JP4744136B2 - Pilsicainide patch - Google Patents

Description

  The present invention relates to a transdermal absorption patch containing pilcainide as an active ingredient.

  Japanese Patent Publication No. 4-46956 describes that 8-substituted pyrrolitidine derivatives such as pildicinide are useful as antiarrhythmic drugs, and in recent years, injections and capsules of pildicinide hydrochloride have been widely used. As administration forms of these antiarrhythmic drugs, conventionally, intravenous administration and oral administration are generally used, and other administration forms have not been studied much.

  On the other hand, the administration method by transdermal absorption generally has a long duration of action by continuous drug absorption, pain avoidance at the time of injection, avoidance of the first-pass effect at the time of gastrointestinal absorption, and rapid removal by removing the transdermal preparation. It may have usefulness such as loss of efficacy (discontinuation of administration). Since the solution itself has no ability to retain on the skin and cannot absorb the drug continuously for a long period of time, it is generally administered transdermally using a preparation in the form of a patch applied to the skin etc. It is. As for pildicinide, a patch (reservoir type patch) is proposed in which a storage layer for a liquid preparation containing pildicinide in the form of hydrochloride (pilcicainide hydrochloride) and a drug release control film are laminated (WO02 / 96465). In this patch, lauric acid diethanolamide or the like is preferably used.

However, a reservoir-type patch that holds a liquid storage layer and a drug release control film is expensive to manufacture and has problems in terms of formulation stability such as liquid leakage. Furthermore, this patch has a poor usability and has a problem in terms of skin irritation caused by lower alcohol (ethanol etc.) used in the liquid storage layer. Therefore, development of a dosage form other than the above-mentioned reservoir-type patch is required as a patch for percutaneously absorbing pilcainide.
Japanese Examined Patent Publication No. 4-46956 WO02 / 96465

  An object of the present invention is to provide a transdermal absorption patch capable of continuously percutaneously absorbing the active ingredient pildicinide, which is an antiarrhythmic agent, effectively preventing the onset of arrhythmia for a long time and / or treating arrhythmia. Is to provide. More specifically, it is an object of the present invention to solve the problems of the reservoir-type patch disclosed in WO02 / 96465 and to provide a patch excellent in production cost, formulation stability, and feeling of use. .

  As a result of intensive research to solve the above problems, the present inventors have produced a patch in which a free form of pilcainide is added to an adhesive layer containing an acrylic adhesive as an adhesive. Was found to be absorbed transdermally. The present invention has been completed based on the above findings.

That is, according to the present invention, a patch comprising pilcainide as an active ingredient, wherein a pressure-sensitive adhesive layer is provided on the surface of the support, and the pressure-sensitive adhesive layer comprises a free form of pilcainide and an acrylic pressure-sensitive adhesive. Provided.
According to a preferred embodiment of the present invention, there are further provided the above-mentioned patch in which a release film is laminated on the surface of the pressure-sensitive adhesive layer; and the above-mentioned patch further containing a plasticizer in the pressure-sensitive adhesive layer.

According to a further preferred embodiment,
The acrylic pressure-sensitive adhesive (a) one or more monomers of (meth) acrylic monomers having an acetoacetyl group in the molecule and (b) one of vinyl monomers having no acetoacetyl group in the molecule The above-mentioned patch which is a copolymer of two or more monomers;
The acrylic adhesive is (a ′) one or more monomers selected from acetoacetoxyalkyl acrylate and acetoacetoxyalkyl methacrylate, and (b) one or two vinyl monomers having no acetoacetyl group in the molecule. The above patch which is a copolymer with the above monomers;
The one or more monomers selected from acetoacetoxyalkyl acrylate and acetoacetoxyalkyl methacrylate are one or more monomers selected from 2-acetoacetoxyalkyl acrylate and 2-acetoacetoxyalkyl methacrylate. Patch;
The above patch, wherein one or more monomers selected from acetoacetoxyalkyl acrylate and acetoacetoxyalkyl methacrylate are 2-acetoacetoxyalkyl acrylate or 2-acetoacetoxyalkyl methacrylate;
Vinyl monomers having no acetoacetyl group in the molecule are 2-ethylhexyl acrylate, methyl methacrylate, diacetone acrylamide, butyl acrylate, ethylene glycol dimethacrylate, ethylene glycol diacrylate, diethylene glycol dimethacrylate, triethylene glycol dimethacrylate, tetra The above-mentioned patch, which is one or more monomers selected from the group consisting of ethylene glycol dimethacrylate, hexaethylene glycol dimethacrylate, and acrylamide;
The above patch, wherein the vinyl monomer having no acetoacetyl group in the molecule is one or more monomers selected from the group consisting of diacetone acrylamide, 2-ethylhexyl acrylate, methyl methacrylate and tetraethylene glycol dimethacrylate. ;
Is provided.

According to another more preferable aspect,
Copolymerization of acrylic adhesive with 2-acetoacetoxyethyl methacrylate and one or more monomers selected from the group consisting of diacetone acrylamide, 2-ethylhexyl acrylate, methyl methacrylate, and tetraethylene glycol dimethacrylate The above-mentioned patch, which is a combination, is provided.

According to another preferred embodiment, the plasticizer is selected from the group consisting of isopropyl myristate, diethyl sebacate, isopropyl palmitate, medium chain triglyceride, hexyl decanol, diisopropyl adipate, liquid paraffin, and octyldodecanol. Or the above-mentioned patch, which is two or more kinds of plasticizers; the above-mentioned patch, wherein the plasticizer is isopropyl myristate; the plasticizer is contained in a proportion of 5 to 35% by weight based on the total weight of the pressure-sensitive adhesive layer The above patch is provided.
Furthermore, another preferable aspect provides the above-mentioned patch, wherein the support is a laminated film of polyolefin and polyethylene terephthalate.
The patch of the present invention can be used as a medicament for preventing and / or treating arrhythmia.

  The patch of the present invention is a patch that eliminates the drawbacks of the conventional reservoir-type patch containing pilcainide hydrochloride as an active ingredient, and is characterized by excellent usability and low cost production. In addition, in the conventional reservoir type patch, there is no problem in the stability of the formulation such as liquid leakage because it is not necessary to use a liquid containing an active ingredient necessary for percutaneously absorbing the drug. Also, there is no problem of skin irritation due to the lower alcohol contained in the liquid. Furthermore, the patch of the present invention has a transdermal absorbability that surpasses conventional reservoir-type patches, and can effectively administer pildikainide, which is an active ingredient, over a long period of time, effectively arrhythmia expression. It can prevent and / or effectively treat arrhythmias.

Pirdicainide ([N- (2,6-dimethylphenyl) -8-pyrrolotidinylacetamide]), which is an active ingredient used in the patch of the present invention, is a substance having the following structural formula, and Japanese Patent Publication No. 4-46956 It can be easily obtained by those skilled in the art according to the method disclosed in the publication.

  As an active ingredient of the patch of the present invention, free form pilcainide (free base) is used. However, when producing the patch of the present invention, a salt form of pilcainide may be used as a raw material or during the production, and the active ingredient contained in the final patch may be a free form of pilcainide. For example, as a raw material or the like, a substance selected from the group consisting of free form pilcainide and salts thereof, and hydrates and solvates thereof can be used. Examples of the salt include acid addition salts with inorganic acids or organic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, lactic acid, tartaric acid, or maleic acid. The free form of pildicinide used as the active ingredient of the patch of the present invention may be a hydrate or a solvate. Further, although not particularly limited, pilcainide is contained in the pressure-sensitive adhesive layer in a proportion of 0.1 to 30% by weight, preferably 1 to 20% by weight, more preferably 5 to 10% by weight of the total weight of the pressure-sensitive adhesive layer. It is.

  The patch of the present invention is characterized in that the above-mentioned active ingredient, free form pildicinide, is contained in the adhesive layer, and the adhesive layer contains an acrylic adhesive. The acrylic pressure-sensitive adhesive is not particularly limited as long as it is produced using at least one acrylic monomer or methacrylic monomer. For example, any of methyl acrylate / acrylic acid-2-ethylhexyl copolymer resin, methacrylic acid / butyl acrylate copolymer, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate, and vinyl acetate can be used. Preferred acrylic pressure-sensitive adhesives include, for example, one or more monomers of a (meth) acrylic monomer having an acetoacetyl group in the molecule and one or more vinyl monomers having no acetoacetyl group in the molecule. A copolymer obtained by copolymerizing two or more monomers is used.

  Examples of (meth) acrylic monomers having an acetoacetyl group include 2-acetoacetoxyethyl methacrylate, 2-acetoacetoxyethyl acrylate, 3-acetoacetoxypropyl methacrylate, 3-acetoacetoxypropyl acrylate, 4-acetoacetoxybutyl methacrylate An acetoacetoxyalkyl methacrylate such as 4-acetoacetoxybutyl acrylate, or an acetoacetoxyalkyl acrylate can be used, and one or more of them can be used. Among these, it is preferable to use 2-acetoacetoxyethyl methacrylate and / or 2-acetoacetoxyethyl acrylate.

  As a vinyl monomer which does not have an acetoacetyl group in a molecule | numerator, what is necessary is just a vinyl monomer which has a double bond copolymerizable in a molecule | numerator, and 1 type, or 2 or more types of vinyl monomers can be used. For example, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, diacetone acrylamide, butyl acrylate, butyl methacrylate, ethylene glycol dimethacrylate, diethylene glycol dimethacrylate, triethylene glycol methacrylate, tetraethylene glycol diacrylate, tetraethylene dimethacrylate, hexaethylene glycol One or more selected from the group consisting of dimethacrylate, hexaethylene glycol diacrylate, methyl methacrylate, acrylamide, methacrylamide, 2-hydroxyethyl acrylate, N-vinyl-2-pyrrolidone, vinyl acetate, and acrylic acid A (meth) acrylic monomer can be used. Preferably, one or more acrylic monomers selected from the group consisting of 2-ethylhexyl acrylate, diacetone acrylamide, butyl acrylate, tetraethylene diacrylate, tetraethylene glycol dimethacrylate, and methyl methacrylate can be used. .

In the production of the copolymer used as the acrylic pressure-sensitive adhesive, the proportion of the monomer having an acetoacetyl group is not particularly limited. For example, it is 1 with respect to the total weight of the copolymer (not including a solvent and a radical initiator). It can be used in a proportion of from wt% to 40 wt%, more preferably from 5 wt% to 40 wt%. When the ratio is less than 1% by weight, the holding ability of the plasticizer may be reduced, and when it exceeds 40% by weight, the network structure becomes too dense and the holding ability of the plasticizer may be reduced. is there.
In the production of the copolymer, although not particularly limited, (a) one or more monomers of a (meth) acrylic monomer having an acetoacetyl group in the molecule and (b) an acetoacetyl group in the molecule The mixing ratio of one or two or more types of vinyl monomers not having a ratio of 1: 1.5 to 1:99 can be used, more preferably 1: 1.5 to 1:19. . If it deviates from the above ratio, the holding ability of the plasticizer and the like may decrease.

  The acrylic pressure-sensitive adhesive can be produced by a method well known in the art. Specific examples include a method in which monomers are dissolved in an organic solvent and polymerization is performed using a radical initiator, and this method is particularly preferable. The total amount of monomers can be dissolved in a predetermined amount of an organic solvent in advance and replaced with nitrogen, followed by heating to polymerize. Alternatively, the monomers can be divided and sequentially introduced into the solvent for polymerization. . At this time, the monomer concentration in the organic solvent is not particularly limited, but is preferably 10% by weight to 80% by weight. If this concentration is less than 10% by weight, it may be difficult to obtain a high degree of polymerization, and if it exceeds 80% by weight, it may be difficult to control the polymerization heat generated during the polymerization.

  The kind of the organic solvent used for the polymerization is not particularly limited, and one or two or more kinds of solvents selected from the group of commonly used organic solvents can be used alone or in combination. It is also possible to sequentially add the same or different solvent during the polymerization. As the solvent, any solvent can be used as long as it is a volatile organic solvent that does not inhibit the polymerization reaction and volatilizes in the heating and drying step in the production process. For example, acetic acid alkyl esters such as acetic acid methyl ester, acetic acid ethyl ester, acetic acid propyl ester, or acetic acid butyl ester, aliphatic hydrocarbons such as hexane, heptane, octane, or cyclohexane, and aromatics such as benzene, toluene, or xylene Organic solvents such as aromatic hydrocarbons, ketones such as acetone or methyl ethyl ketone, or ethers such as isopropyl ether, tetrahydrofuran, or dioxane. Among these, one or more solvents can be used alone. Or can be used as a mixture.

  As the radical initiator, a compound selected from peroxides or azo initiators or a mixture thereof can be used, and the amount used is a monomer (a (meth) acrylic monomer having an acetoacetyl group in the molecule). The total amount of vinyl monomers having no acetoacetyl group in the molecule) is preferably 0.001 to 2.00 parts by weight, more preferably 0.005 to 0. 1 part by weight. Examples of the peroxide include benzoyl peroxide, lauroyl peroxide, t-butyl hydroperoxide, di (2-ethylhexyl) peroxydicarbonate, or 1,1′-di-tertbutyl-peroxy-2-methyl. And cyclohexane. Examples of the azo initiator include 2,2′-azobisisobutyronitrile, 4,4′-azobis-4-cyanovaleric acid, or 2,2′-azobis (2-amidinopropane) dihydrochloride. Etc. The polymerization temperature may be a temperature at which the radical initiator generates an appropriate radical, and is generally preferably 50 ° C to 120 ° C.

Further, the acrylic pressure-sensitive adhesive can be converted into an aqueous emulsion type acrylic pressure-sensitive adhesive in which a copolymer is dispersed in an aqueous solvent together with a surfactant having little skin irritation.
Examples of surfactants with less skin irritation to be added to the aqueous emulsion type adhesive include anionic surfactants such as sodium lauryl sulfate and sodium dodecylbenzenesulfonate, cationic, polyoxyethylene lauryl ether, polyoxy One or two or more surfactants selected from nonionic surfactants such as ethylene oleyl ether or peptide surfactants such as surfactin may be used alone or in combination. it can.

The amount of the residual monomer of the acrylic adhesive is preferably as small as possible for the irritation to the skin and the stability of the drug, and is preferably 20000 ppm or less based on the adhesive solid content. In order to reduce the residual monomer, for example, a radical initiator can be added after the polymerization is completed, or a treatment at a higher temperature can be performed in a pressurized state.
When the molecular weight of the acrylic adhesive copolymer increases, the tackiness tends to decrease, and when the molecular weight decreases, the cohesive force tends to decrease. The molecular weight of the copolymer is preferably a molecular weight of tens of thousands to several millions in terms of weight average molecular weight.

（式中、Ｗｉはｉ成分のモノマーの重量分率（％）、Ｔｇｉはｉ成分のホモポリマーのガラス転移点（°Ｋ）を表す。） The glass transition temperature (hereinafter referred to as “Tg”) of the acrylic adhesive copolymer may also have a great influence on the adhesive strength and cohesive strength of the adhesive. When Tg is high, the pressure-sensitive adhesive tends to be hard, and when Tg is low, the pressure-sensitive adhesive tends to be soft. The Tg of the copolymer is preferably in the range of −60 ° C. to −5 ° C. More preferably, it is -50 degreeC--10 degreeC. When the plasticizer is added at a temperature lower than −60 ° C., the cohesive strength of the pressure-sensitive adhesive may become too weak. On the other hand, at a Tg exceeding −5 ° C., even if a large amount of the plasticizer is added, the adhesive strength is reduced. It may be difficult to express.
In general, the glass transition point can be confirmed by measurement with a DSC apparatus or measurement of viscoelasticity. It can also be calculated from the glass transition point of the homopolymer according to the following formula.

(In the formula, Wi represents the weight fraction (%) of the monomer of i component, and Tgi represents the glass transition point (° K) of the homopolymer of i component.)

  In the adhesive layer of the patch of the present invention, in addition to pilcainide, which is an active ingredient, and an acrylic adhesive, a plasticizer, a tackifier, a solubilizer, a percutaneous absorption enhancer, or an enhancer, if necessary. It is also possible to mix a dosage form or the like.

  As the plasticizer that can be blended in the acrylic pressure-sensitive adhesive layer, an oily substance having a high boiling point can be generally used. For example, isopropyl myristate, diethyl sebacate, diisopropyl adipate, ethyl oleate, palmitic acid Fatty acid ester derivatives such as isopropyl, ethyl laurate, octyl palmitate, isotridecyl myristate, or medium chain fatty acid triglycerides; higher alcohol derivatives such as hexyl decanol or octyldodecanol; polys such as polyethylene glycol or polypropylene glycol Alkylene glycols; or oils and fats such as olive oil or castor oil can be used. These may be used alone or in admixture of two or more. Among these, isopropyl myristate and / or isopropyl palmitate acts as a plasticizer for the adhesive, and also has an effect of promoting the diffusibility of the drug in the patch and the skin permeability of the drug. Therefore, it is preferably used. Most preferably used is isopropyl myristate. The blending amount of the plasticizer is not particularly limited, but is preferably 50% by weight or less, more preferably 5% by weight to 35% by weight, and further preferably 10% by weight to 30% by weight with respect to the total weight of the pressure-sensitive adhesive layer. %, Most preferably 15 to 30% by weight. When the blending amount of the plasticizer exceeds 50% by weight, the oily substance cannot be retained in the pressure-sensitive adhesive layer, and bleeding that causes the oily substance to leak out may occur.

  The pressure-sensitive adhesive layer of the patch of the present invention can obtain an appropriate pressure-sensitive adhesive force only with the above-mentioned acrylic pressure-sensitive adhesive, but if a higher pressure-sensitive adhesive force is required, a tackifier is blended in the pressure-sensitive adhesive layer. Can increase the adhesive strength. As the tackifier, for example, an alicyclic saturated hydrocarbon resin or a rosin ester derivative is preferably used. Examples of the alicyclic saturated hydrocarbon include Alcon P-100 (trade name; manufactured by Arakawa Chemical Industries), and examples of the rosin ester derivative include ester gum H (trade name; manufactured by Arakawa Chemical Industries). It is also possible to use seeds or a mixture of two or more.

  The type of the solubilizer is not particularly limited. For example, a solvent that dissolves pilcainide and does not cause skin irritation can be used. Specifically, lower alcohols such as ethanol, propanol, and isopropanol can be used. Intermediate alcohol such as hexanol or octanol, polyhydric alcohols such as glycerin, ethylene glycol, or diethylene glycol, higher fatty acid esters, polyvinyl alcohol, N-methylpyrrolidone, or crotamiton are used. These solvents can be used alone or in combination as a solubilizer, but the solubilizer is not limited to these solvents.

  As the percutaneous absorption enhancer, any kind of substance may be used as long as it has a function of promoting percutaneous absorption of pilsicainide. For example, fatty acid esters such as isopropyl myristate, isopropyl palmitate, or diethyl adipate, fatty acid polyhydric alcohol esters such as caprylic acid monoglyceride, caprylic acid triglyceride, or sorbitan fatty acid ester, or l-menthol, mint oil, or Those commonly used for transdermal absorbents in the form of patches, such as terpenes such as limonene, can be used.

  Examples of the excipient include silicon compounds such as silicic anhydride or light anhydrous silicic acid, cellulose derivatives such as ethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, or hydroxypropyl methyl cellulose, and water-soluble polymers such as polyvinyl alcohol. In addition, there are antioxidants such as dibutylhydroxytoluene, or powders such as kaolin and titanium oxide, and fragrances and coloring agents can be added within a pharmaceutically acceptable range.

  Although the thickness of the support body used for the patch of this invention is not specifically limited, Usually, it is 5-400 micrometers, Preferably it is about 5-250 micrometers. A stretchable support is more preferable, but a non-stretchable support having flexibility is preferably used. The material of the support is not particularly limited, but is preferably a material that is impermeable to pilcainide or an adhesive. Either a single-layer structure support or a support in which two or more identical or different film-like materials are laminated may be used. In the case of a support having a single layer structure, for example, a plastic film such as polyethylene, polyester, polypropylene, vinyl chloride, polycarbonate, or polyurethane, or metal films are preferably used, and the surface of the film is treated with silicon. It is also possible to apply. The support may be colorless and transparent, or may be a support colored in white or skin color. Examples of the support colored in white or skin color include those prepared by coating the surface of the support with a dye, and those obtained by uniformly kneading a dye or pigment in the support.

  In the case of using a support having a laminated structure, it is desirable that at least one layer is a film impermeable to pilcainide or an adhesive, and such a film can be selected in the same manner as a support film having a single layer structure. For example, it can be obtained by laminating one or more film materials selected from plastic films such as polyethylene, polyester, polyurethane, or polypropylene, nonwoven fabrics, woven fabrics, knitted fabrics, paper, and metal films. A laminated film can be used.

The support used in the patch of the present invention is not particularly limited. Specifically, a polyethylene film, a polyolefin film, a polyethylene terephthalate film, a laminated film of polyolefin and polyethylene terephthalate, and the like are suitable. since the humidity is too high to affect the skin permeability, those having the moisture permeability 500g / m ² / 24hr is preferred.

  In the patch of the present invention, it is desirable to provide a release film on the pressure-sensitive adhesive surface for the purpose of protecting the pressure-sensitive adhesive layer or preventing the pressure-sensitive adhesive layer from drying. Before the patch of the present invention is applied to the skin, the release film can be peeled off from the patch and the patch can be applied to the application site. Although the thickness of a peeling film is not specifically limited, Usually, about 15-200 micrometers, Preferably it is about 40-100 micrometers. As the release film, any material film can be used as long as it can be easily peeled off from the surface of the pressure-sensitive adhesive layer and is impermeable to pildicainide and pressure-sensitive adhesive. For example, a single-layer film selected from materials such as plastic films such as polyethylene, vinyl chloride, polyester, or polypropylene, paper, metal film, or cloth, or a laminate of two or more kinds of film-like materials is used. You may use the film which silicon-treated the surface of these films.

  The patch of the present invention comprises a solution or suspension containing pildicainide and an adhesive, and optional components such as a plasticizer, a tackifier, a solubilizer, a transdermal absorption enhancer, and an excipient as necessary. After coating on the surface of the release film, heat-dry at a temperature of 40 to 150 ° C. to form a pressure-sensitive adhesive layer, and then on the surface of the pressure-sensitive adhesive layer (the surface opposite to the surface on which the release film is adhered). It is possible to manufacture by laminating the support and cutting it into an appropriate size. When a water-impermeable support is used as the support, an adhesive solution containing pilcainide and, if necessary, a plasticizer is applied to the support and dried by heating, and then a release film is formed on the adhesive surface. It is also possible to laminate. The drying temperature is not particularly limited as long as it is equal to or higher than the temperature at which the solvents are volatilized. If the drying temperature is too low, the solvents may not completely evaporate and remain in the pressure-sensitive adhesive layer. If the drying temperature exceeds 150 ° C., pilcainide, a plasticizer, or a transdermal absorption accelerator may be decomposed.

EXAMPLES Hereinafter, although an Example demonstrates this invention further more concretely, this invention is not limited by these Examples.
<Manufacture of acrylic adhesive (1)>
A monomer liquid was prepared by uniformly dissolving 158 g of 2-ethylhexyl acrylate, 35.1 g of 2-acetoacetoxyethyl methacrylate, 76.2 g of methyl methacrylate, 80.3 g of diacetone acrylamide, and 1.0 g of tetraethylene glycol dimethacrylate. 100 g of this monomer solution was charged into a 2 liter four-necked flask equipped with a Jimroth condenser, thermometer, nitrogen gas blowing tube, and stirring blade, and 350 g of ethyl acetate was added as a solvent. The temperature was raised to 75 ° C. while blowing nitrogen gas at a flow rate of 100 ml / min, and maintained at 75 ° C. for 30 minutes. Then, 0.35 g of benzoyl peroxide as a radical initiator was dissolved in 5 g of ethyl acetate and added. Was set to 85 ° C. After confirming the reflux of the solvent, the remaining monomer solution was continuously added in 3 hours. From the start of continuous charging of the monomer liquid, 1 hour later, 500 g of ethyl acetate was continuously charged in 3 hours. After stirring for 12 hours after adding ethyl acetate, 0.5 g of benzoyl peroxide was added as an additional catalyst, heat treated for 12 hours, and then cooled to prepare a solvent-type acrylic pressure-sensitive adhesive solution.

<Manufacture of acrylic adhesive (2)>
In a 2 liter four-necked flask equipped with a Jimroth condenser, thermometer, nitrogen gas blowing tube, and stirring blade, 157.5 g of 2-ethylhexyl acrylate, 35 g of 2-acetoacetoxyethyl methacrylate, 80.5 g of diacetone acrylamide Then, 76 g of methyl methacrylate was charged, and 525 g of ethyl acetate was added as a solvent and dissolved until uniform. The temperature was raised to 75 ° C. while blowing nitrogen gas at a flow rate of 100 ml / min. After maintaining at 75 ° C. for 30 minutes, 0.21 g of benzoyl peroxide as a radical initiator was dissolved in 5 g of ethyl acetate and added, and the external temperature was set to 85 ° C. After 3, 5, and 7 hours after the initiator was charged, 300 g of toluene was divided and added in 100 g portions. During the polymerization, nitrogen gas was continuously blown at a flow rate of 100 ml / min.
Twelve hours after the last addition of toluene, 0.35 g of benzoyl peroxide was added as an additional catalyst, and then the external temperature was set at 95 ° C. for 12 hours, followed by cooling to obtain acrylic pressure-sensitive adhesive 2.

Example 1
35.69 g of the solvent-based acrylic pressure-sensitive adhesive (1) produced above was weighed into a screw bottle, and 4.5 g of isopropyl myristate and 1.5 g of pilucainide (free body) were weighed and stirred for 1 hour. On a laminated film (PO / PET) of polyolefin and polyethylene terephthalate as a support using a coating tester (LTE-S, Wener Mathis) so that the coating weight after drying is 100 mg / 10 cm ^2. After coating and drying, one surface was coated so that the silicone-treated surface of the polyester-treated release film was in contact with the pressure-sensitive adhesive, and 10% by weight of pilucainide and isopropyl myristate 30 in the pressure-sensitive adhesive layer. The pilsicainide patch of Example 1 containing% by weight was obtained.
Pilsicainide (free body) 10% by weight
Isopropyl myristate 30% by weight
Acrylic adhesive (1) 60% by weight

Example 2
The same procedure as in Example 1 was carried out except that 1.5 g of pilcainide (free body), 40.19 g of the solvent-type acrylic pressure-sensitive adhesive (1) produced above was used, and isopropyl myristate was not used. A pilcainide patch of Example 2 containing 10% by weight of pilcainide in the layer was obtained.

Example 3
As a pressure-sensitive adhesive, a commercially available solvent-type acrylic pressure-sensitive pressure-sensitive adhesive (Nissetsu PE300, manufactured by Nippon Carbide Co., Ltd., pressure-sensitive adhesive composition: 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate, vinyl acetate = 17: 2: 1) was used. The same procedure as in Example 1 was carried out except that isopropyl myristate was not used, and the pilcainide patch of Example 3 containing 10% by weight of pilcainide in the adhesive layer was obtained.

Comparative Example 1
The same procedure as in Example 1 was conducted except that 1.5 g of pilcainide hydrochloride was used instead of 1.5 g of pilucainide (free form), and 10% by weight of pilcainide hydrochloride and isopropyl myristate 30 in the adhesive layer. A patch of pildcainide hydrochloride of Comparative Example 1 containing% by weight was obtained.

Comparative Example 2
The same operation as in Comparative Example 1 was conducted except that 0.45 g of lauric acid diethanolamide was blended and 35.24 g of a solvent-type acrylic pressure-sensitive adhesive was used. A patch of pildicinide hydrochloride of Comparative Example 2 containing 30% by weight of isopropyl myristate and 3% by weight of lauric acid diethanolamide was obtained.

Example 4
The same procedure as in Example 2 was performed except that 0.75 g of pildcainide (free form) and 40.94 g of solvent-type acrylic pressure-sensitive adhesive were used. 4 pilsicainide patches were obtained.

Example 5
In the pressure-sensitive adhesive layer, the same operation as in Example 1 was carried out except that 0.75 g of pilcainide (free body), 40.19 g of solvent-type acrylic pressure-sensitive adhesive, and 0.75 g of isopropyl myristate were used. Thus, a pildcainide patch of Example 5 containing 5% by weight of pilucainide and 5% by weight of isopropyl myristate was obtained.

Example 6
In the pressure-sensitive adhesive layer, the same operation as in Example 1 was performed except that 0.75 g of pildcainide (free body), 39.44 g of solvent-type acrylic pressure-sensitive adhesive, and 1.5 g of isopropyl myristate were used. Thus, a pildcainide patch of Example 6 containing 5% by weight of pilcainide and 10% by weight of isopropyl myristate was obtained.

Example 7
In the pressure-sensitive adhesive layer, the same operation as in Example 1 was carried out except that 0.75 g of pilcainide (free body), 38.69 g of solvent-type acrylic pressure-sensitive adhesive, and 2.25 g of isopropyl myristate were used. Thus, a pildcainide patch of Example 7 containing 5% by weight of pilcainide and 15% by weight of isopropyl myristate was obtained.

Example 8
In the pressure-sensitive adhesive layer, the same operation as in Example 1 was carried out except that 0.75 g of pilcainide (free body), 37.94 g of solvent-based acrylic pressure-sensitive adhesive, and 3.0 g of isopropyl myristate were used. Thus, the pildcainide patch of Example 8 containing 5% by weight of pilucainide and 20% by weight of isopropyl myristate was obtained.

Example 9
The same operation as in Example 1 was performed except that 0.75 g of pilcainide (free body), 37.19 g of solvent-type acrylic pressure-sensitive adhesive and 3.75 g of isopropyl myristate were used. The pildcainide patch of Example 9 containing 5% by weight of pildcainide and 25% by weight of isopropyl myristate was obtained.

Example 10
The same operation as in Example 1 was carried out except that 0.75 g of pildcainide (free form) and 36.44 g of a solvent-type acrylic pressure-sensitive adhesive were used. In the pressure-sensitive adhesive layer, 5% by weight of pilcainide and isopropyl myristate were used. The pilcainide patch of Example 10 containing 30% by weight was obtained.

Example 11
The same operation as in Example 1 was performed except that 0.75 g of pilcainide (free body), 35.69 g of solvent-type acrylic pressure-sensitive adhesive, and 5.25 g of isopropyl myristate were used. The pildcainide patch of Example 11 containing 5% by weight of pildcainide and 35% by weight of isopropyl myristate was obtained.

Example 12
The same operation as in Example 1 was conducted except that 0.75 g of pilcainide (free body), 34.94 g of solvent-type acrylic adhesive, and 6 g of isopropyl myristate were used. The pildicainide patch of Example 12 containing 40% by weight and 40% by weight of isopropyl myristate was obtained.

Example 13
The same operation as in Example 1 was performed except that 0.75 g of pilcainide (free body), 34.19 g of solvent-type acrylic adhesive, and 6.75 g of isopropyl myristate were used. The pildicainide patch of Example 13 containing 5% by weight of pilcainide and 55% by weight of isopropyl myristate was obtained.

Example 14
Except that isopropyl palmitate was used instead of isopropyl myristate, the same operation as in Example 7 was carried out, and the pildicainide of Example 14 containing 5% by weight of pilcainide and 15% by weight of isopropyl palmitate in the adhesive layer. A patch was obtained.

Example 15
Except that isopropyl palmitate was used instead of isopropyl myristate, the same operation as in Example 9 was carried out, and the pilcainide of Example 15 containing 5% by weight of pilcainide and 25% by weight of isopropyl palmitate in the adhesive layer. A patch was obtained.

Example 16
The same operation as in Example 7 was carried out except that the solvent-type acrylic pressure-sensitive adhesive (2) was used in place of the solvent-type acrylic pressure-sensitive adhesive (1), and 5% by weight of pildicainide and myristin were contained in the pressure-sensitive adhesive layer. The pildicainide patch of Example 16 containing 15% by weight of isopropyl acid was obtained.

Example 17
The same operation as in Example 8 was carried out except that the solvent-type acrylic pressure-sensitive adhesive (2) was used instead of the solvent-type acrylic pressure-sensitive adhesive (1), and 5% by weight of pildicainide and myristin were contained in the pressure-sensitive adhesive layer. The pildicainide patch of Example 17 containing 20% by weight of isopropyl acid was obtained.

Example 18
The same operation as in Example 9 was carried out except that the solvent-type acrylic pressure-sensitive adhesive (2) was used in place of the solvent-type acrylic pressure-sensitive adhesive (1), and 5% by weight of pildicainide and myristin were contained in the pressure-sensitive adhesive layer. The pildicainide patch of Example 18 containing 25% by weight of isopropyl acid was obtained.

Example 19
The same as Example 8 except that the solvent-type acrylic pressure-sensitive adhesive (2) was used instead of the solvent-type acrylic pressure-sensitive adhesive (1) and that isopropyl palmitate was used instead of isopropyl myristate. The operation was carried out to obtain a pildicinide patch of Example 19 containing 5% by weight of pildicinide and 20% by weight of isopropyl palmitate in the pressure-sensitive adhesive layer.

Example 20
The same operation as in Example 8 was carried out except that 1.05 g of pilcainide (free form) and 37.64 g of a solvent-type acrylic adhesive were used, and 7 wt% of pilcainide in the adhesive layer. And a pildicainide patch of Example 20 containing 20% by weight of isopropyl myristate.

Example 21
The same operation as in Example 8 was conducted except that 1.5 g of pilcainide (free body) and 37.19 g of a solvent-type acrylic pressure-sensitive adhesive were used, and 10% by weight of pilcainide in the pressure-sensitive adhesive layer. And the pildicainide patch of Example 21 containing 20% by weight of isopropyl myristate was obtained.

Comparative Example 3
In the screw bottle, 9.8 g of styrene-isoprene-styrene block copolymer, 9.8 g of escorez (synthetic petroleum resin), 4.0 g of liquid paraffin, 0.15 g of dibutylhydroxytoluene, 1.25 g of pilucainide (free form), and 25 g of toluene Were weighed and the mixture was stirred for 1 hour. Using a coating tester (LTE-S, Wener Mathis), one surface is coated on the silicone-treated surface of a polyester release film that has been subjected to silicone treatment so that the coating weight after drying is 100 mg / 10 cm ^2. Coated and dried. Thereafter, the polyester knitted fabric of the support was coated so as to be in contact with the pressure-sensitive adhesive, and a pilcainide patch of Comparative Example 3 having the following formulation containing 5% by weight of pilcainide in the pressure-sensitive adhesive layer was obtained.
Pilsicainide (free body) 5.0% by weight
Styrene-isoprene-styrene block copolymer 39.5% by weight
Escorez (synthetic petroleum resin) 39.5% by weight
Liquid paraffin 16.0% by weight

Comparative Example 4
The operation was performed in the same manner as in Comparative Example 3 in accordance with the following formulation to obtain a pilcainide patch of Comparative Example 4 containing 7.5% by weight of pilcainide in the pressure-sensitive adhesive layer.
Pilsicainide (free body) 7.5% by weight
Styrene-isoprene-styrene block copolymer 38.25% by weight
Escorez (synthetic petroleum resin) 38.25% by weight
Liquid paraffin 16.0% by weight

Comparative Example 5
The operation was performed in the same manner as in Comparative Example 3 in accordance with the following formulation to obtain a pilcainide patch of Comparative Example 5 containing 10% by weight of pilcainide in the pressure-sensitive adhesive layer.
Pilsicainide (free body) 10% by weight
Styrene-isoprene-styrene block copolymer 37% by weight
Escorez (synthetic petroleum resin) 37% by weight
Liquid paraffin 16% by weight

Test Example 1: Pig Skin Permeation Test Using the pildcainide patches of Examples 1 to 3 and Comparative Examples 1 and 2, drug skin permeability test was conducted using pig skin (Yucatan micropig, female, 5 months old). I did it.
0.05 mol / L McIlvaine buffer (pH 7.4) was added to the dermis side (receiver side) of porcine skin of the vertical diffusion cell, and each pildicinide patch was applied to the stratum corneum side (donor side). After sampling the receiver solution at each time point, the same amount of 0.05 mol / L McIlvine buffer was added. The drug concentration in the sampling solution is measured using HPLC, and the flux value (value of the skin permeation rate in the steady state of the drug), the cumulative permeation amount for 48 hours, and the cumulative drug permeation rate from each patch (%) Was calculated. The above test was conducted using each pilcainide patch, and the results shown in FIG. 1 and Table 1 were obtained. As is clear from FIG. 1, the patches of Examples 1 to 3 using pilsicainide (free body) exhibited higher drug skin permeability than the patches of Comparative Examples 1 and 2 using pirkainide hydrochloride.

Test Example 2: Pig Skin Permeation Test A skin permeability test was conducted in the same manner as in Test Example 1 using the pildicainide patches of Examples 4 to 10, and the results shown in FIG. 2 and Table 2 were obtained. As is clear from FIG. 2, the patch without isopropyl myristate (plasticizer) and the patch without any plasticizer showed good skin permeability, but the patch with the plasticizer added was used. The preparation showed higher skin permeability than the additive-free patch.

Test Example 3: Evaluation of Adhesiveness / Self-adhesiveness Using the pildicainide patches of Examples 4 to 19, the adhesiveness and self-adhesiveness were evaluated. The evaluation was performed according to the following sensory evaluation method. As shown in Table 3, the self-adhesiveness and the adhesiveness were good for the patches of all the examples, but the adhesive containing the plasticizer was more excellent for the adhesiveness.
<Adhesiveness>
Prior to evaluation, hands were washed to remove oil and moisture. The index finger was brought into contact with the adhesive surface of the test patch for a short time (about 1 second), and the sensation of immediately separating it was evaluated.
"Evaluation criteria"
◎: Good ○: Good △: Slightly weak ×: Weak <Self-adhesion>
The pressure-sensitive adhesive surfaces of the test patch were bonded to each other, and the ease of peeling when evaluated was evaluated.
"Evaluation criteria"
○: (excellent) can be removed without resistance;
Δ: (good) There is a little resistance, but can be peeled off:
X: (Poor) There is considerable resistance and it is difficult to peel off.

Test Example 4: Hairless Rat VIVO Test Skin permeability VIVO test was conducted using hairless rats (female, 5 months old) using the pildicainide patches of Examples 8, 20, and 21 and Comparative Examples 3-5. I did it.
Pilsicainide patch (20 cm ² ) was affixed to the abdomen of hairless rats, covered with an unemployed cloth adhesive bandage, and the trunk was wound and fixed with an adhesive cloth elastic bandage. Blood samples were collected from the jugular vein before application, 2, 4, 8, 12, 24 hours after application, 2 hours after removal of the pilsicainide patch (26 hours after application) and 4 hours (28 hours after application) after removal. The collected blood was centrifuged (10 ° C., 3000 rpm, 10 minutes), and plasma was collected. Plasma was stored at −40 ° C. until analysis. The concentration of pilsicainide in plasma was quantified by LC-MS / MS. As shown in FIG. 3, the patch of the present invention showed a higher plasma drug concentration than the comparative patch, and particularly gave a significantly higher plasma drug concentration in the initial stage (0 to 8 hours).

Test Example 5: Dog VIVO test (single, 5 consecutive days)
Using the pilcainide patches of Examples 20 and 21, skin permeability VIVO tests were performed using beagle dogs (18 months of age or older) and compared with oral administration.
A test sample of pilcainide patch (140 cm ² ) was affixed to the chest of a vehicle dog, covered with an unemployed cloth adhesive bandage, and the body was wound and fixed with an adhesive cloth elastic bandage. Separately, an aqueous solution of pilcainide hydrochloride prepared as 5 mg / mL as pilcainide was forcibly administered into the stomach by oral sonde at 5 mg / kg with respect to the dog body weight. Blood was collected over time, and the collected blood was centrifuged (10 ° C., 3000 rpm, 10 minutes), and plasma was collected. Plasma was stored at −40 ° C. until analysis. The concentration of pilsicainide in plasma was quantified by LC-MS / MS. As shown in FIG. 4, in a single administration, the patch of the present invention showed a sustained plasma drug concentration compared to oral administration, and showed rapid drug disappearance after the patch was peeled off. In addition, as shown in FIG. 5, in the continuous administration for 5 days, the patch of the present invention showed a sustained plasma drug concentration compared to oral administration. In addition, the patch of the present invention showed a suitable drug concentration with a smaller number of administrations compared to oral administration (oral: 3 times / day, patch: once / day).

Test Example 6: Canine VIVO Pharmacological Test The pharmacological action on the electrical stimulation-induced atrial fibrillation model was evaluated by transdermally administering the pildicainide patch of Example 20 to a chronic complete atrioventricular block dog having myocardial remodeling.
1. Test strains and breeds: Dogs; Beagle dogs (chronic complete atrioventricular block dogs)
Number of animals available: 8 when obtained Age: 18 months of age or older Sex: Male and female when obtained Weight range: 9-15 kg

2. Composition of test group Pilsicainide patch (Example 20) was applied to 4 dogs at a dose of 98 mg / 10 kg, and the evaluation time was 8 hours.
3. Administration method: The test substance (70 cm ² ) 2/10 kg was applied to the chest and administered.
Number of administrations: A single administration on the measurement day.

4). Test Method Surgery: Anesthesia was induced by intravenous administration of pentobarbital (30 mg / kg) and a tracheal cannula was inserted. To maintain anesthesia, an appropriate amount of pentobarbital was intravenously administered every hour. The tracheal cannula was connected to a ventilator (Shinano Manufacturing Co., Ltd.), and artificial respiration (about 15 times / min, about 20 mL / kg) was performed with 100% and oxygen. A blood pressure measurement cannula was inserted into the right femoral artery, and an electrocardiogram measurement electrode was attached so that the lead II could be measured. Next, a pacing / potential recording quadrupole electrode catheter was inserted from the right femoral vein and placed in the upper right atrium. Further, a potential recording quadrupole electrode catheter was inserted into the esophagus and placed at a position where the left atrial potential could be recorded. Further, a monophasic potential recording / pacing electrode catheter was inserted from the left femoral vein and placed at the apex of the right ventricle.
Atrial fibrillation induction: Atrial fibrillation was induced by applying burst electrical stimulation with a stimulation period of 50-100 ms, a stimulation width of 10 ms, and an output of 60-80 V to the right atrium via a pacing electrode for 10 seconds. If atrial fibrillation persisted for more than 30 seconds, it was stopped by cardioversion and the burst electrical stimulation protocol continued. The atrial fibrillation duration in this case was 30 seconds. This operation was repeated 10 times, and the duration was measured when atrial fibrillation was induced. Atrial fibrillation was again induced by burst stimulation 1, 2, 4, 6 and 8 hours after drug administration, and the duration of atrial fibrillation was evaluated.

Interatrial conduction velocity: Interatrial conduction time at each time point was measured by programmed stimulation.
Blood drug concentration: To measure blood drug concentration, blood (3 mL) was collected with heparin calcium added before, 1, 2, 4, 6, and 8 hours after drug administration. Plasma was separated and stored frozen (−80 ° C.) until measurement.
Analysis: Atrial fibrillation inhibitory action was calculated from shortening of fibrillation duration. The interatrial conduction time at each time point was measured using an intracardiac electrocardiogram recorded from the right atrium and the left atrium after performing basic stimulation for about 30 seconds in the basic period (200, 300, 400 ms).

  The results are shown in Table 4. Interatrial conduction time is 2-8 hours after sinus rhythm by administration of the patch of the present invention, 1-8 hours after 400 ms stimulation cycle, 4-8 hours after 300 ms stimulation cycle, and 4-8 after 200 ms stimulation cycle. Each was extended after hours. In addition, the administration of the patch of the present invention shortened the duration of atrial fibrillation after 2 to 8 hours. Thus, the pildicinide patch of the present invention showed an excellent effect of extending the atrial transmission rate and shortening the onset time of atrial fibrillation.

It is the figure which showed the result of the skin permeability test (Test Example 1) of pildicinide using the patch of the present invention. It is the figure which showed the result of the skin permeability test (Test Example 2) of pildicinide using the patch of the present invention. It is the figure which showed the result of the skin permeability test (Test Example 4) of the pildicinide using the patch of this invention. It is the figure which showed the result of the skin permeability test (Test Example 5, single administration) of pilsicainide using the patch of the present invention. It is the figure which showed the result of the skin permeability test (Test Example 5, 5 days continuous administration) of pildicinide using the patch of the present invention.

Claims (14)

A patch comprising pilcainide as an active ingredient, wherein a pressure-sensitive adhesive layer is provided on the surface of the support, and the pressure-sensitive adhesive layer comprises free form pilcainide and an acrylic pressure-sensitive adhesive. The acrylic pressure-sensitive adhesive (a) one or more monomers of (meth) acrylic monomers having an acetoacetyl group in the molecule and (b) one of vinyl monomers having no acetoacetyl group in the molecule The patch according to claim 1, which is a copolymer of two or more monomers. The acrylic adhesive is (a ′) one or more monomers selected from acetoacetoxyalkyl acrylate and acetoacetoxyalkyl methacrylate, and (b) one or two vinyl monomers having no acetoacetyl group in the molecule. The patch according to claim 1, which is a copolymer with the above monomers. The one or more monomers selected from acetoacetoxyalkyl acrylate and acetoacetoxyalkyl methacrylate are one or more monomers selected from 2-acetoacetoxyalkyl acrylate and 2-acetoacetoxyalkyl methacrylate. 3. The patch according to 3. The patch according to claim 3, wherein the one or more monomers selected from acetoacetoxyalkyl acrylate and acetoacetoxyalkyl methacrylate are 2-acetoacetoxyalkyl acrylate or 2-acetoacetoxyalkyl methacrylate. Vinyl monomers having no acetoacetyl group in the molecule are 2-ethylhexyl acrylate, methyl methacrylate, diacetone acrylamide, butyl acrylate, ethylene glycol dimethacrylate, ethylene glycol diacrylate, diethylene glycol dimethacrylate, triethylene glycol dimethacrylate, tetra The patch according to any one of claims 2 to 5, which is one or more monomers selected from the group consisting of ethylene glycol dimethacrylate, hexaethylene glycol dimethacrylate, and acrylamide. The vinyl monomer having no acetoacetyl group in the molecule is one or more monomers selected from the group consisting of diacetone acrylamide, 2-ethylhexyl acrylate, methyl methacrylate and tetraethylene glycol dimethacrylate. 6. The patch according to any one of 6 above. Copolymerization of acrylic adhesive with 2-acetoacetoxyethyl methacrylate and one or more monomers selected from the group consisting of diacetone acrylamide, 2-ethylhexyl acrylate, methyl methacrylate, and tetraethylene glycol dimethacrylate The patch according to claim 1, which is a combined body. The patch according to any one of claims 1 to 8, wherein the adhesive layer contains a plasticizer. The plasticizer is one or more plasticizers selected from the group consisting of isopropyl myristate, diethyl sebacate, isopropyl palmitate, medium chain triglyceride, hexyl decanol, diisopropyl adipate, liquid paraffin, and octyldodecanol. The patch according to claim 9. The patch according to claim 9, wherein the plasticizer is isopropyl myristate. The patch according to any one of claims 9 to 11, comprising a plasticizer in a proportion of 5 wt% to 35 wt% with respect to the total weight of the pressure-sensitive adhesive layer. The patch according to any one of claims 1 to 12, wherein the support is a laminated film of polyolefin and polyethylene terephthalate. The patch according to any one of claims 1 to 13, wherein a release film is laminated on the surface of the pressure-sensitive adhesive layer.

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