TW201542250A - Bisoprolol-containing adhesive patch - Google Patents

Abstract

The present invention relates to a bisoprolol-containing adhesive patch that is provided with: a support body; and an adhesive layer that contains bisoprolol and an adhesive and that is stacked on one surface of the support body. The bisoprolol-containing adhesive patch is characterized by the halogen atom content within the adhesive layer being 0.01-100 weight ppm. The present invention makes it possible to minimize decreases in adhesive strength, discoloration, and the like in a bisoprolol-containing adhesive patch during storage thereof.

Description

Attachment preparation containing bisoprolol

The present invention relates to a Pisoplot-containing patch preparation for sustained absorption of Pisopoulol into the living body through the skin.

In recent years, there have been various developments of skin-attached type patch preparations for administering drugs to the living body through the skin, and among these, in particular, a patch preparation containing a drug which exerts a systemic pharmacological action has been attracting attention. These adhesive preparations are formed by forming an adhesive layer such as an acrylic adhesive or a rubber-based adhesive and mixing them into various adhesive layers of a transdermally absorbable drug, and attaching them to the skin. The drug is absorbed into the body through the skin and exerts excellent pharmacological effects.

However, in the case of such a patch preparation, there is a case where the patch preparation is colored or the adhesion is lowered.

In order to suppress such coloring, a method of adding a decomposition inhibitor such as 2-thiol benzimidazole or propyl gallate (antioxidant, stabilizer) to an adhesive layer has been proposed (Patent Document) 1) Wait.

[Previous Technical Literature] [Patent Literature]

Patent Document 1: Japanese Patent Laid-Open No. Hei 11-79978

An object of the present invention is to suppress a decrease in adhesion, coloration, and the like of a Pisoplot-containing patch preparation during storage.

The inventors of the present invention have intensively studied in order to achieve the above object, and as a result, it has been found that in the adhesive preparation containing Pisoppro, the content of the halogen atom in the adhesive layer is 0.01 to 100 ppm by weight. The adhesiveness of the patch preparation is lowered, the color is changed, and the like, and the present invention has been completed.

Based on the above findings, the present invention is as follows.

[1] A bisopprox-containing patch preparation comprising: a support body, and an adhesive layer laminated on one surface of the support body and containing a Bisopoulol and an adhesive; wherein the adhesive layer The halogen atom content is 0.01 to 100 ppm by weight.

[2] The Pisoppro-containing patch preparation according to the above [1], wherein the content of the halogen atom is a total content of a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[3] The Pisoppro-containing patch preparation according to the above [1] or [2], wherein the Bisoppro is a salt thereof.

[4] The Pisoppro-containing patch preparation according to the above [3], wherein the salt-based mineral acid salt.

According to the present invention, it is possible to suppress the occurrence of a decrease in adhesion, coloration, and the like of the Pisoplot-containing patch preparation during storage.

1‧‧‧Support

2‧‧‧Adhesive layer

3‧‧‧Release liner

10‧‧‧ Attachment

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a schematic cross-sectional view showing an embodiment of a Pisoplot-containing patch preparation of the present invention.

Fig. 1 is a schematic cross-sectional view showing an embodiment of a Bisoppro-containing patch preparation (hereinafter referred to as "adhesive preparation") of the present invention. The patch preparation 10 shown in Fig. 1 includes a support 1 and an adhesive layer 2 laminated on one surface of the support 1 and a release liner 3 laminated on the surface thereof. In addition, the release liner 3 may not be provided. Adhesive layer 2 contains Bisoppro and an adhesive.

The present invention is characterized in that the content of the halogen atom in the adhesive layer containing the Pisoppro-containing patch preparation is controlled to 0.01 to 100 ppm by weight. By controlling the content of the halogen atom, it is possible to suppress the adhesion reduction, coloring, and the like of the attached preparation during storage. Moreover, by containing a halogen atom of 0.01 ppm by weight or more in the adhesive layer, it is presumed that when the adhesive layer is attached to the skin, it can impart an antibacterial effect to the skin surface. The halogen atom content is preferably from 0.01 to 50 ppm by weight, more preferably from 0.01 to 40 ppm by weight.

Here, the "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. In the present invention, the content of the halogen atom in the adhesive layer is controlled to 0.01 to 100 ppm by mass by screening the bisopron having a specific halogen atom content or using the bisoppro which is purified by the method described later.

The content of the halogen atom in the adhesive layer can be measured in accordance with a known method (for example, an ion chromatography analyzer). An example of the method for measuring the content of the halogen atom is, for example, about 10 to 30 mg of the adhesive layer of the attached preparation, and the sample is used as a sample, and the weight thereof is measured, and the sample is burned by using an automatic sample burning device at 900 to 1000 ° C. The absorption liquid (pure water, etc.) absorbs the generated halogen gas or hydrogen halide gas. The halogen atom absorbed by the absorption liquid was measured in accordance with JIS K 0127 [Ion Chromatography Analyzer Method (Conductivity Detector)], and the halogen atom content was calculated.

Bisoppro-based highly selective β1 blocker used in the present invention, chemical name (2RS)-1-(4-{[2-(1-methylethoxy)ethoxy]methyl }phenoxy)-3-[(1-methyl) Ethyl)amino]propan-2-ol. The patch preparation of the present invention uses a free body (free base) of bisoppro. Bisoppro salt can also be used with the Bisopoul. The Bisoppro salt may be, for example, an inorganic acid salt such as Pisopoul hydrochloride or an organic acid salt such as Bisopprofate or Bisoppromethanesulfonate. Bisopoulol and its salts can be produced according to known methods.

The content of the Bisoppro in the adhesive layer can be appropriately set, and is usually 0.5 to 40% by weight, preferably 0.5 to 30% by weight. If the content is more than 0.5% by weight, a therapeutically effective amount of drug release can be expected. On the other hand, if the content is 40% by weight or less, the therapeutic effect can be exhibited and it is advantageous to the economical level, and when it is 30% by weight or less, it is more advantageous to the economical level.

In order to control the content of the halogen atom in the adhesive layer, for example, Bisoppro which is limited to the Bisoppro salt (for example, its hydrochloride) by a general purification method can be used. Typical purification methods are, for example, solvent extraction, poor solubility, crystallization, adsorption treatment, chromatography, membrane treatment, and the like. The content of the Bisoppro salt in Bisopoul is preferably 0.001 to 8% by weight, more preferably 0.001 to 4% by weight.

The adhesive used in the present invention is not particularly limited, and is preferably, for example, a water-insoluble adhesive. The water-insoluble adhesive may be, for example, an acrylic adhesive containing an acrylic polymer; and contains: a styrene-diene-styrene block copolymer (for example, styrene-isoprene-styrene block copolymerization) Rubber adhesive for styrene-butadiene-styrene block copolymer, polyisoprene, polyisobutylene, polybutadiene, etc.; containing: polyoxyxylene rubber, dimethyl decane a polyfluorene-based adhesive such as diphenyloxane; a vinyl ether-based adhesive comprising polyvinyl methyl ether, polyethylene diethyl ether or polyethylene isobutyl ether; and a vinyl acetate-ethylene copolymer or the like a vinyl ester-based adhesive; comprising: a polyester composed of a carboxylic acid component and a polyol component such as ethylene glycol, such as dimethyl terephthalate, dimethyl isophthalate or dimethyl phthalate; Ester-based adhesives and the like. Among these, it is preferred that the rubber is sticky. A primer and an acrylic adhesive, and more preferably a rubber adhesive.

In the case of using a rubber-based adhesive, the content in the adhesive layer is preferably 15 to 60% by weight, more preferably 15 to 55% by weight. A preferred rubber-based adhesive may be, for example, at least one selected from the group consisting of polyisobutylene, polyisoprene, butyl rubber, and styrene-diene-styrene block copolymer, and 15 parts by weight in the adhesive. More than % of rubber-based adhesive. Among them, polyisobutylene is preferably used from the viewpoint of high drug stability and ability to take into consideration the necessary adhesion and cohesive force. The rubber-based adhesive may be one type of polyisobutylene or two or more kinds of polyisobutylene having different molecular weights.

When the rubber-based adhesive is one type of polyisobutylene, the polyisobutylene content in the adhesive layer is preferably 15 to 60% by weight, more preferably 15 to 55% by weight. If the content is less than 15% by weight, the internal cohesive force of the adhesive layer may not be easily applied. On the other hand, if it exceeds 60% by weight, the skin adhesion and adhesion of the adhesive layer may be lowered. .

The molecular weight of the polyisobutylene is not particularly limited. When only one type of polyisobutylene is used, the viscosity average molecular weight is preferably from 40,000 to 5,500,000, more preferably from 45,000 to 5,000,000. If the viscosity average molecular weight is less than 40,000, it is difficult to impart the necessary internal cohesive force to the adhesive layer. On the other hand, if it exceeds 5,500,000, the skin adhesion and viscosity of the adhesive layer may be lowered.

In order to easily balance the moderate cohesive force of the adhesive layer with moderate softness and skin adhesion, it is preferred to use a rubber-based adhesive containing two or more types of polyisobutylene having different molecular weights. In the present specification, "two or more types of polyisobutylene having different molecular weights" mean a molecular weight distribution peak measured by a gel permeation chromatography (GPC), and polyisobutylene present in two or more independent regions (that is, a molecular weight distribution peak is One of the polyisobutylenes contains a mixture of two or more kinds). In addition, the polyisobutylene usually has a molecular weight distribution peak of about one. The two or more kinds of polyisobutylenes having two or more kinds of polyisobutylenes having different molecular weights are, for example, a mixture of a first polyisobutylene and a second polyisobutylene having a molecular weight relatively smaller than that of the first polyisobutylene. The first polyisobutylene can impart moderate cohesive force to the adhesive layer, and the second polyisobutylene can impart moderate flexibility and skin adhesion to the adhesive layer.

The molecular weight of the first polyisobutylene and the second polyisobutylene is not particularly limited, and the viscosity of the first polyisobutylene is preferably 1,800,000 to 5,500,000, in order to obtain good adhesion and sufficient release property with the besoprofen. Preferably, the viscosity average molecular weight of the second polyisobutylene is from 40,000 to 85,000, more preferably from 45,000 to 65,000. If the viscosity average molecular weight of the first polyisobutylene is less than 1,800,000, it is difficult to impart the necessary internal cohesive force to the adhesive layer. On the other hand, if it exceeds 5,500,000, the adhesion and adhesion of the adhesive layer may be lowered. After that. Further, if the viscosity average molecular weight of the second polyisobutylene is less than 40,000, there is a stickiness of the adhesive layer or contamination of the skin surface. On the other hand, if it exceeds 85,000, the skin of the adhesive layer is followed. The difference between sex and viscosity. Further, the first and second polyisobutylene systems may be used in combination of two or more kinds in the respective molecular weight distribution ranges.

In addition, the term "viscosity average molecular weight" in the present specification means a flow time of 20 ° C from a capillary of an Ubbel-type viscometer, and a Schulz-Blaschke type (the following formula (1)) is used to calculate a viscosity index (J _{0 ).} (Staudinger index), the value obtained by the following formula (2) using the J ₀ value.

J ₀ =η _SP /c(1+0.31η _SP )(cm ³ /g)(Schulz-Blaschke) (1)

η _SP =t/t ₀ -1

t: flow time of the solution (determined by Hagenbach-Couette correction formula)

t ₀ : solvent flow time (determined by Hagenbach-Couette correction formula)

c: concentration of the solution (g/cm ³ )

J ₀ =3.06×10 ^-2 Mv ^0.65 (2)

Mv: viscosity average molecular weight

When the rubber-based adhesive is two or more types of polyisobutylene having different molecular weights, the total content of the polyisobutylene in the adhesive layer is preferably 15 to 60% by weight, more preferably 15 to 55% by weight. When the total content of the polyisobutylene is less than 15% by weight, it is difficult to impart the necessary internal cohesive force to the adhesive layer. On the other hand, if it exceeds 60% by weight, the skin adhesion and adhesion of the adhesive layer may occur. Reduce the embarrassment.

When the rubber-based adhesive is a mixture of two kinds of polyisobutylene having different molecular weights, the weight ratio of the first polyisobutylene (a) to the second polyisobutylene (b) (a: b) is preferably 1:0.1 to 1: 3. Better system 1: 0.1~1:2.5, especially good 1:0.3~1:2. In the two types of polyisobutylene, when the blending ratio of the second polyisobutylene (b) exceeds the above upper limit, the internal cohesive force of the adhesive layer may decrease, and if the lower limit is not exceeded, The skin with the adhesive layer is then reduced in strength.

The acrylic adhesive is preferably a polymer of an alkyl (meth)acrylate, and an acrylic adhesive is preferably contained in an amount of 50% by weight or more, more preferably 60% by weight or more, based on the adhesive. The polymerization system can be any of a monomer or a copolymer of an alkyl (meth)acrylate. In other words, the alkyl (meth)acrylate may be used alone or in combination of two or more. Among them, the alkyl (meth) acrylate preferably has an alkyl carbon number of 4 to 12. The alkyl group may be a straight chain or a branched chain. The alkyl group may be, for example, butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, isooctyl, 2-ethylhexyl, decyl, isodecyl, decyl, undecyl. , dodecyl and the like. Among these, 2-ethylhexyl group is preferred.

Further, the copolymer of the alkyl (meth)acrylate may be a copolymer of an alkyl (meth)acrylate and another monomer copolymerizable therewith. Other single systems may be, for example, monomers having a carboxyl group such as (meth)acrylic acid, itaconic acid, maleic acid, maleic anhydride; styrenesulfonic acid, allylsulfonic acid, (methyl) a monomer having a sulfo group such as sulfopropyl acrylate, (meth) propylene decyl naphthalenesulfonic acid or acrylamide methyl sulfonic acid; hydroxyethyl (meth)acrylate; hydroxypropyl (meth)acrylate; a monomer having a hydroxyl group; (meth) acrylamide, dimethyl (meth) acrylamide, N-butyl (meth) acrylamide, N-hydroxymethyl (meth) acrylamide, Monomer having a mercaptoamine group such as hydroxyethyl (meth) acrylamide; amine ethyl (meth) acrylate, dimethylaminoethyl (meth) acrylate, and tert-butylamino (meth) acrylate Aminoalkyl (meth)acrylate such as ethyl ester; methoxyethyl (meth)acrylate, ethoxyethyl (meth)acrylate, tetrahydrofurfuryl (meth)acrylate, etc. (methyl) Alkoxy acrylate; methoxyethylene glycol (meth)acrylate, methoxydiethylene glycol (meth)acrylate, methoxypolyethylene glycol (meth)acrylate, (methyl) (meth) propylene such as methoxypolypropylene glycol acrylate Alkoxy alkylene glycol ester; (meth) acrylonitrile; vinyl acetate, vinyl propionate, vinyl pyrrolidone, methyl vinyl pyrrolidone, vinylpyridine, vinyl piperidone, vinyl pyrimidine, vinyl piperazine , vinylpyrrole, vinylimidazole, vinyl caprolactam, ethylene Azole, ethylene A vinyl compound such as a phenyl compound or the like. The alkyl (meth)acrylate and the other monomers may be used alone or in combination of two or more. The amount of the alkyl (meth)acrylate unit in the copolymer is preferably 40% by weight or more, more preferably 50% by weight or more.

When an acrylic adhesive is used, the acrylic adhesive content in the adhesive layer is preferably 30 to 75% by weight, more preferably 35 to 70% by weight, in order to impart sufficient skin adhesion to the adhesive layer. Tejia is 40~65% by weight.

When the adhesive layer contains a rubber-based adhesive, in order to impart a moderate adhesiveness to the adhesive layer, for example, a rosin-based resin, a polyterpene resin, a coumarone-indene resin, or a petroleum resin is preferably used. A tackifier such as a terpene-phenol resin or a xylene resin. The adhesive may be used alone or in combination of two or more. The tackifier is preferably a petroleum resin. The petroleum resin can be, for example, an aliphatic (C5-based) petroleum resin, an aromatic (C9-based) petroleum resin, a copolymer-based (C5-C9-based) petroleum resin, and an aromatic (C9-based) petroleum. A resin, an alicyclic saturated hydrocarbon resin obtained by partial hydrogenation or complete hydrogenation, or the like.

When a tackifier is used, the content in the adhesive layer is preferably from 10 to 55% by weight, more preferably from 10 to 50% by weight, particularly preferably from 10 to 45% by weight. When the content of the adhesive is less than 10% by weight, the viscosity and the cohesive force may be insufficient. On the other hand, when the content exceeds 55% by weight, the adhesive layer may be hard and the skin adhesion tends to be lowered.

Further, the softening point of the tackifier is preferably from 90 ° C to 150 ° C, more preferably from 95 ° C to 145 ° C. When the softening point is from 90 ° C to 150 ° C, it is easily dissolved in the respective components of the adhesive layer, and tends to be easily mixed uniformly. Further, the softening point of the present invention is a value measured by a ring and ball method.

In order to provide comfort when the skin is attached, a liquid or paste-like organic component may be further added to the adhesive layer. Here, the "liquid or paste-like organic component" means a viscosity at 25 ° C of 0.01 mPa ‧ s to 10000 Pa ‧ s. The viscosity measurement system described above can be carried out using, for example, an E-type viscometer (manufactured by Tokyo Keiki Co., Ltd.: EMD-type cone-plate type rotary type). The liquid or paste-like organic component is not particularly limited, and is preferably one having a transdermal absorption promoting effect. The liquid or paste-like organic component can be, for example, glycols such as ethylene glycol, diethylene glycol, propylene glycol, triethylene glycol, polyethylene glycol, polypropylene glycol, etc.; glycerin; olive oil, castor oil, and horn shark Alkali, lanolin and other oils and fats; hydrocarbons such as mobile paraffin; surfactants such as polyoxyethylene hardened castor oil; ethoxylated stearyl alcohol; oleic acid monoglyceride, octanoic acid monoglyceride, lauric acid monoglyceride, etc. Triglycerides; diglycerides; triglycerides such as caprylic acid triglycerides; ethyl laurate, isopropyl myristate, isotridecyl myristate, octyl palmitate, palmitic acid Fatty acid alkyl esters such as propyl ester, ethyl oleate, diisopropyl adipate, diethyl sebacate; fatty acids such as oleic acid and caprylic acid; 1-dodecanol, 1-tetradecanol, 1 a linear aliphatic alcohol such as cetyl alcohol; 2-hexyl-1-nonanol, 2-octyl-1-dodecanol, 2-hexyl-1- a branched chain aliphatic alcohol such as tetradecyl alcohol; N-methylpyrrolidone; 1,3-butanediol or the like. The liquid component or the paste-like organic component may be used alone or in combination of two or more.

When a liquid or paste-like organic component is used, in order to prevent the organic component from oozing out from the adhesive layer, the content of the organic component in the adhesive layer is preferably 5 to 70% by weight, more preferably 10 to 65% by weight. It is 20~50% by weight.

Further, in the patch preparation of the present invention, it is removed before the adhesion of the adhesive layer is lifted, and the adhesive layer may contain a suitable filler as needed. The filler is not particularly limited and may, for example, be inorganic fine particles such as cerium oxide, titanium oxide, zinc oxide, magnesium oxide, iron oxide, aluminum hydroxide, talc, kaolin, bentonite, barium sulfate or calcium carbonate; Organic fine particles such as carbon black, polyvinylpyrrolidone, polyester, polyolefin, polyurethane, polyamide, cellulose, acrylic resin; and polyester, polyolefin, polyurethane, Polyamide, cellulose, acrylic, glass and other fibers.

Further, if necessary, the upper patch or the like may be attached to cover a part or the whole of the patch preparation of the present invention to reinforce the skin adhesion, and the adhesion to the skin may be enhanced.

The adhesive layer is, for example, Bisoppro, an adhesive, and optionally an adhesive, a liquid or paste-like organic component and other ingredients, dissolved in a suitable solvent (for example, toluene), and the obtained adhesive is obtained. The solution is applied to a release liner or support and formed by drying. The thickness of the adhesive layer after drying is preferably 10 to 300 μm, more preferably 10 to 250 μm, and particularly preferably 15 to 250 μm. When the thickness of the adhesive layer is less than 10 μm, there is a possibility that peeling of the attached preparation occurs in the attachment due to insufficient adhesion to the skin. On the other hand, when the thickness of the adhesive layer exceeds 300 μm, the components constituting the adhesive layer bleed out from the peripheral portion of the patch preparation and the like, and the gel is contaminated.

Further, the adhesive layer may be subjected to physical crosslinking by radiation such as ultraviolet irradiation or electron beam irradiation; or trifunctional isocyanate may be used. Chemical crosslinking treatment of various crosslinking agents such as an isocyanate compound, an organic peroxide, an organic metal salt, a metal alkoxide, a metal chelate compound, and a polyfunctional compound.

The support is not particularly limited, and a plastic film, a nonwoven fabric, a paper, a woven fabric, a woven fabric, a metal foil, or the like can be used. The support may also be subjected to metal deposition on a plastic film. The material of the plastic film is not particularly limited, and may be, for example, polyvinyl chloride; ethylene, propylene, vinyl acetate, acrylic acid, acrylate, methacrylic acid, methacrylic acid ester, acrylonitrile, styrene, vinylidene chloride, etc. a copolymer composed of a monomer; a polyolefin such as polyethylene or polypropylene; a copolymer of an olefin and other monomers such as an ethylene-vinyl acetate copolymer; a polyester such as polyethylene terephthalate (PET); and a polyether. Polyester; polyether-polyamine block copolymer. The thickness of the support is, for example, 5 to 500 μm, preferably 10 to 200 μm.

The release liner is not particularly limited and may be, for example, a plastic film (for example, a polyester film such as a PET film, a polyimide film, a polypropylene film, a polyethylene film, a polycarbonate film, etc.); Metal-plated metal-deposited plastic film; Japanese paper, machine paper, kraft paper, cellophane, high-grade paper, etc.; non-woven fabric, cloth and other fibrous materials; metal foil. Further, a laminate of a plastic film and a paper, a laminate of a plastic film and a metal foil, or the like may be used as a release liner. There are many types of industrial products, and most of them are commercially available for the appropriate thickness of the attached preparation. In order to easily select the required quality, the release liner is preferably a plastic film, a better polyester film, and a special system. PET film. The thickness of the release liner is, for example, 10 to 200 μm, preferably 25 to 150 μm. The release liner may be easily peeled off from the adhesive layer to form a cut mark, and a light release layer which has been subjected to release treatment may be formed on one side of the adhesive layer.

[Examples]

The invention is specifically described below by way of examples, but the examples are not intended to limit the invention.

(Examples 1 to 4)

15.1 parts by weight of the first polyisobutylene (viscosity average molecular weight: 4,000,000), 26.1 parts by weight of the second polyisobutylene (viscosity average molecular weight: 55,000), and 27.4 parts by weight of a tackifier (alicyclic saturated hydrocarbon resin having a softening point of 140 ° C) 30 parts by weight of a liquid organic component (isopropyl myristate) and 1.4 parts by weight of Pisoppro were mixed with 400 parts by weight of toluene, and a toluene solution was prepared by dissolving. Further, the above-mentioned Bisoppro is a method of using Pisoppro, or a salt of Bisopprol hydrochloride and controlling the hydrochloride content of Bisoppro. The amount of hydrochloride contained in the Pisopoulol used (=100 × the amount of the hydrochloride contained in the Bisopoul / (the total amount of the hydrochloride contained in the Bisopoul and Bisopoul)), such as Table 1 shows. The obtained toluene solution was applied to a polyethylene terephthalate (PET) liner (thickness: 75 μm) subjected to polysilicon oxide stripping treatment so that the thickness of the adhesive layer after drying became 160 μm. The adhesive layer was formed by drying it in a hot air circulating dryer at 100 ° C for 5 minutes. This adhesive layer was bonded to a non-woven fabric of a film of PET having a thickness of 3.5 μm and a laminated film of a nonwoven fabric of 12 g/m ² of PET to obtain a Bisoppro-containing patch preparation.

(experiment method)

The obtained preparation product containing Pisopoul is used in a temperature of 20±10° C. and a relative humidity of 30±10%, and the punching is 60 mm×60 mm, and the PET/Al/polyacrylonitrile resin is used. The packaging material (100 mm × 100 mm) composed of the laminated body was packaged so that the polyacrylonitrile-based resin became the inner surface, and stored at 50 ° C, and the adhesive strength, the color b* value, and the analog mass of the Bisopoulol described later were measured. Here, the "similar substance of Bisopoul" refers to a product of decomposition of Bisopoul or a product produced by the reaction of components such as Bisopoulol and Bisoppro.

(1) Adhesion

The adhesion of the Pisoppro-containing patch preparations (Examples 1 to 4) before storage, after storage for 1 month, and after 3 months, was measured according to the following method. The surface of the stainless steel plate (SUS304 steel plate specified in JIS G4305) was first uniformly polished by using No. 360 water-resistant abrasive paper, and then washed with a cloth impregnated with ethyl acetate. The test preparation containing Pisoppro was cut, and a test piece having a width of 24 mm and a length of 50 mm was prepared. The adhesive surface of the test piece after the release liner was applied to a surface polished and washed with a stainless steel plate using a mass of 850 g of a rubber roller (rubber roller passing speed of 300 mm/min, passing times twice). The stainless steel sheet to which the test piece was attached was allowed to stand in an environment of 23 ± 2 ° C and 50 ± 10% R. H. for 30 minutes. The test piece was peeled from the stainless steel plate by about 5 mm at one end, and folded back at an angle of 180°, and an auxiliary paper (width 30 mm) was attached. Using a tensile tester, clamp the end of the auxiliary paper to the upper hook and clamp the stainless steel plate to the lower clamp at a speed of 300 mm/min at 23 ± 2 ° C and 50 ± 10% RH. The test piece was continuously torn in the direction of 180°, and the adhesion was measured. The results (values measured using a test piece of 24 mm width) are shown in Table 2. Further, in Table 2, the ratio of the adhesive force after storage to the adhesive force before storage (= 100 × adhesion after storage / adhesion before storage) was also recorded.

(2) color b* value

The color b* value (L*a*b* color system) of the Pisoppro-containing patch preparations (Examples 1 and 2) after 6 months of storage was obtained by using a color difference meter (model CR-400, Konica Minolta Co., Ltd. was measured [measuring surface: PET film surface of laminated film (support)]. The results are shown in Table 3. The higher the color b* value, the more yellow it is.

(3) Similar substances

The Pisoppro-containing patch preparation (Examples 1 and 2) after 6 months of storage was extracted with tetrahydrofuran, and the extract was analyzed by HPLC under the following conditions. Total HPLC peak area of all similar substances in Pisoplot, relative to the ratio of HPLC peak area of Pisopoul (=100×total peak area of all similar substances/HPLC peak area of Bisoppro) The mass of the analog is calculated and calculated. The results are shown in Table 4.

(HPLC measurement conditions)

Pipe column: stainless steel tube with inner diameter of 4.6mm and length of 15cm, liquid crystal layer analyzer with particle size of 3μm, octyl decyl phthalocyanine

Column temperature: 40 ° C

Mobile phase: mobile phase A (phosphate buffer (pH 2.5))

Mobile phase B (phosphate buffer (pH 2.5) / acetonitrile = 1/4)

Dissolution conditions: changing the mixing ratio of mobile phase A and mobile phase B for concentration gradient control

Flow rate: 1.2mL/min

Detector: UV spectrophotometer (wavelength: 225 nm)

From the results of Table 2, it was found that as the content of the halogen atom in the paste preparation containing Pisopoulol increased, the adhesive strength decreased, and the tendency was that the longer the storage period, the more obvious. However, even after 3 months of storage, the adhesion reduction of the Pisoppro-containing patch preparations of Examples 1 to 4 was practically not a problem.

Further, as is apparent from the results of Table 3, the color b* value increases as the content of the halogen atom in the paste preparation containing Pisoppro increases. However, even after 6 months of storage, the Pisoplot-containing patch preparations of Examples 1 and 2 were not visually noticeable to a significant degree of yellowing, and were not practically problematic.

Further, as is apparent from the results of Table 4, as the content of the halogen atom in the Pisoppro-containing patch preparation was increased, it was confirmed that the quality of the Bisoppro analog was increased. However, the quality of the analogs of the Pisoplot-containing patch preparations of Examples 1 and 2 was not practically problematic even after 6 months of storage.

Detailed description of the present invention with reference to specific aspects, but without escaping Various changes and modifications can be made without departing from the spirit and scope of the invention, which can be easily considered by those skilled in the art.

In addition, the present application is based on the Japanese Patent Application (Japanese Patent Application No. 2013-185599) filed on Sep.

Claims (4)

An adhesive preparation containing Pisoppro, comprising: a support body, and an adhesive layer laminated on one side of the support body and containing a Bisopoulol and an adhesive; wherein the adhesive layer is The halogen atom content is 0.01 to 100 ppm by weight. The Pesopoulin-containing patch preparation according to the first aspect of the invention, wherein the content of the halogen atom is a total content of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. A Bisopoulin-containing patch preparation according to claim 1 or 2, wherein the Bisoppro is a salt thereof. The pharmaceutical preparation containing the Pisopoulol according to the third aspect of the patent application, wherein the salt is a mineral acid salt.