the quality of the plasticizer can be generally used oil substance, having a high boiling point. Examples of the plasticizer include ester derivatives of fatty acids, such as isopropylmyristate, diethylsilane, diisopropylamide, etiloleat, isopropyl, tillaart, octylpyrimidine, strideselect and triglyceride medium chain fatty acids; derivatives of higher alcohols, such as hexyldecanol and octyldodecanol; polyalkylene glycols such as polyethylene glycol and polypropyleneglycol; fats and oils such as olive oil and castor oil, and the like. Among them isopropylmyristate, isopropyl and the like are preferred because they not only act as plasticizers, but also have effects acceleration of the diffusion of the medicinal component in percutaneous absorbed the drug and accelerate the penetration of the medicinal component through the skin. They can be used individually or two or more of them may be used in combination. The amount of added plasticizer is preferably from 1% to 40% by weight, more preferably from 5% to 35% by weight and most preferably from 6% to 30% by weight on the total weight of the adhesive layer. When using type adhesive agent, in which the acrylic copolymer (a) and acrylic copolymer (B) are mixed and stitched, as described in the crust is present embodiment, in particular, if the oily substance, such as nicotine, used as a medicinal component, a good percutaneous absorbed the drug can be obtained without the use of plasticizer. In this case, the plasticizer is optional.

Antioxidant inhibits oxidation of the components contained in the adhesive layer, and the phenomenon staining adhesive layer (impregnated drug surface) observed during storage percutaneous absorbed drug for a long time, is reduced. Thus, the storage stability of percutaneous absorbed drug may be improved. Examples of the antioxidant include phenolic antioxidants, such as dibutylaminoethanol (BHT, name according to IUPAC (international Union of pure and applied chemistry): 2,6-bis(1,1-dimethylethyl)-4-METHYLPHENOL) and dibutylamine hydroxyanisol (BHA); ascorbic acid, tocopherol and ester derivatives of tocopherol, 2-mercaptobenzimidazole and the like. Among these antioxidants is preferred dibutylaminoethanol (EIT). The amount of the antioxidant is preferably from 0.1% to 20% by weight and more preferably from 0.5 to 10% by weight on the total weight of the adhesive layer.

The solvent for dissolving Lekarstvo the th component is not limited specifically as long while it dissolves the drug, and preferably is a solvent which does not cause skin irritation. Examples of such a solvent include lower alcohols such as ethanol, propanol and isopropanol; secondary alcohols such as hexanol and octanol; a polyalcohol such as glycerin, ethylene glycol and diethylene glycol; esters of fatty acids, polyvinyl alcohols, N-organic, lactic acid, and the like. They can be used individually or two or more of them may be used in combination.

As available described above, an example of the formation of the adhesive layer in percutaneous absorbed the drug according to the present embodiment includes a technique in which the components to be contained in the adhesive layer, such as the above-mentioned mixture of resins, organic acid, medicinal component and the like, dissolved in a solvent to obtain a solution and the solvent contained in the solution is heated and evaporated in a known manner. The solvent used in this method is not limited specifically as long as he is an organic solvent which is evaporated during the stage of drying by heating in obtaining percutaneous absorbed drug. Examples of solvents may include organic rest ritali, for example ketones, such as acetone and methyl ethyl ketone; esters of acetic acid such as methyl acetate, ethyl acetate, propyl and butyl acetate; aliphatic hydrocarbons such as hexane, heptane, octane and cyclohexane; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as isopropyl ether, tetrahydrofuran and dioxane; and the like. They can be used individually or two or more of them may be used in combination.

Medicinal component

Medicinal component used in percutaneous absorbed the drug according to the present embodiment, is contained in the adhesive layer and is absorbed into the skin through the saturated drug surface corresponding to the surface of the adhesive layer and the surface of contact with the skin. A view of the medicinal component used in percutaneous absorbed the drug according to the present embodiment is not limited specifically. As described in this application, when using the primary drug as a medicinal component development reaction crosslinking acrylic copolymer (a) and acrylic copolymer (B), which are adhesive agents, slows down. Thus, there is a tendency to prolong the period of aging in the manufacture of percutaneous absorbed p is eparate. From this point of view, the effect of accelerating the crosslinking reaction by adding the above-mentioned organic acids will also be implemented with the use of primary drug as a medicinal component.

Examples of the medicinal component include AIDS for Smoking cessation such as nicotine; local anesthetics, such as lidocaine hydrochloride, procaine hydrochloride and lidocaine;

narcotic analgesics, such as morphine sulfate, fentanyl citrate and fentanyl; drugs against dementia, such as donepezil hydrochloride; drug, facilitate dysuria, such as tamsulosin hydrochloride; sedative-hypnotic drugs, such as flurazepama hydrochloride and rilmazafone hydrochloride;

anti-inflammatory analgesic agents, such as butorphanol tartrate and personsal citrate; psychostimulants, such as methamphetamine hydrochloride and methylphenidate hydrochloride; psihonevroticheskih agents, such as chlorpromazine hydrochloride, imipramine hydrochloride, risperidone, aripiprazole, and olanzapine; muscle relaxants, such as tizanidina hydrochloride, eperisone hydrochloride and pridinol mesilate; autonomic agents, such as cabrone chloride and neostigmine bromide; ANTIPARKINSONISM agents, is such as trihexyphenidyl hydrochloride, amantadine hydrochloride and pergolid mesilate; antihistamines, such as clemastine fumarate and diphenhydramine tannat; bronchodilators such as tulobuterol hydrochloride and procaterol hydrochloride; cardiotonic drugs such as izoprenalin hydrochloride and dopamine hydrochloride;

coronary vasodilators such as diltiazem hydrochloride and verapamil hydrochloride; peripheral vasodilators such as Nicoletta citrate and tolazoline hydrochloride; cardiovascular drugs, such as flunarizin hydrochloride and nicardipine hydrochloride; antiarrhythmic agents, such as propranolol hydrochloride and alprenolol hydrochloride;

anti-allergic agents, such as ketotifen fumarate and azelastina hydrochloride; agents against seasickness, such as betahistine mesilate and difenidol hydrochloride; anti-emetics antagonists of serotonin receptors; and the like. Among them, preferably used, in particular, nicotine, lidocaine and fentanyl.

The above medicinal ingredients can be used in free base form and in the form of a pharmaceutically acceptable salt accession acid, and both forms can be used in combination. Although salt accession acid basic medicines, water plants the PRS may exhibit neutral to acid reaction, depending on the added acid, this salt accession acid is also known as the main drug in the present invention. The number above the medicinal component is preferably from 1% to 60% by weight on the total weight of the adhesive layer with the physical qualities of the drug and percutaneous absorbability of the drug. The above medicinal components can be used individually or two or more of them may be used in combination.

Basis

Preferably, the base is impermeable or poorly permeable to the drug component and is flexible. Specific examples include films of resins such as polyethylene, polypropylene, copolymer of ethylene-vinyl acetate, copolymer of ethylene-vinyl acetate-carbon monoxide copolymer ethylene-butyl acrylate-carbon monoxide, nylon, complex polyester(polyethylene terephthalate, polybutylene terephthalate and the like, as well as aluminum sheets and the like. They can be laminated and made in the form of sheet or can be laminated with a woven material or non-woven material. In addition, with the aim of improving the adhesion with the adhesive layer of the surface of the base may be subjected to surface treatment, such as treatment by corona discharge, the plasma discharge processing and the like, and processed adhesive coating with a fixing agent.

The second embodiment of the percutaneous absorbed drug according to the present invention

Next will be described a second embodiment of the percutaneous absorbed drug of the present invention. In the following description of the second embodiment of the content, overlapping with the content of the above-mentioned first embodiment, reduced and will be mainly described the other parts.

Percutaneous absorbed the drug according to the present embodiment differs from the above first embodiment is used as the adhesive agent resin blends containing 100 parts by weight of the above acrylic copolymer (a) and from 0.05 to 2 parts by weight polyamino connection, and the remainder is the same as in the above first embodiment. Thus, the following description will be described polyamine connection.

Polyamine connection

Polyamine compound used in the present embodiment, is a low-molecular compound. As used in this application, low-molecular coupling means monomolecular compound not forming polymer or oligomer by polymerization. Polyamine compound is a compound having two or more amino groups in the molecule. As described above, the AK is silt copolymer (A) is a copolymer, obtained by polymerization of diacetonitrile as an essential monomer, and contains in the molecule ketogroup originating from diacetonitrile. Polyamine connection is stitched to the acrylic copolymer (A) by the interaction of geograpy and amino groups contained in polyamino connection.

Example polyamino connection often involves connecting hydrazine or hydrazinehydrate.In light of the ability to show good reactivity towards ketogroup originating from diacetonitrile contained in the acrylic copolymer (A), however, the amino group contained in polyamino connection, preferably associated with other nitrogen atoms. Examples of such compounds include polyhydrazides compounds obtained by reacting hydrazine powered connection with polybasic organic acid.

Preferred examples polyhydrazides compounds include dihydrazide dicarboxylic acids. Examples of such compounds include dehydrated phthalic acid, dihydrazide isophthalic acid, terephtalic acid dihydrazide, dihydrated oxalic acid, dihydrazide sabatinovka acid, dihydrazide adipic acid and the like. Especially preferred polyhydrazides compounds include saturated, alipate the mini-dicarboxylic acid, among them dihydrazide saturated aliphatic dicarboxylic acids having from 2 to 10 carbon atoms. Examples of such compounds include dihydrated oxalic acid, dihydrazide sabatinovka acid and dehydrated adipic acid. Among them, preferred is dehydrated adipic acid. Dehydrated adipic acid is also known as diamine adipic acid or adipogenesis.

The above polyamine compound is mixed with the acrylic copolymer (A) obtaining a mixture of resin, which is an adhesive agent. The number of added polyamino compound is from 0.05 to 2 parts by weight and more preferably from 0.1 to 1 part by weight per 100 parts by weight of acrylic copolymer (A). When the number polyamino connection that is added is 0.05 parts by weight or more per 100 parts by weight of acrylic copolymer (A), then the acrylic copolymer (A) can be successfully sewn and can be obtained adhesive agent having a suitable cohesion. When the number polyamino connections that add is 2 parts by mass or less to 100 parts by weight of acrylic copolymer (A), then gelation acrylic copolymer (A) can be suppressed.

The above mixture of resins, and medicinal component, organic kislotoi, if necessary, other components are dissolved in a solvent to obtain a solution and the solution is applied on the surface of the base with the formation of the adhesive layer on the substrate surface. The procedure is the same as in the description of the first embodiment, and reduced here.

In the present embodiment as the first embodiment described above, the adhesive layer further comprises an organic acid. Also the reaction of crosslinking acrylic copolymer (a) and acrylic copolymer (b) as described above, although the reaction of crosslinking acrylic copolymer (A) with polyamines connection in the present embodiment may be delayed when using essential medicine as a medicinal component, the slowdown is inhibited due to the presence of organic acids in the adhesive layer. Thus, even when using essential medicine as a medicinal component aging after manufacturing percutaneous absorbed drug may be reduced, and the speed of production in the manufacture of percutaneous absorbed drug may be increased.

The third embodiment of the percutaneous absorbed drug according to the present invention

Next will be described the third embodiment of the percutaneous absorbed drug of the present invention. The following is the Scripture of the third embodiment of the contents, overlapping with the content of the above-mentioned first embodiment and second embodiment, reduced and will be mainly described the other parts.

Percutaneous absorbed the drug according to the present embodiment has an "adhesive layer" described in the first and second embodiments as the layer that holds the drug. Percutaneous absorbed the drug according to the present embodiment has as the contact surface with the skin adhesive layer (patching layer) for percutaneous insertion of absorbed drug to the skin for absorption of the medicinal component contained in the percutaneous absorbed the drug into the skin. Membrane controlled release placed, if necessary, between the above layer, holding a medicine, and an adhesive layer. That is transdermally absorbed the drug according to the present embodiment includes on the reverse side of the leather, on which is applied transdermally absorbed drug Foundation; the layer that holds the drug; the membrane controlled release and an adhesive layer, which are formed sequentially, or base layer, holding the drug, and an adhesive layer, which are formed sequentially. The layer that holds the drug is identical to the "adhesive layer", as described above, and can successfully hold the AMB medicinal component inside the mesh, formed by stitching. Percutaneous absorbed the preparation of such embodiments are also included in the scope of the invention as it has this adhesive layer (the layer that holds the drug) on one surface of the base.

Percutaneous absorbed drugs from the above first and second embodiments have as a contact surface with the skin adhesive layer having good property of adhesion to the skin and the ability to retain the drug. Thus, although percutaneous absorbed drugs from the first and second embodiments have a good ability to deliver the drug to the skin, good ability of drug delivery may vary depending on types of the medicinal component. Accordingly, in percutaneous absorbed the drug according to the present embodiment, the adhesive layer containing a drug component, is used as the layer that holds the drug, which is not in contact with the skin, and, if necessary, place the membrane controlled release to control the speed of delivery of the medicinal component of the layer holding the drug, between the layer holding the drug, and an adhesive layer, which is the contact surface with the skin. When Cresco is but absorbed the drug has no membrane controlled release then the above-mentioned adhesive layer controls the rate of drug delivery component of the layer holding the drug. Percutaneous absorbed the drug according to the present embodiment is preferably used for medicinal component, is particularly necessary to maintain a stable concentration in the blood over a long period of time.

The layer that holds the drug, according to the present embodiment is identical to the "adhesive layer" described above, and is not described here. Because the adhesive layer (i.e. the layer that holds the drug) in the present embodiment is a layer intended for direct application to the skin, the adhesive property is not required.

Membrane controlled release is placed between the layer holding the drug, and an adhesive layer, and it controls the speed of delivery of the medicinal component of the layer that holds the drug in the adhesive layer. Through this controlled rate of drug delivery component of the dermal absorbed drug to the skin.

Known membrane controlled release can be used without special restrictions. An example of such membranes with controlled-release includes copolymer ethylene-vinyl acetate (EVA) or polyethylene porous membrane. The thickness, quality, size of the resulting pores and the like characteristics of the membrane can be appropriately determined in the light of the desired speed of delivery of the medicinal component. The way in which the membrane layer controlled release placed in percutaneous absorbed drug is not specifically limited, and its example includes a method in which the membrane controlled release, made in the form of a sheet, is applied by pressing on the adhesive surface of the layer that holds the drug is formed on the substrate surface.

An adhesive layer is placed to attach percutaneous absorbed drug to the skin. The adhesive layer is a contact surface with the skin in percutaneous absorbed the drug, therefore, it plays a role in the delivery of the medicinal component to the skin. In addition, in a form that does not use the above membrane controlled release, such an adhesive layer has the function of controlling the speed of delivery of medicines from the layer that holds the drug.

Substance for the formation of the adhesive layer is not specifically limited as long as it has adhesiveness, and its examples include rubber materials such as polyisobutylene, styrene-isoprene-styrene BC is K-copolymer and natural rubber; acrylic substance, such as a copolymer of acrylate-octylacrylate, copolymer of 2-ethyl hexyl acrylate-2-ethylhexylacrylate-dodecylmercaptan and copolymer of 2-ethyl hexyl acrylate-diacetonitrile-acetoacetotoluidide-methyl methacrylate; and the like. These substances can be used individually or several substances can be used in combination. The method of forming the adhesive layer is not specifically limited, and examples include a method in which the above substance is dissolved in a suitable solvent and then the solution is applied on the surface of the membrane controlled release with her, followed by drying; a method in which the above substance is produced in the form of a sheet, and the sheet then by pressing placed on the surface of the membrane controlled release; and the like. The thickness of the adhesive layer is not specifically limited and can be determined appropriately by taking into account the properties required for percutaneous absorbed drug.

If necessary, an adhesive layer may be added to the amplifier adhesive, plasticizer, antioxidant, stabilizer and the like other than the above substances.

Percutaneous absorbed the drug of the present invention has been described using specific embodiments. However, the present invention is not limited icepets the above embodiments and can be implemented with a modification or change, within the scope of the present invention.

EXAMPLES

Percutaneous absorbed the drug of the present invention will be described hereinafter in more detail with the help of his examples. However, it should be understood that the present invention is not limited to the following examples.

Example: obtaining the adhesive agent (a mixture of resins)

Solution of acrylic copolymer (a) and a solution of acrylic copolymer (B) obtained according to the methods of synthesis described below, were mixed so that the mass ratio of the resin, stargames in solution, was 100:5 (acrylic copolymer (A): acrylic copolymer (B)) to obtain the adhesive agent (a mixture of resins).

- Acrylic copolymer (A)

To 200 parts by weight of 2-ethylhexyl acrylate was added to 100 parts by weight of butyl acrylate, 50 parts by weight of diacetonitrile and 300 parts by weight of ethyl acetate and mixed. This mixture was transferred to a removable flask equipped with stirrer and reflux condenser, and were heated to 75°C. under stirring and blowing with nitrogen. The solution in which 2 parts by weight of benzoyl peroxide were dissolved in 20 parts by weight of ethyl acetate, was divided into five aliquot and one aliquot was added in a removable flask to initiate the polymerization reaction. Each aliquot of the remaining four aliquot was added at intervals of one hour after 2 hours the after initiation of the polymerization reaction. After complete addition, the reaction was carried out for a further 2 hours. After initiation of the reaction, 50 parts by weight of ethyl acetate was added four times at 2-hour intervals to adjust the viscosity. After completion of the reaction, the reaction mixture was cooled and then added ethyl acetate to obtain a solution of acrylic copolymer (A) with 30% concentration of solids by weight. In the obtained acrylic copolymer (A) srednedlinny molecular weight was about 680000, and srednevekovaja molecular weight was approximately 1200000.

- Acrylic copolymer (B)

To 660 parts by weight of ethyl acrylate were added 70 parts by weight of diacetonitrile, 40 parts by weight of dodecylmercaptan as a molecular weight modifier and 400 parts by weight of ethyl acetate and mixed. This mixture was transferred to a removable flask equipped with stirrer and reflux condenser, and were heated to 70°C. under stirring and blowing with nitrogen. A solution in which 5 parts by weight of azobisisobutyronitrile was dissolved in 100 parts by weight of ethyl acetate, was divided into five aliquot and one aliquot was added in a removable flask to initiate the polymerization reaction. Each aliquot of the remaining four aliquot was added at intervals of one hour after 2 hours after initiation of the polymerization reaction. After conclusion of the Oia adding the reaction was carried out for a further 2 hours. After initiation of the reaction, 50 parts by weight of ethyl acetate was added four times at 2-hour intervals to adjust the viscosity. Then to the mixture was added a solution in which 40 parts by weight dihydrazide adipic acid were dissolved in a mixed liquid consisting of 40 parts by weight of purified water, 1,600 parts by weight of methanol and 260 parts by weight of ethyl acetate, and then to the mixture were added 5 parts by weight of concentrated hydrochloric acid, and the resulting mixture was then heated to 70°C. After completion of the reaction, the reaction mixture was cooled and then washed three times with purified water. The obtained product was dissolved in a mixed solvent consisting of 700 parts by weight of ethyl acetate, 1400 parts by weight of acetone and 400 parts by weight of methanol to obtain a solution of acrylic copolymer (b) with 30% concentration of solids by weight. In the obtained acrylic copolymer (B) srednedlinny molecular weight was about 6500, and srednevekovaja molecular weight was about 11,000.

Examples 1-11

To a solution of adhesive agent (a mixture of resins) obtained in example obtaining above, was added nicotine (free form) as a medicinal component and various organic acids and the entire solution was mixed to homogeneity to obtain a mixed liquid. With the aim of obtaining dezuniga layer thickness of 67 μm after drying, this mixed liquid was applied on a basis where the base has a surface that was subjected to the treatment by corona discharge, and which is a PET (polyethylene terephthalate) film with a thickness of 25 μm, and dried to obtain an adhesive layer. Received percutaneous absorbed preparations of Examples 1-11. The organic acid used in each example shown in Table 1. Each component was added so that the value in % by weight after drying was as shown in Table 1. Each value shown in Table 1, means % by mass.

Comparative examples 1-3

Percutaneous absorbed preparations of Comparative examples 1-3 were obtained using similar procedures as in Examples 1-11 above, except that instead of the organic acid was added inorganic acid or no added acid. Each component was added so that the value of % by weight after drying was as shown in Table 2. Each value shown in Table 2, means % by mass.

Estimates of the rate of crosslinking

Each percutaneous absorbed the preparation of Examples 1-11 and Comparative examples 1-3 were left at 25°C. after fabrication and investigated the time (day), which is required for the adhesive layer acquired cohesion, without leaving adhesive agent on the skin. This time corresponds to the period of aging. Shorter time shows is on high speed stitching adhesive agent. The results are shown in Tables 1 and 2.

Table 1
Example
1234567891011
the adhesive agent52,652,652,652,652,652,652,652,652,652,652,6
nicotine46,746,746,746,746,746,746,746,746,746,746,7
Moloch the I acid 0,7
salicylic acid-0,7---------
succinic acid--0,7--------
thioglycolate acid0,7
maleic acid0,7
malonic acid0,7-
adipic acid------0,7----
benzoic acid---- -~~0,7
capric acid0,7
sorbic acid0,7
malic acid0,7
registered 1111 day1 day1 day21322
agingdaydaydaydaysdaydaysdaysdays

Table 2
Comparative example
123
the adhesive agent52,652,653,3
nicotine46,746,746,7
hydrochloric acid 0,7--
phosphoric acid-0,7-
registered aging14 days11 days11 days

Examples 12-33

Percutaneous absorbed preparations of Examples 12-33 were obtained using the same procedures as in Examples 1-11 above, except that as a medicinal agent used lidocaine and isopropylmyristate (IPM) was added as a plasticizer. Organic acids used in each Example are shown in Tables 3 and 4. Each component was added so that the amount in % by weight after drying was as shown in Tables 3 and 4. Each value shown in Tables 3 and 4, means % by mass.

Then also assessed the speed of stitching percutaneous absorbed drugs example 12-33 in the same way as for percutaneous absorbed drugs in Examples 1-11 and Comparative examples 1-3 above. The results are shown in Tables 3 and 4.

Comparative examples 4-6

Percutaneous absorbed preparations of Comparative examples 4-6 were obtained using the same procedures as in Examples 12-33 above, IP is connection, instead of organic acid was added inorganic acid. Each component was added so that the amount in % by weight after drying was as shown in Table 5. Each value shown in Table 5, means % by mass.

Speed stitching percutaneous absorbed preparations of Comparative examples 4-6 were also evaluated in the same way as for percutaneous absorbed preparations of Examples 1-11 and Comparative examples 1-3 above. The results are shown in Table 5.

Table 3
Example
1213141516171819202122
the adhesive agent51,9551,951,751,551,051,551,551,5 51,551,551,5
lidocaine18,018,018,018,018,018,018,018,018,018,018,0
IPM30,030,030,030,030,030,030,030,030,030,030,0
lactic acid0,050,10,30,51,0
salicylic acid 0,5
adipic acid0,5
capric acid0,5
succinic acid 0,5--
sorbic acid---------0,5-
thioglycolate acid----------0,5
registered aging3 days2 days1 day1 day1 day1 day3 days3 days1 day3 days1 day

Table 4
Example
2324252627282930313233
the adhesive agent51,551,551,551,551,551,551,551,551,551,551,5
lidocaine18,018,018,018,018,018,018,018,018,018,018,0
IPM30,030,0 30,030,030,030,030,030,030,030,030,0
citric acid0,5
tartaric acid0,5
palmitic acid0,5the
fumaric acid0,5
propionic acid0,5
Baganova acid0,5
myristic acid 0,5
maleic acid0,5"
malonic acid0,5
malic acid-----0,5
benzoic acid 0,5
registered aging5 days5 days5 days5 days5 days5 days5 days1 day1 day1 day1 day

Table 5
Comparative example
456
the adhesive agent51,551,551,5
lidocaine18,018,018,0
IPM30,0 30,030,0
hydrochloric acid0,5--
sulfuric acid-0,5-
phosphoric acid--0,5
registered aging14 days11 days11 days

Estimated number of penetrated drug

Leather yucatán microvilli (age 5 months, female) was removed unwanted subcutaneous fat and the like and cut out certain pieces of suitable size. Test percutaneous absorbed the drug was applied on one surface of the skin and examined the total number of penetrated drugs by measuring the total amounts of nicotine, lirovannomu in the receiver through the skin after 4 hours, 8 hours and 24 hours after the start of the test. The results are shown in Table 6. The test was performed using a percutaneous absorbed preparation Example 1 and a commercially available nicotine patch (NICODERM (TM)), and the area is saturated, in addition to the public by means of surfaces for percutaneous absorbed drugs used in the test was 0.95 cm2for percutaneous absorbed drug from Example 1 and 1,77 cm2for commercially available nicotine patch.

Table 6
The amount of nicotine bweremana in the receiver (µg)
After 4 hoursAfter 8 hoursAfter 24 hours
Example 1151,4±87,8744,3±307,21915,7±257,4
control164,2±80,3663,2±206,41863,4±240,11

Estimating the effect of inhibiting the staining antioxidant (Examples 34-38)

In a solution of adhesive agent (a mixture of resins) obtained in example obtaining above, was added nicotine (free form) as a medicinal component, lactic acid as an organic acid and dibutylaminoethanol (BHT, IUPAC name: 2,6-bis(1,1-dimethylethyl)-4-METHYLPHENOL) as an antioxidant, and the entire solution was mixed to homogeneity to obtain a mixed liquid. With the aim of obtaining adhesive CL the I thickness of 67 μm after drying, this mixed liquid was applied on a basis with the coating surface, which was subjected to treatment by corona discharge and was a PET film with a thickness of 25 μm, and dried to obtain an adhesive layer. Received percutaneous absorbed preparations of Examples 34-38. Each component was added so that the value in % by weight after drying was as shown in Table 7. Each value shown in Table 7, means % by mass.

Percutaneous absorbed preparations of Examples 34-38 left at 40°C for one month and evaluate the degree of staining adhesive layer (impregnated drug surface) from receiving percutaneous absorbed drugs by color differences (DE). The results are shown in Table 7. For the color difference (AE) was measured chromaticity of the surface of the adhesive layer, using a spectrophotometer (Model SP64, produced by X-Rite Inc.), and received changes in chromaticity of the drugs directly after production and after conditioning at 40°C during the month using the following formula for computing. When the degree of black-and-white, red-green and blue-yellow represented in the form L-scale,-scale and b-scales, respectively, then the color difference is represented in the form of the square root of the sum of squared differences for each of the scales ΔE(=((Δa)2+(Δ b)2+(ΔL)2)1/2).

<>
Table 7
Example
3435363738
the adhesive agent52,652,151,649,647,6
nicotine46,746,746,746,746,7
lactic acid0,70,70,70,70,7
EIT-0,51,03,05,0
the color difference (DE)10,52,42,11,31,0

As shown in the Tables 1, 3 and 4, found that in the case of percutaneous absorbed preparations of Examples 1-33 containing organic acid in the adhesive layer, the acquisition of sufficient cohesion of the adhesive layer was occupied from about 1 to 5 days after production (i.e., the degree of reaction of the crosslinking acrylic copolymer (a) and acrylic copolymer (B) was sufficient). On the contrary, as shown in Tables 2 and 5, found that in the case of percutaneous absorbed preparations of Comparative examples 1-6, containing inorganic acid in the adhesive layer and not containing the acid, the acquisition of sufficient cohesion adhesive layer took 11 days or more. Thus, it is clear that the reaction of crosslinking acrylic copolymer (a) and acrylic copolymer (B) contained in the adhesive agent, has been accelerated by adding an adhesive layer of an organic acid, and the period of aging after manufacturing percutaneous absorbed drug could be reduced. It is clear that such trend was observed when using nicotine and when using lidocaine as a medicinal component.

Also, as shown in Table 3, transdermally absorbed the product from Example 1 is the amount of drug penetrated into the skin, roughly equivalent to the number of commercially available nicotine patch, thus, PON the IDT, what percutaneous absorbed the drug of the present invention can be preferably used for the nicotine patch.

Also, in comparison with Examples 34-38, shown in Table 7, it is clear that the staining adhesive layer eventually inhibited by addition of BHT in the adhesive layer. Thus, it is clear that the stability in time of percutaneous absorbed drug may be improved by adding BHT in the adhesive layer.

Example 39

After rubbing and drying has received a mixed liquid consisting of 53 parts by weight of the adhesive agent obtained in example obtain the above (a mixture of resins), 42 parts by weight of nicotine (free form) as a medicinal component, 0.2 parts by weight of lactic acid and 4.8 parts by weight of BHT. The mixed liquid was applied to the nonwoven material, where the non-woven material is the basis in which the non-woven fabric having a basic weight of 12 g/cm2that was layered on a PET film with thickness of 12 μm and dried so that the thickness after drying was 87 μm, with the formation of the layer holding the drug. Porous polyethylene membrane, membrane controlled release (product name: CoTran 9719, manufactured by 3M) by pressing was applied to the surface of the layer holding the drug. Then to the solution and the 40 parts by weight of polyisobutylene (PIB) in heptane was added 50 parts by weight aliphatic hydrocarbon resin, the amplifier adhesive (product name: ARKON P-100, manufactured by ARAKAWA CHEMICAL INDUSTRIES, LTD.) and liquid paraffin, and the resulting solution was applied to a polyester film which had been subjected to treatment with silicone and dried so that the thickness after drying was 67 μm, to obtain an adhesive layer. The adhesive layer was coated side of the membrane controlled release layer that holds the drug, prior to obtaining percutaneous absorbed preparation of Example 39. The rate of crosslinking of the layer holding the drug, a percutaneous absorbed the preparation of Example 39 was evaluated in the same way as described above.

Registered ageing period was one day and was quite short.

The number of penetrated medicines from percutaneous absorbed drug from Example 39 (area impregnated with the medicinal product surface: 0.95 cm2the content of 3.7 mg/cm nicotine) was evaluated in the same way as for percutaneous absorbed preparation Example 1. Commercially available nicotine patch (NICODERM (TM), containing 5.2 mg/cm2nicotine) that has the same size as percutaneous absorbed the product from Example 39 (0.95 cm), was used as control sample. Accordingly, as shown in Table 8, the total number of nicotine, e is wirojanagud in the receiver after 4 hours, 8 hours and 24 hours from the beginning of the test, respectively 198 mg, 451,9 mcg and 942,8 μg per 1 cm2percutaneous absorbed drug. The results confirmed that the type of percutaneous absorbed drug with membrane controlled release of the present invention, also successfully delivered a medicinal component to the skin.

In particular, percutaneous absorbed drug has fewer drugs than the number in commercially available nicotine-patch, but it has a number of penetrated drug, roughly equivalent to the number of the commercially available product. Thus, it is clear that percutaneous absorbed the drug of the present invention can be preferably used for the nicotine patch.

Table 8
The amount of nicotine lirovannomu in the receiver (µg/cm2)
after 4 hoursafter 8 hoursafter 24 hours
Example 39198,0±14,8451,9±18,3942,8±23,5
control223,0±23,0511,7±25,6999,8±25,8

1. Percutaneous absorbed preparation having a base and an adhesive layer which is placed on the base and which contains an adhesive agent and a medicinal component,
where the adhesive agent comprises a mixture of resins containing 100 parts by weight of acrylic copolymer (A) described below, and from 0.1 to 30 parts by weight of acrylic copolymer (B) described below, or from 0.05 to 2 parts by weight of low-molecular polyamino compounds having at least two amino groups in one molecule and not polymerizable with the formation of the polymer or oligomer, and where the adhesive layer further comprises an organic acid,
where the acrylic copolymer (A) is an acrylic copolymer that contains complex alkilany ester of (meth)acrylic acid as a main monomer component and contains from 3 to 45% by weight of diacetonitrile as an essential monomer component, but does not contain a free carboxyl group,
where the acrylic copolymer (B) is an acrylic copolymer that contains complex alkilany ester of (meth)acrylic acid as a main monomer component and contains a primary amino group and/or carboxylicacid group is as side chains, but does not contain a free carboxyl group.

2. Percutaneous absorbed the drug under item 1, containing as an organic acid of at least any of lactic acid, salicylic acid, succinic acid, thioglycolic, maleic acid, malonic acid, adipic acid, benzoic acid, capric acid, sorbic acid, malic acid, citric acid, tartaric acid, palmitic acid, fumaric acid, propionic acid, beganovi acid, myristic acid, and their hydrates.

3. Percutaneous absorbed the drug under item 1, where the medicinal component is a nicotine, or lidocaine, or their salts.

4. Percutaneous absorbed the drug under item 3, where the medicinal component is a nicotine or its salt.

5. Percutaneous absorbed the drug under item 1, where the adhesive layer further comprises an antioxidant.

6. Percutaneous absorbed the drug under item 5, where the antioxidant is dibutylaminoethanol.

7. Percutaneous absorbed the drug according to any one of paragraphs. 1-6, further containing an adhesive layer, which provides the property of adhesion to the skin, or sequentially containing membrane controlled release, which controls the release of the medicinal component of the adhesive layer, and glue is a first layer, which provides the property of adhesion to the skin on the surface of the adhesive layer.



 

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2 ex

FIELD: veterinary medicine.

SUBSTANCE: intramesovarian blockade of ovarian and cranial uterine nerves is carried out by laparotomy and administration in the mesovarium of 0.5-1% solution of novocaine or lidocaine. Blockade is carried out by inserting the needle of the syringe into the mesovarium in the vicinity of the ovarian bursa and uterine horn at an acute angle to the surface of the ovarian mesenterium to a depth of 3-4 cm. At that 3 ml of anaesthetic is administered to small breeds of dogs and fur-bearing animals, and from 3 to 9 ml of anaesthetic is administered to large and giant breeds of dogs as from one and from the opposite side of the body.

EFFECT: effective implementation of intramesovarian blockade by taking into account the anatomical and the breed features of the animal category.

1 tbl

FIELD: medicine.

SUBSTANCE: patient is laid on his/her side opposite a block region. A guide mark is a vertical line in a projection of Petit's triangle from the twelfth rib to a wing of ilium. A needle is pricked into the skin on the vertical line at 1.5-2.5cm above the wing of ilium. 0.25% Novocaine is administered in layers into the skin and subcutaneous fat. The needle is advanced into the lumbar region from back to front in the medial direction along the lateral edge of broadest muscle of back at 6-8cm. Novocaine 120ml is administered into the lower order of the lumboiliac fossa formed in this region.

EFFECT: effective and safe pain management in the given category of patients by providing the required Novocaine concentration in the retroperitoneal space.

1 dwg, 1 ex

FIELD: biotechnology.

SUBSTANCE: aqueous composition for anaesthesia is proposed, which comprises propofol as an active agent, the PEG-660-12-hydroxystearate as a solubiliser, benzyl alcohol, or chloroethanol or parabens as preservative, the tocopherol and arginine or glycine at a specific content of components wt %. The GABA agonists can be additionally added to the composition, e.g. aminophenyl-butyric acid, local anesthetics such as lidocaine, alpha-2-adrenoceptor agonists such as xylazine. The method is proposed for implementing anaesthesia comprising administering to a patient of an effective amount of the claimed composition.

EFFECT: invention provides low toxicity of dosage form and high efficiency.

5 cl, 3 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: radionuclide indicator is administered to record the dynamics of its distribution in limb tissues by a radionuclide method. The examination is performed at rest and during a load test. The load test represents an epidural block by gradual administration of bupivacaine 25-30 mg between L2-L3 vertebrae for 5-7 minutes. That is followed by measuring a blood flow as a percentage of its value to the same level in an analogous segment of a collateral limb.

EFFECT: qualitative assessment of the circulation reserve in various categories of patients, including disabled ones by inhibiting sympathetic and minimally sensory activity with maintaining the patients' motor activity.

2 dwg, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to abdominal surgery and anaesthesiology, and can be used where it is necessary to anaesthetise after the prosthetic hernioplasty for median postoperative ventral hernias. That is ensured by placing an endoprosthesis under the aponeurosis, a polyvinylchloride catheter is placed into the formed spaced around the periphery of a postoperative wound in the form of an oval above the endoprosthesis plane at 2.5-3 cm from its edges. Along its full length, the catheter has multiple side holes. Single openings are created in a projection of a lower corner of the wound, and the catheter ends are brought out onto the skin. An inlet of the catheter is attached to a local anaesthetic dosage device by means of a cannula. That is followed by a controlled prolonged irrigation with 2.5% Ropivacaine 20 ml every 6-8 hours during 2-3 days.

EFFECT: method enables the adequate postoperative anaesthesia, as well as the length of the postoperative intestinal distention by providing the uniform controlled administration of the local anaesthesia solution.

7 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to anaesthesiology and surgery, and can be used in case of anaesthesia necessity in patients after herniorrhaphy with inguinal access in case of inguinal hernias. For this purpose after the main stage of operation - hernioplasty, before suturing of the aponeurosis of the external oblique abdominal muscle, through subcutaneous adipose cellular tissue a puncture of 1 cm more medially and 1 cm higher than the anterior-superior iliac spine is made. A multiperforated catheter is introduced through the puncture under finger and visual control in such a way that its distal end is near the pubic tubercle. The catheter is placed under the aponeurosis of the external oblique abdominal muscle in the inguinal canal above and parallel to the spermatic cord in men or the round ligament of uterus in women. All the side holes of the catheter must be located in the subaponeurotic space. The first 48 hours of the post-operation period the local anaesthetic is continuously introduced by drop infusion at a rate of 2-4 ml/h or by bolus introduction in a dose of 10 ml each 4-6 hours through the catheter. After 48 hours the catheter is removed.

EFFECT: method provides adequate anaesthesia in the said category of patients in the post-operation period without application of additional anaesthetic preparations due to blockade of ilioinguinal, ilioceliac and hollow branch of genitofemoral nerves.

2 dwg, 2 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, and may be used in treating the patients suffering headaches and facial pains. There are presented versions of a drug delivery device comprising an injector a first end of which is left outside patient's nasal passages. Another end of the injector comprises one or more holes for spraying a drug upwards, and/or to the side, and/or to the front towards a sphenopalatine ganglion, an input device interacting with a patient's nostril and comprising a canal for receiving the injector. Additionally, the device can comprise a handle connected to the input device and provided for receiving the canal of the input device. The injector can move between a storage position before the interaction, and an interaction position related to the interaction. There are also presented versions of the method of using the above device that involve introducing the injector through the nasal passage into median and/or posterior and/or inferior region in relation to the patient's sphenopalatine ganglion, and spraying the drug.

EFFECT: group of inventions provides faster and more effective headache and facial pain relief by safe and accurate drug delivery of the therapeutic substances blocking the sphenopalatine ganglion.

49 cl, 4 dwg, 30 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel biologically active 2,6-dimethylanilide of N-cyclohexylpyrrolidine-2-carboxylic acid, having surface, infiltration and conduction anaesthesia activity, considerably better than bupivacaine and ropivacaine with the same or less toxicity.

EFFECT: improved compounds.

2 tbl

Antiviral agent // 2542488

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to an antiviral agent and aims at inactivating a wide range of viruses. The antiviral agent contains an active agent presented by particles of at least one type of iodide formed by iodine and an element formed in 4-6th periods of the 8-10th or 12-15th groups of the periodic table, Cu or Au. The above element found in the 4-6th periods of the 8-10th or 12-15th groups of the periodic table represents Sb, Ir, Ge, Sn, Tl, Pt, Pd, Bi, Fe, Co, Ni, Zn, In or Hg. What is also presented is the antiviral agent containing particles of at least one type of a cuprous compound as an active ingredient. The above cuprous compound represents chloride, acetate, sulphide, iodide, bromide, peroxide, oxide or thiocyanide.

EFFECT: using the group of inventions provides the agent having the high antiviral activity; the above agent is able to exhibit and maintain its antiviral activity easily since it requires no preparation or special washing.

5 cl, 4 tbl, 27 ex

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